Regulatory frameworks for cell therapy products in Japan.

This paper reviews regulatory frameworks for cell therapy products in Japan. Two procedures are used to investigate the use of new cell therapy products in Japan. One is to perform clinical trials in accordance with the provisions of the Pharmaceuticals Affairs Act (PAA); the other is to perform clinical research in accordance with the provisions of the Medical Practitioners Act. For full commercialization of medical products in Japan, we must consider the universal health care system. All medical products used to treat patients in the system must be approved, in accordance with the provisions of the PAA, as drugs or medical devices. Thus, researchers in academia who have developed new cell therapy products should consider performing clinical trials in accordance with the provisions of the PAA to test their products clinically. This article describes development and review processes for new drug/device applications in accordance with the provisions of the PAA and gives an example of clinical review of a cell therapy product by the Pharmaceuticals and Medical Devices Agency.

Effects of cryotherapy after contusion using real-time intravital microscopy.

PURPOSE: To examine effects of local tissue cooling on contusion-induced microvascular hemodynamics and leukocytes behavior using real-time intravital microscopy. METHODS: Male Wistar rats (N = 21, 130-150 g) were randomly assigned to intensive cooling group (3 degrees C, N = 7), a moderate cooling group (27 degrees C, N = 7), or control group (37 degrees C, N = 7). Contusion was induced by dropping a plastic ball on exposed cremaster muscle. After 5 min, the cremaster muscle was superfused with a saline solution for 10 min at controlled temperature of either 3 degrees C (cooling), 27 degrees C (moderate cooling), or 37 degrees C (control). Microvascular hemodynamics (vessel internal diameter, blood flow rate and erythrocyte velocity) and leukocyte behavior (rolling and adhesion) were measured from recorded videotapes in the same venules before and after contusion, and after cooling. RESULTS: Cooling-induced vasoconstriction was marked at 3 degrees C and moderate at 27 degrees C compared with that at 37 degrees C. Blood flow rate and erythrocyte velocity were markedly lower at 3 degrees C compared to 37 degrees C. At 27 degrees C, erythrocyte velocity was higher than that at 37 degrees C, but blood flow rate was maintained at a level similar to that at 37 degrees C. The number of rolling and adhering leukocytes at 3 degrees C and 27 degrees C were significantly less than at 37 degrees C. CONCLUSION: Our results suggest that local tissue cooling, similar to cryotherapy, improves edema and inflammatory reaction, and may be useful for reducing inflammatory response without inhibiting blood flow after contusion.

Sodium nitroprusside decreases leukocyte adhesion and emigration after hemorrhagic shock.

UNLABELLED: The adhesion of polymorphonuclear leukocytes to the capillary endothelium is one of the key events in the pathophysiology of hemorrhagic shock. We studied sodium nitroprusside (SNP) for its ability to modulate leukocyte-endothelial cell interactions induced by hemorrhagic shock and reinfusion of blood by using intravital microscopy of the rat mesentery. Administration of SNP at a dose of 0.1 microg x kg(-1) x min(-1) infusion neither significantly decreased mean arterial blood pressure nor significantly altered bleedout volumes in hemorrhagic rats, indicating that SNP at this dose did not modify the severity of the shock protocol. Resuscitation from 1 h of hemorrhagic shock (mean arterial blood pressure approximately 45 mm Hg) significantly increased the number of adherent and emigrated leukocytes in the rat mesenteric microcirculation. However, infusion of SNP, started 15 min before hemorrhage, and continued over the entire experimental period, markedly reduced the leukocyte adhesion after reinfusion and emigration during hemorrhagic shock and after reinfusion. We concluded that the nitric oxide donor SNP is effective at reducing the leukocyte-endothelial interaction after blood reinfusion after hemorrhagic shock in rats. IMPLICATIONS: The i.v. infusion of 0.1 microg x kg(-1) x min(-1) of sodium nitroprusside, a dose that does not exert a significant vasodilator effect, reduces leukocyte adhesion and emigration after hemorrhagic shock.

Blood flow does not correlate with the size of metastasis in our new intravital observation model of Lewis lung cancer.

We previously reported a novel in situ observation model for microcirculation of lung metastasis from subcutaneously implanted Lewis lung cancer into mouse. Using this model, we studied the correlation of blood flow and the size of lung metastasis. It was revealed that metastatic growth and its angiogenesis are suppressed by circulating angiogenesis inhibitors, such as angiostatin or endostatin, released from primary tumor. When we removed the primary tumor, the metastasized lung cancer significantly grew faster and larger. But the blood flow per area did not increase either inside or outside of the metastatic tumor. This suggests that the growth of metastatic tumor is directly regulated not by blood flow increase but by the other effects of the circulating factors.