A magnetic anti-cancer compound for magnet-guided delivery and magnetic resonance imaging.

Research on controlled drug delivery for cancer chemotherapy has focused mainly on ways to deliver existing anti-cancer drug compounds to specified targets, e.g., by conjugating them with magnetic particles or encapsulating them in micelles. Here, we show that an iron-salen, i.e., µ-oxo N,N'- bis(salicylidene)ethylenediamine iron (Fe(Salen)), but not other metal salen derivatives, intrinsically exhibits both magnetic character and anti-cancer activity. X-Ray crystallographic analysis and first principles calculations based on the measured structure support this. It promoted apoptosis of various cancer cell lines, likely, via production of reactive oxygen species. In mouse leg tumor and tail melanoma models, Fe(Salen) delivery with magnet caused a robust decrease in tumor size, and the accumulation of Fe(Salen) was visualized by magnetic resonance imaging. Fe(Salen) is an anti-cancer compound with magnetic property, which is suitable for drug delivery and imaging. We believe such magnetic anti-cancer drugs have the potential to greatly advance cancer chemotherapy for new theranostics and drug-delivery strategies.

Exploring Ethnic Differences in Toxicity in Early-Phase Clinical Trials for Oncology Drugs.

During oncology drug development, it is important that ethnic differences are evaluated to determine the optimal dose and administration schedule in a new region based on the clinical data from other regions. The objective of this study was to explore the possibility of detecting ethnic differences in toxicity during early-phase clinical trials. Data were reviewed from phase I clinical trials for new drug applications conducted in Japan and Western countries. The maximum tolerated doses (MTDs), recommended phase II doses (RP2Ds), and approved doses in Japan were compared with those in Western countries. There were 4 of 28 drugs eligible for analysis that showed differences in MTDs or RP2Ds between Japanese and Western patients. Differences in MTDs or RP2Ds in 2 phase I trials were associated with ethnic differences in toxicity. It may be worthwhile to evaluate ethnic differences in toxicity during early-phase clinical trials for oncology drugs.

Points to consider on the non-clinical safety evaluation of anticancer drugs.

Since malignant tumors are life-threatening, the death rate from these diseases is high, and existing therapies have limited effectiveness, it is desired to provide new effective anticancer drugs to tumor patients sooner. However, there is no guideline regarding non-clinical safety studies on the development of anticancer drugs required for the first in human clinical trials and for the approval applications in Japan. Then, the Ministry of Health, Labour and Welfare (MHLW) established the collaboration group including regulatory, academic and industrial scientists to prepare the guideline on the non-clinical safety evaluation of anticancer drugs in 2004. As a guide for basic concept of non-clinical safety studies on anticancer drugs, the "Points to Consider" document was prepared by this group in 2007.

[Consideration of clinical development for new anticancer drugs on Japan, proposal from approval reviewer].

There become problems about a delay on clinical development of anticancer drug in Japan and drug lag. I consider causes and solutions of the problems from a position of drug approval reviewer. I think the drug lag may cause by stating later state in global clinical development or stagnation of clinical trial activities. To prevail against drug lag,it is necessary to attend to multinational clinical studies,and to mature Japanese clinical trial environment and post-market planning. Then, I believe that the most important point is to make a start on early stage of global clinical development.

Undesirable effects of citrus juice on the pharmacokinetics of drugs: focus on recent studies.

It is well known that intake of grapefruit juice affects the pharmacokinetics of various kinds of drugs. It has been reported that other citrus juices also interact with certain drugs. To re-evaluate citrus juice-drug interactions based on currently available evidence, a literature search was conducted for new and updated information since the grapefruit juice-drug interaction was last reviewed in 1998. MEDLINE (1998-October 2004) was accessed and more than 200 reports were found. The effects of grapefruit juice ingestion on the pharmacokinetics of orally administered drugs have been reported for 40 drugs since the reviews published in 1998. Increases in either area under the concentration-time curve (AUC) or maximum plasma concentration (C(max)) were found with 34 of these, the major mechanism being considered to be inactivation of intestinal cytochrome P450 3A4, a so-called mechanism-based inhibition. Although recent reports point to the inhibitory effects of grapefruit juice on the function of P-glycoprotein, which transports substrates from enterocytes back into the lumen, the contribution to the bioavailability of drugs that are substrates of P-glycoprotein has not been established yet. Dramatic decreases in AUC and C(max) for two drugs in association with grapefruit juice ingestion has been reported and, in these cases, inhibitory effects on organic anion transporting polypeptide, which mediates absorption from the intestinal lumen to enterocytes, might be involved. Other citrus juices such as Seville (sour) orange juice and commonly ingested varieties of orange juice also showed significant effects on the AUC and C(max) of some drugs. Although the situation is complex and uncertainties remain, we recommend that patients avoid citrus juice intake while taking medications and that healthcare providers advise against citrus juice intake in this setting until any interactions with subject drugs can be clarified in clinical studies.

[Improvement of package insert CYP information for prescription drugs marketed in Japan].

In clinical practice, one drug is frequently used in combination with one or more other drugs, rather than as a sole regimen, and therefore healthcare providers need to carefully consider drug interactions. As mechanisms of drug interactions, metabolic enzymes of drugs are seen as one of the most likely interactive sites, where a majority of drugs are metabolized by cytochrome P450 (CYP). For this reason, providing appropriate information on CYP in package inserts is of grave importance. In fact, the package insert is the primary tool for supplying information on drugs to healthcare providers. The present study was designed to determine how many package inserts of prescription drugs marketed in Japan were providing CYP information. We searched the April 2003 version of "Drugs in Japan DB," which listed 2,022 prescription drugs, and found that only 239 package inserts (11.8%) mentioned CYP information and that only 194 (9.6%) specified CYP isozymes. To assess the improvement of package inserts, we searched "Drugs in Japan DB" from the January 2000 version to the April 2003 version. We found that CYP information had increased year by year (eg, 7.8-11.8% annually). For newly approved drugs, an analysis of the relationship between approval year and CYP information in package inserts (April 2003 version) revealed that recently approved drugs had more CYP information (eg, 45.5-51.3% of drugs in 1999-2002, compared to 6.8-26.1% in 1991-1996). A search for regulatory review documents for new drugs approved from 1999 to 2002 suggested that this recent improvement could be related to the increased number of studies identifying CYP isozymes involved in the metabolism or interaction with other drugs. Another reason for the recent improvement may be the fact that the guideline for package inserts for prescription drugs was revised in 1997, and the guidelines for drug interaction and pharmacokinetic studies were published between 1997 and 1999.