An Empirical Analysis of Japan's Drug Development Lag Behind the United States.

The "drug lag" (ie, the approval lag for new drugs) hinders patients' access to innovative new medicines. The drug lag was heavily debated in Japan from the late 2000s to the early 2010s. It consists of "development lag" (ie, the submission date lag for new drug applications) and "review lag" (ie, the difference in review periods). As the 2 lags have different causes and display significantly different recent trends in Japan, we focus on the development lag-in contrast with most previous literature-between Japan and the United States, based on a database we created for all new drugs from 2008 to 2018 using publicly available data sources. First, we found that Japan's development lag relative to the United States did not shrink in terms of the overall distribution rather than the median, which was the focus of most prior studies. Second, we examined the factors (product characteristics) that significantly affected the development lag and found that products that underwent multiregional clinical trials and those that were certified as "breakthrough therapies" in the United States had significantly shorter development lags with high robustness, whereas products receiving price premiums did not. Finally, we discussed the policy implications of these results. For instance, innovative new drugs that are presumed to receive price premiums require enhanced policy support for early application from the initial stages of clinical trials. It is also essential to promote information sharing regarding evaluations by foreign reviewing authorities for efficient use in the home country.

Molecular cloning of a multidomain cysteine protease and protease inhibitor precursor gene from the tobacco hornworm (Manduca sexta) and functional expression of the cathepsin F-like cysteine protease domain.

A Manduca sexta (tobacco hornworm) cysteine protease inhibitor, MsCPI, purified from larval hemolymph has an apparent molecular mass of 11.5 kDa, whereas the size of the mRNA is very large (∼9 kilobases). MsCPI cDNA consists of a 9,273 nucleotides that encode a polypeptide of 2,676 amino acids, which includes nine tandemly repeated MsCPI domains, four cystatin-like domains and one procathepsin F-like domain. The procathepsin F-like domain protein was expressed in Escherichia coli and processed to its active mature form by incubation with pepsin. The mature enzyme hydrolyzed Z-Leu-Arg-MCA, Z-Phe-Arg-MCA and Boc-Val-Leu-Lys-MCA rapidly, whereas hydrolysis of Suc-Leu-Tyr-MCA and Z-Arg-Arg-MCA was very slow. The protease was strongly inhibited by MsCPI, egg-white cystatin and sunflower cystatin with K(i) values in the nanomolar range. When the MsCPI tandem protein linked to two MsCPI domains was treated with proteases, it was degraded by the cathepsin F-like protease. However, tryptic digestion converted the MsCPI tandem protein to an active inhibitory form. These data support the hypothesis that the mature MsCPI protein is produced from the MsCPI precursor protein by trypsin-like proteases. The resulting mature MsCPI protein probably plays a role in the regulation of the activity of endogenous cysteine proteases.

Neuromagnetic evidence that gingiva area is adjacent to tongue area in human primary somatosensory cortex.

The somatotopic organization of the human primary somatosensory (SI) area in the cerebral cortex has been intensively studied for the hand, lip, and tongue, but little is known about the gingiva. Penfield concluded that the gingival SI area was above the tongue area, as shown in his famous homunculus map. However, our recent study suggested that the lingual gingiva area was not so different to the tongue area. To delineate the fine SI somatotopy of the gingiva area, evoked magnetic fields were measured in 6 healthy subjects for the stimulus of the anterior or posterior and upper or lower parts of the lip, buccal and lingual gingiva, and tongue. Source position was estimated by a current dipole model at the first peak of the posterior-oriented current in a total of 12 cerebral hemispheres contralateral to the stimulation side. No significant difference was found between the positions of anterior and posterior or upper and lower parts of each structure. Both buccal and lingual gingiva areas were localized adjacent to the tongue area, but significantly lower than the lip area. We believe that the fine SI somatotopy of the human oral structures should be reconsidered.