A novel phenylphthalimide derivative, pegylated TC11, improves pharmacokinetic properties and induces apoptosis of high-risk myeloma cells via G2/M cell-cycle arrest.

Despite the development of new drugs for multiple myeloma (MM), the prognosis of MM patients with high-risk cytogenetic abnormalities such as t (4; 14) and del17p remains poor. We reported that a novel phenylphthalimide derivative, TC11, induced apoptosis of MM cells in vitro and in vivo, and TC11 directly bound to α-tubulin and nucleophosmin-1 (NPM1). However, TC11 showed low water solubility and poor pharmacokinetic properties. Here we synthesized a water-soluble TC11-derivative, PEG(E)-TC11, in which HOEtO-TC11 is pegylated with PEG through an ester bond, and we examined its anti-myeloma activity. We observed that PEG(E)-TC11 and its hydrolyzed product, HOEtO-TC11, induced G2/M arrest and the apoptosis of MM cells. Intraperitoneal administration of PEG(E)-TC11 to xenografted mice revealed improved pharmacokinetic properties and significantly delayed tumor growth. TC11 and its derivatives did not bind to cereblon (CRBN), which is a responsible molecule for thalidomide-induced teratogenicity. These results suggest that PEG(E)-TC11 is a good candidate drug for treating high-risk MM.

Anethole restores delayed gastric emptying and impaired gastric accommodation in rodents.

Functional dyspepsia (FD), a functional gastrointestinal disorder, is characterized by persistent or recurrent postprandial upper abdominal discomfort and epigastric pain. The high prevalence of FD and associated healthcare costs suggests that treatment of this condition by methods other than prescribed medicines, such as natural products, could be beneficial. Delayed gastric emptying and impaired gastric accommodation play important roles in the development of FD. Anethole (1-methoxy-4-((E)-propenyl)-benzene), a major component of essential fennel oil, has been used as a flavoring, in alcoholic beverage production and in pharmaceutical formulations for many years. In this study, we examined the effects of anethole on delayed gastric emptying and impaired gastric accommodation in rodents. Oral administration of anethole improved clonidine-induced delayed gastric emptying but did not affect normal gastric emptying in mice. Fennel oil and Anchu-san (a Japanese herbal medicine containing anethole) also restored delayed gastric emptying. Furthermore, oral administration of anethole stimulated gastric accommodation in rats. These results suggest that anethole could be beneficial for the treatment of FD.

Antinociception by fluoro-loxoprofen, a novel non-steroidal anti-inflammatory drug with less ulcerogenic effects, in rat models of inflammatory pain.

The use of non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of inflammatory pain is limited by gastrointestinal complications. The rapid action of NSAIDs is associated with better pain relief. Previously, we demonstrated that fluoro-loxoprofen, a novel NSAID, has less ulcerogenic potential than other NSAIDs, attributable to its gastroprotective properties. The aim of this study was to investigate and compare the effects of fluoro-loxoprofen on inflammatory pain in rats with those of other NSAIDs. Oral administration of fluoro-loxoprofen, loxoprofen, and celecoxib resulted in equivalent analgesic action against yeast-induced inflammatory pain. The antinociceptive effect of fluoro-loxoprofen was maximized within 1 h after administration, which is less time than that observed for loxoprofen (2 h) and celecoxib (3 h). We confirmed that both fluoro-loxoprofen and loxoprofen suppressed the increases in prostaglandin E2 in inflamed paws. In addition to yeast-induced pain, fluoro-loxoprofen produced a similar effect against adjuvant-induced inflammatory pain, with faster peak analgesic effects than those observed for loxoprofen and celecoxib. Taken together, these results suggest that the analgesic effect of fluoro-loxoprofen is equivalent to that of loxoprofen and celecoxib. Moreover, the analgesic effect of fluoro-loxoprofen against inflammatory pain was more rapid than that of other NSAIDs, and this may be associated with its rapid absorption property.

Aldioxa improves delayed gastric emptying and impaired gastric compliance, pathophysiologic mechanisms of functional dyspepsia.

Delayed gastric emptying and impaired gastric accommodation (decreased gastric compliance) play important roles in functional dyspepsia (FD). Here we screen for a clinically used drug with an ability to improve delayed gastric emptying in rats. Oral administration of aldioxa (dihydroxyaluminum allantoinate) partially improved clonidine- or restraint stress-induced delayed gastric emptying. Administration of allantoin, but not aluminium hydroxide, restored the gastric emptying. Both aldioxa and allantoin inhibited clonidine binding to the α-2 adrenergic receptor, suggesting that antagonistic activity of the allantoin moiety of aldioxa on this receptor is involved in the restoration of gastric emptying activity. Aldioxa or aluminium hydroxide but not allantoin restored gastric compliance with restraint stress, suggesting that aluminium hydroxide moiety is involved in this restoration. We propose that aldioxa is a candidate drug for FD, because its safety in humans has already been confirmed and its ameliorating effect on both of delayed gastric emptying and impaired gastric compliance are confirmed here.