The interaction between platelet glycoprotein Ib and von Willebrand factor (vWF) plays a crucial role in platelet-mediated thrombus formation under high-shear-stress conditions. The aim of this study was to investigate the antiplatelet profile of a humanized anti-vWF monoclonal antibody, AJW200. In vitro studies were performed with a modified cone-and-plate viscometer and human platelets. AJW200 inhibited high-shear-stress-induced platelet adhesion, aggregation, and thrombin generation, but it did not have such effects under low-shear-stress conditions. Although abciximab inhibited platelet aggregation under both shear stress conditions, it did not inhibit platelet adhesion and thrombin generation. In addition, the pharmacokinetics and pharmacodynamics of AJW200 were evaluated in cynomolgus monkeys. Sustained inhibition of ristocetin-induced platelet aggregation was observed over 24 hours, 6 days, and 2 weeks after a single bolus injection of 0.3, 1, and 3 mg/kg, respectively. Moderate prolongation of the bleeding time was observed at the doses of 1 and 3 mg/kg. Abciximab markedly prolonged the bleeding time at 0.4 mg/kg, at which concentration complete inhibition of ADP-induced platelet aggregation was observed. These results suggest that glycoprotein Ib-vWF blockade with AJW200 results in a sustained antiplatelet effect without extensive prolongation of the bleeding time, probably due to a shear-stress-dependent inhibitory action.

Because of its chemical structure, risedronate was thought to form a complex with divalent cations, e.g., Ca(2+), and to be likely to show changes in the efficiency of absorbance from the gastrointestinal tract according to the presence of food. Therefore, we conducted a crossover study using healthy Japanese adults to examine the effects of food intake on absorption after the oral administration of risedronate and to choose the best timing of regimen for risedronate. Using single doses of 5 mg risedronate, the following four dose times were investigated: (a) in the morning under a fasting condition without breakfast; (b) 30 min before breakfast; (c) 30 min after breakfast; and (d) 3 h after breakfast. The results showed that the C(max) and AUC(0-24) of the plasma risedronate concentrations and its cumulative urinary excretions decreased in the following order: fasting without breakfast >>30 min before breakfast >>3 h after breakfast >>30 min after breakfast. In other words, it was demonstrated that the absorption of risedronate decreases due to the effects of food. Several adverse events, whose causality with risedronate was unknown or possibly related, were observed, including headaches, diarrhea, increased CK-BB, and an increased urinary Beta(2)-microglobulin excretion rate, but none of these events was clinically significant, and none differed in frequency or severity from the events after a single oral administration. In consideration of the optimal practical timings required to administer risedronate for Japanese patients, therefore, it was found that ingesting the drug immediately after waking up in the morning, when the stomach is empty, was optimal, and that it was necessary to refrain from eating and drinking for at least 30 min after drug ingestion. Therefore, we determined that the optimal time for risedronate to be administered in Japanese patients is 30 min before breakfast.

To evaluate the effect of introducing a saccharide moiety to poly(amino acids) on tissue distribution, several glycoconjugates of epsilon-(2-methoxyethoxyacetyl)-poly(L-lysine) of three molecular weights were synthesized using an octylene spacer between the sugar and polymer chain. Methoxyethoxyacetylation of the epsilon-amino group of the lysine unit in poly(L-lysine) was useful for avoiding nonspecific distribution to many tissues as the result of cationic charges. The tissue-targeting ability of each saccharide moiety was considered as the actual amount changed in each tissue caused by saccharide modification. Galactose terminated saccharides such as galactose, lactose and N-acetylgalactosamine accumulated exclusively in the liver, probably by the hepatic receptor. These conjugates could therefore be good carriers for a drug delivery system to the liver. On the other hand, the mannosyl and fucosyl conjugates were preferentially delivered to the reticuloendothelial systems such as those in the liver, spleen and bone marrow. In particular, fucosyl conjugates accumulated more in the bone marrow than in the spleen. Xylosyl conjugates accumulated mostly in the liver and lung. Generally, the accumulated amount in the target tissue increased with increasing molecular weight and an increased number of saccharides on one molecule of polymer.

The tolerability and pharmacokinetics of risedronate after a single oral administration and during multiple oral administrations were examined in healthy adult male volunteers. In the single dose study, the dose was increased gradually from 1 mg to 2.5, 5, 10, or 20 mg. Subsequently, risedronate was given by multiple administration, 5 mg per dosing, once daily, for 7 days. The observed adverse events, whose causality was possibly related or unknown, included headache, diarrhea, increased body temperature, increased CK-BB, and increased urinary Beta(2)-microglobulin excretion rate. However, none of these adverse events was clinically significant. The results thus showed that risedronate was well tolerated when delivered as a single administration of up to 20 mg or as a multiple administration of up to 5 mg/day. In the multiple dose study, changes in urinary deoxypyridinoline suggested the bone antiresorptive activity of risedronate. In the single dose study, AUC and C(max), after the administration of risedronate at 1, 2.5, 5, 10, and 20 mg, increased dose dependently, and the T(max), t(1/2), and urinary excretion rates were nearly constant. Therefore, the pharmacokinetic profile of risedronate was considered to show linearity in a dosage range of up to 20 mg. Furthermore, the results obtained in the multiple administration study indicated that the plasma concentrations of risedronate reached a steady state on day 4 of administration. The plasma concentrations of risedronate after the administration of 2.5 mg risedronate to the Japanese population were nearly comparable to the serum concentrations after the administration of 5 mg risedronate to the United Kingdom study population.