The first trial of CIM331, a humanized antihuman interleukin-31 receptor A antibody, in healthy volunteers and patients with atopic dermatitis to evaluate safety, tolerability and pharmacokinetics of a single dose in a randomized, double-blind, placebo-controlled study.

BACKGROUND: The cytokine interleukin-31 (IL-31) is considered to be responsible for the development of pruritus in humans. At present, no available evidence has been provided on the safety and efficacy of blocking the IL-31 signal in humans for the amelioration of pruritus in atopic dermatitis (AD). CIM331 is a humanized antihuman IL-31 receptor A (IL-31RA) monoclonal antibody, which binds to IL-31RA to inhibit subsequent IL-31 signalling. OBJECTIVES: To assess the tolerability, safety, pharmacokinetics and preliminary efficacy of CIM331 in healthy Japanese and white volunteers, and Japanese patients with AD. METHODS: In this randomized, double-blind, placebo-controlled phase I/Ib study, CIM331 was administered in a single subcutaneous dose. The primary outcomes were safety and tolerability; the exploratory analysis was efficacy. RESULTS: No deaths, serious adverse events (AEs) or discontinuations due to AEs were reported in any part of the study. No dose-dependent increase in the incidence of AEs occurred in any part of the study. In healthy volunteers, all AEs occurred once in the placebo groups, and increased creatine phosphokinase was more common in the CIM331 groups. In patients with AD, CIM331 reduced pruritus visual analogue scale score to about -50% at week 4 with CIM331 compared with -20% with placebo. CIM331 increased sleep efficiency and decreased the use of hydrocortisone butyrate. CONCLUSIONS: A single subcutaneous administration of CIM331 was well tolerated in healthy volunteers and patients with AD. It decreased pruritus, sleep disturbance and topical use of hydrocortisone. CIM331 may become a novel therapeutic option for AD by inhibiting IL-31.

Pharmacokinetics and metabolism of N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-α-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate (advantame) in the rat, dog, and man.

The pharmacokinetics and metabolism of advantame were evaluated in rats, dogs, and humans. The oral pharmacokinetic studies using (14)C-advantame showed that advantame undergoes rapid but incomplete absorption, with an oral bioavailability of total radioactivity in the range of 4-23%. Data indicated that absorption was mainly as ANS9801-acid (de-esterified advantame), which was formed in the gastrointestinal tract as a result of the hydrolysis of the methyl ester group of the parent compound. In the dog, plasma ANS9801-acid was present largely in the form of an unidentified conjugate. Advantame (chiefly in the form of metabolites) was mainly excreted in the feces in rats, dogs, and humans (>80% in each species), with urinary excretion representing a minor route. The predominant metabolite of (14)C-advantame detected in the feces and the urine of rats, dogs, and humans was ANS9801-acid, with lower amounts of 3-[3-hydroxy-4-methoxyphenyl]-1-propylamine (termed HU-1) or N-(3-(3-hydroxy-4-methoxy phenyl))propyl-L-aspartic acid (termed HF-1) present, as well as other minor metabolites and areas of indistinct radioactivity. ANS9801-acid, HU-1, and HF-1 were detected and identified in the urine of rats, humans, and dogs, while ANS9801-acid and HF-1 were identified in the feces of humans and dogs. In the feces of rats, in addition to ANS9801-acid, other additional metabolites were detected, including demethylated ANS9801-acid (designated as RF-1) and another unidentified metabolite (designated as RF-2). Overall, the data show generally similar pharmacokinetics of advantame and ANS9801-acid in animals and in humans and close similarity with neotame. Metabolites of advantame that occur in humans are also found in the 2 species utilized in the toxicology studies, and the metabolism studies support the interpretation of safety data from studies conducted in rats and dogs.

Structure determination of metabolites isolated from urine and bile after administration of AY4166, a novel D-phenylalanine-derivative hypoglycemic agent.

Molecular structures of 10 metabolites, which were isolated from urine (M1-M8) or bile (M9 and M10) after administration of AY4166 (N-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine), a novel amino acid derivative with hypoglycemic activity, have been elucidated by mass spectrometry and nuclear magnetic resonance. Four of these (M1, M2, M3 and M8) were determined to be hydroxyl derivatives of AY4166, two (M9 and M10) were carboxylate derivatives via oxidization of M2 and M3, three (M4, M5 and M6) were glucronic acid conjugates and the other (M7) was a dehydro derivative. The estimated structures for M1, M2, M3, M7, M8, M9 and M10 were confirmed by the coincidence of the retention time of HPLC, MS and 1H NMR spectra between the isolated metabolites and authentic synthesized substances. For three glucronic acid conjugates, M4, M5 and M6, structural confirmation was performed by a selective enzymatic digestion with beta-glucronidase. M1 and M2/3 were about 5-6 and 3 times less potent than AY4166, respectively, and M7 was almost as potent as AY4166.

High-performance liquid chromatographic determination of sulphobromophthalein and its conjugates.

A simple, sensitive and selective high-performance liquid chromatographic method for the determination of sulphobromophthalein and its mercaptide conjugates in rat bile was developed. These pigments, which have an absorption maximum at 580 nm in alkaline solution, were separated isocratically on an alkali-resistant ODS column by paired-ion chromatography. Analysis of bile samples obtained after intravenous administration of sulphobromophthalein to rats showed the presence of at least twenty peaks of metabolites, of which thirteen were identified and seven quantified.

Dipeptidyl-aminopeptidase II in human cerebrospinal fluid: changes in patients with Parkinson's disease.

By using a sensitive and specific method, DAP II activity was found in CSF. DAP II activity in CSF of control patients without neurological diseases was 0.416 +/- 0.141 (mean +/- SD) nmole/min/ml and was higher than DAP IV activity in CSF, 0.221 +/- 0.062 (mean +/- SD) nmole/min/ml. In contrast, DAP II activity in serum was 1.16 +/- 0.16 (mean +/- SD) nmole/min/ml and was lower than serum DAP IV activity [41.85 +/- 3.36 (mean +/- SD) nmole/min/ml]. This relatively high activity of DAP II in CSF compared with the activity of DAP IV in CSF together with recent histochemical evidence on the localization of DAP II in some neurons (7) suggests that CSF DAP II may be derived from the brain and may be a marker of some peptidergic neurons. DAP II activity in CSF of patients with Parkinson's disease was significantly increased, whereas DAP IV activity in CSF did not change significantly.

Serum activities of dipeptidyl-aminopeptidase II and dipeptidyl-aminopeptidase IV in tumor-bearing animals and in cancer patients.

Serum activities of dipeptidyl-aminopeptidases (DAP) II and IV were measured in tumor-bearing animals and in patients with blood and solid cancers using highly sensitive and specific fluorometric methods. In mice with intraperitoneal or subcutaneous implantation of Ehrlich ascites tumor cells, serum DAP II activity was increased and serum DAP IV activity was decreased, resulting in a significant increase in the ratio of serum DAP II and DAP IV activities. The increase in the ratio of these two activities paralleled the size of the subcutaneous tumors. However, both serum DAP II and DAP IV activities were increased in rats with experimental hepatic cancer induced by 3'-methyl-4-dimethylaminoazobenzene, and the increase in the ratio of the two activities was not significant. In cancer patients, as compared with healthy subjects, serum DAP II activity was increased and serum DAP IV activity was decreased, the ratio of serum DAP II and DAP IV activities being markedly increased in cancer patients. Both serum DAP II and DAP IV activities were increased in patients with hepatic cancer as were those in rats with hepatic cancer, but the increase in DAP II was greater than that of DAP IV; thus the ratio of the two activities increased significantly. These data suggest that the increase of the serum DAP II/DAP IV ratio could be a biochemical index of cancer.