Exploring the structural basis of neurotoxicity in C(17)-polyacetylenes isolated from water hemlock.

Water hemlock, Cicuta virosa, belonging to the Umbelliferae, is well-known as a toxic plant responsible for lethal poisonings in humans as well as animals, causing tonic and clonic convulsions and respiratory paralysis. Cicutoxin (1), being a major violent toxin of the plant, is a chemical in the class of C(17)-polyacetylenes bearing a long pi-bond conjugation system, a terminal hydroxyl, and an allylic hydroxyl in its structure, and a variety of its analogues have been isolated from the plant. In the present study, various derivatives of these toxins were synthesized through acetylation, methylation, and oxidation of cicutoxin (1) and virol A (3) and B (4). 1-Dehydroxyvirol A (28) was prepared through the coupling of (7S)-dodeca-3,5-dien-1-yn-7-ol and 1-iodopentyne under Sonogashira's conditions. A monoacetylenic compound (29) was also prepared through the coupling of (5S)-1-chlorodeca-1,3-dien-5-ol and 1-iodopentyn-5-ol. The structure-activity relationships involved in the acute toxicity of cicutoxin derivatives in mice were investigated, and the length and geometry of pi-bond conjugation and the O-functional groups were found to be important for activity. The potency in inhibition of the specific binding of the noncompetitive GABA antagonist, [(3)H]EBOB, to GABA-gated Cl(-) channels of GABA receptors in rat brain cortex was found to be correlated with acute toxicity, indicating that the ability to bind to these channels plays an important role in the acute toxicity of these compounds.

Stimulation of sarcoplasmic reticulum Ca(2+)-ATPase by gingerol analogues.

We have reported previously that [8]-gingerol increased Ca(2+)-ATPase activity. Here we synthesized gingerol related compounds (AP-004, AP-005 and AP-015) and investigated the effects of gingerols ([6]-gingerol, [8]-gingerol and [10]-gingerol) and the synthesized compounds on the Ca(2+)-ATPase activity of sarcoplasmic reticulum (SR). The Ca(2+)-ATPase activity and the Ca(2+)-pumping activity increased by these compounds in a concentration-dependent manner. It is probable that both the o-methoxyphenol and hydrocarbon chain in the molecule of gingerol analogues are necessary for the activation of the Ca(2+)-pumping ATPase activity of SR.

The mode of inhibitory action of alpha-mangostin, a novel inhibitor, on the sarcoplasmic reticulum Ca(2+)-pumping ATPase from rabbit skeletal muscle.

alpha-Mangostin, the principal ingredient of the fruit hull of Garcinia mangostana, caused a concentration-dependent decrease in the activities of both Ca(2+)-ATPase and Ca(2+)-transport of the sarcoplasmic reticulum from rabbit skeletal muscle with an IC50 value of 5 microM. Neither Ca2+ release nor other enzyme activities were affected by alpha-mangostin. Kinetic analysis of the inhibitory effects of alpha-mangostin on Ca(2+)-ATPase suggests that the inhibition of the ATPase is a noncompetitive-type with respect to ATP or Ca2+. alpha-Mangostin may become a useful pharmacological tool for clarifying the physiological functions of Ca(2+)-pumping ATPase and sarcoplasmic reticulum.

Pharmacokinetics of a new human monoclonal antibody against cytomegalovirus. Third communication: correspondence of the idiotype activity and virus neutralization activity of the new monoclonal antibody, regavirumab in rat serum and its pharmacokinetics in rats and monkeys.

TI-23 consists of lyophilized regavirumab (monoclonal antibody C23, MCA C23), a new human monoclonal antibody against cytomegalovirus (CMV), human serum albumin (HSA) and amino acetic acid. The pharmacokinetics of MCA C23 was studied in rats and monkeys, and virus neutralization activity was investigated after intravenous administration of TI-23 in rats. MCA C23 idiotype activity (antigenicity against idiotype antibody) was not affected by heat treatment. The rat serum obtained after injection of TI-23 showed a potent inhibition activity of plaque formation. A good correlation (r = 0.873) was observed between idiotype activity and the inhibition activity of plaque formation in the diluted serum samples. After single or repeated injection of TI-23 to cynomolgus monkeys, the MCA C23 concentration in plasma was determined by an immunological method. 1 h after single injection, 60.8 +/- 5.1 micrograms/ml of MCA C23 was detected in plasma, then the plasma level decreased with an elimination half-life of 20.5 +/- 6.2 days and the AUC value was 18.3 +/- 3.4 mg.h/ml. In the repeated administration experiment (2 mg/kg/week, 5 times), the MCA C23 plasma concentration reached a steady state (74.4 +/- 11.8 micrograms/ml) at 24 h after the fourth injection. The elimination half-life after the final injection was similar to that after the single injection.

Enhancement of oral bioavailability of d-alpha-tocopherol acetate by lecithin-dispersed aqueous preparation containing medium-chain triglycerides in rats.

In order to evaluate oral dosage forms of d-alpha-tocopherol acetate (VEA), d-alpha-tocopherol (VE) concentration in the plasma was examined following oral administration of three VEA preparations; lecithin-dispersed aqueous preparation, polysorbate 80 (PS-80)-solubilized aqueous solution and soybean oil solution. The lecithin-dispersed preparation gave the highest Cmax and the largest AUC0-24h, while Tmax was delayed. In the thoracic duct fistula rat, no increase in VE plasma concentration was observed after intraduodenal administration of lecithin-dispersed VEA preparation via the lymphatic route. The delayed Tmax and prolonged VE plasma concentration obtained with the lecithin-dispersed preparation in comparison with PS-80-solubilized aqueous solution could be explained by the different route of absorption.