PMDA's challenge to accelerate clinical development and review of new drugs in Japan.

In recent years, Japan's Pharmaceuticals and Medical Devices Agency (PMDA) has conducted several projects to shorten drug development and review times in Japan to resolve the "drug lag." Key to achieving this goal is greater involvement by the PMDA in drug development through enhancement of scientific consultation and improvement of the review process by reinforcing the operational system, including hiring more reviewers. We discuss here the current projects of the PMDA as well as future challenges.

A case of severe low back pain associated with Richard disease (lumbosacral transitional vertebra).

The imaging findings in some cases of low back pain are difficult to describe and the pathophysiology is not clear because subjective findings are usually difficult to document. This report concerns a rare case about the lumbosacral joint causing persistent severe back pain which in itself does not usually have any pathological meaning. We describe the diagnosis, treatment, and outcome of a patient suffering from low back pain with lumbosacral transitional vertebra. The radiological examination showed the congenitally malformed transverse processes of the 5th lumbar vertebra to create a facet joint-like shape at the sacral ala region on both sides. Surgery resulted in immediate disappearance of the low back pain. When the lumbosacral junction shows some instability without fusion, the joint-like region could be the cause of low back pain. The lumbosacral transitional vertebra may be associated with low back pain. Electric denervation of the space between the transverse process of 5th lumbar vertebra and sacral ala is minimally invasive and effective for pain eradication.

Lipid peroxidation-derived cytotoxic aldehyde, 4-hydroxy-2-nonenal in smoked pork.

The contents of 4-Hydroxy-2-nonenal (HNE), cytotoxic aldehyde, in smoked meat products (ham, bacon and sausage) were analyzed. All the samples analyzed contained HNE, although large differences in the contents between the different samples were observed. In one lot of ham (H1) and wiener sausage (WS1) a high level in HNE was observed. The changes of HNE contents of pork meats containing 0, 0.1, 0.5 and 1% Sugi wood vinegar (SWV) stored at 0 °C were also analyzed for 7 days. As an index of lipid peroxidation level, malonaldehyde (MA) contents were also analyzed in these samples. After 7 days of storage, HNE was detected only in pork meats containing 1% SWV and the level was similar to those of H1 and WS1. Judging from MA contents, SWV may act as a pro-oxidant in pork meats and HNE may accumulate in pork in which lipid peroxidation is in progress.

Cervical vertigo after hair shampoo treatment at a hairdressing salon: a case report.

STUDY DESIGN: A case report of cervical vertigo that occurred after shampoo treatment in a hairdressing salon. Abnormalities were detected on magnetic resonance images and magnetic resonance angiography scans. OBJECTIVES: To describe the diagnosis of cervical vertigo caused by neck hyperextension. SUMMARY OF BACKGROUND DATA: Neck hyperextension may induce vertigo and dizziness; the pathophysiology remains unclear, however, because subjective findings are usually difficult to document. METHODS: The diagnosis, treatment, and outcome of a patient with cervical vertigo that occurred after hair shampoo treatment in a hair dressing salon were assessed. RESULTS: Magnetic resonance angiography demonstrated narrowing of the left vertebral artery, whereas magnetic resonance imaging showed cerebellar infarction. Treatment included rest and drugs that activate cerebral circulation and prevent platelet aggregation. Improvement was noted within few days. CONCLUSIONS: The authors suggest that the hyperextended neck position during hair shampoo treatment in a beauty parlor may be a risk factor for back lifting or cerebellum vascular insufficiency. Public education should lead to avoidance of this position during hair shampoo treatment at hair dressing salons.

[Evaluation of dissolution behavior for the products containing tegafur and uracil].

Generic drugs are widely used with the object of cost saving in many Japanese therapeutic scenes now. The products containing the same active ingredient(s), even if they are innovative drugs or generic ones, must be designed to possess the equivalent quality. In this report, we observed the dissolution behavior patterns of three generic drugs that contain Tegafur and Uracil, drugs A, B, and C, and compared them with that of an innovative product, UFT. Drugs B and C were similar to UFT in the dissolution rate of Tegafur, but drug A was not. On the dissolution rate of Uracil, all the generic products, drugs A, B and C, did not amount to the level equivalent to that of UFT. Therefore, these generic products did not indicate the same dissolution behavior pattern as UFT. It was suggested that the pharmaceutical technology used in the manufacture was not equivalent even if the products of the same dosage form contain the same kind and content of the active ingredient(s).

Diagnosis of lumbar disc herniation by three-dimensional MRI.

The lumbo-sacral region has anatomical lordosis and two-dimensional magnetic resonance imaging (2D-MRI) cannot therefore show spinal roots including the dorsal root ganglions in one picture. This makes it difficult to present the lateral part of spinal root lesions. We have recently described a new three-dimensional magnetic resonance imaging (3D-MRI) method which allows a stereoscopic view of the spinal cord and spinal nerve roots. In the present study, we evaluated three 3D-MRI techniques, rapid imaging spin echo (RISE) small tip angle gradient echo (STAGE), and short TI inversion recovery (STIR), for detecting disc tissue degeneration, and spinal cord and nerve root compression for identification of nerve roots and detecting signal changes indicative of thickening of the nerve root, and for evaluation of the extent of herniation in 30 patients with lumbar disc herniation. The RISE method was superior for detecting signal changes in disc degeneration, (in 100% of patients) compared with the STAGE method (in 56.1% of patients). All methods poorly identified L4 roots compared with L5 or S1 roots. The STIR method was the best for identifying nerve roots (L4, 62.5%; L5, 87. 5%; S1, 91.7%). STAGE and STIR were useful for detecting injuries of the nerve roots. RISE showed disc extrusion better than the other techniques (in 64.7% of patients). The presurgical diagnosis on 3D-MRI agreed with the pathology findings at surgery in 71.4% of STIR, 55.6% of RISE, and 33.3% of STAGE MR images. Our results indicate that 3D-MRI is most useful for the diagnosis of lumbar disc herniation and spinal cord and nerve root compression. The STIR method is best for identifying abnormalities of the spinal cord, roots, and intervertebral discs.

Multiple inhibition of platelet activation by aurintricarboxylic acid prevents vascular stenosis after endothelial injury in hamster carotid artery.

Activated platelets are instrumental in restenosis due to their role in thrombus formation. Aurintricarboxylic acid (ATA) has been reported to prevent platelet activation by inhibiting von Willebrand factor binding to platelet glycoprotein (GP)Ib. We investigated the effects of ATA in vitro and in vivo in hamsters. ATA inhibited the in vitro platelet aggregation induced by ADP, botrocetin and thrombin, but not by collagen. The IC50 values during the ex vivo platelet aggregation by ADP, botrocetin and thrombin were 8.2 +/- 1.8 microM, 0.9 +/- 0.4 microg/ml and 2.4 +/- 0.8 unit/ml, respectively. The platelet retention time to collagen-coated beads of hamster blood samples was inhibited by ATA (0.1, 0.3 and 1.0 mg/kg per hour) in a dose-dependent manner. Continuous administration of ATA (0, 0.1, 0.3, 1.0, 3.0 and 10.0 mg/kg per h) via an infusion pump produced dose-dependent antithrombotic effects: the time to occlude the carotid artery after vascular injury with a modified catheter was prolonged. Only when infused at doses of 3.0 and 10.0 mg/kg per hour, bleeding times were significantly prolonged. The continuous treatment with ATA (1.0 mg/kg per h) using a 2ML1 Alzet infusion pump for 2 weeks, resulted in a decrease in neointimal area by 22.2 +/- 6.8% when measured 2 weeks after injury induction. DNA synthesis using DDT1MF2 hamster SMCs was decreased by ATA in a dose-dependent manner. ATA reduced the number of platelets adhering on the injured area, as detected by electron microscopy. These results indicated that treatment with ATA inhibited platelet adhesion but also SMC proliferation. These observations may explain the effect of ATA on neointima formation.

Aluminum accumulation in the skin in end-stage renal failure.

Accumulation of aluminum (Al) of the skin of end-stage renal failure (ESRF) patients was analysed by means of an energy dispersive X-ray spectrometer (Kevex 7000 series). The Al detecting ratio was higher in the hemodialysis (HD) groups than in the non-dialysis ESRF group (p less than 0.025) and the normal volunteer group (p less than 0.01). There were no significant differences between the duration of HD (group I and group II), and between the non-dialysis ESRF and the normal volunteer groups. High Al accumulation detected in the skin of the HD groups may be attributed to the dosing of aluminum hydroxide gel (Al-gel), judging from the fact that all cases in the HD groups had been dosed with Al-gel (0.75-4.5 g/day). High Al detections were observed in 2 cases each of the HD and nondialysis ESRF groups responding HBs-antigen positive.

Microangiopathic changes of subepidermal capillaries in end-stage renal failure.

Skin biopsies were taken from 63 patients with end-stage renal failure (ESRF) and 5 normal volunteers, 53 of whom were on maintenance hemodialysis (HD) and the other 10 without HD. They were examined with light and electron microscopy and subepidermal capillaries were subjected to image analysis. Thickening of the basement membrane (BM) with multilamination of the basal lamina, endothelial activation and chronic inflammatory cell infiltration with participation of mast cells were evident. The extent of these BM changes was correlated with the duration of HD, but not significantly correlated with the clinical findings indicative of arteriosclerosis. There was significant correlation between the duration of HD and mast cell proliferation or eosinophilia. We suspect that the subepidermal capillary changes represent an inflammatory reaction provoked by uremic toxins or by the repeated use of an artificial organ.

Pruritus and mast cell proliferation of the skin in end stage renal failure.

We studied the relationships between dermal mast cell proliferation and pruritus or hyperparathyroidism in hemodialysis (HD). Skin biopsies were taken from 59 patients in end stage renal failure; 51 were on maintenance HD, and the other 8 were not. As a control, 34 non-renal failure pruritic patients were used. Thirty-one of the 59 end stage renal failure patients (52.5%) had pruritus. The incidences of pruritus found in patients on HD and those not on HD were 56.9% and 25%, respectively. Significantly larger numbers of dermal mast cells were found in HD patients than in the control. There was no clear relationship between dermal mast cell proliferation and serum parathyroid hormone (PTH) levels. We speculated that the cause of pruritus in the patients undergoing maintenance HD was due to an increase of dermal mast cells and a release of histamine as a result of extra-corporeal circulation.

[Fundamental and clinical studies on CT gas myelography of the cervical spine].

We applied CT gas myelography at the cervical spinal region and investigated the clinical value of CT gas myelography as a supplementary diagnostic method for the spinal cord and vertebral diseases. Fundamental studies of the conditions of window width and window height and the permitted limit of the angle of incidence were made with phantoms of human neck to establish proper conditions of these factors. In clinical studies, 23 adult persons, who had no abnormality in the cervical spine and in the cervical spinal cord were observed to have normal CT gas myelograms of the cervical region, whereas 37, of clinical cases including 18 of cervical spondylosis, 10 of OPLL, 2 of cervical discopathy, 3 of fracture and dislocation of the cervical spine, 2 of cervical vertebral tumor and 2 of CYL, were found to show clear pathologic findings in the cross sections of the vertebral foramen, subarachnoidal space and spinal cord on the CT gas myelograms. The representative cases of these diseases were presented. The gas myelograms were morphologically classified and investigated in relation to the clinical findings. From the result of these investigations, CT gas myelography appears to be highly useful as a supplementary diagnostic method for diseases of the cervical spine and the cervical spinal cord. Furthermore, we compared the effect of this method with that of CT myelography using metrizamide, a recently developed water-soluble contrast medium.