Microsomal Cytochrome P-450 Monooxygenase System and Its Drug-metabolizing Activity after Partial Portal Vein Ligation in the Rat

RID=" ID=" <E5>Correspondence to:</E5> K. Izuishi, M.D.     

Z-350, a new chimera compound possessing α1-adrenoceptor antagonistic and steroid 5α-reductase inhibitory actions

The effects of Z-350, (S)-4-[3-(4-{1-(4-methylphenyl)-3-[4-(2-methoxyphenyl)piperazine-1-yl]propoxy} benzoyl)indole-1-yl]butyric acid hydrochloride, a newly synthesized compound possessing α₁-adrenoceptor antagonistic and steroid 5α-reductase inhibitory actions, were studied in vitro. In functional experiments, Z-350 shifted the concentration/response curve for the phenylephrine-induced contraction of rabbit prostate, urethra and aorta to the right with pA₂ values of 8.04, 7.57 and 7.13, respectively. The binding affinity of Z-350 for α₁-adrenoceptors in rabbit prostate, urethra and aorta were estimated by the displacement of [³H]prazosin. The pK _i values for this action of Z-350 were 7.53, 7.95 and 7.62 for the prostate, urethra and aorta, respectively. α₁-Adrenoceptor subtype selectivities were studied in the submaxillary gland (α_1A) and liver (α_1B) of rat. Z-350 inhibited the specific binding of [³H]prazosin to α_1A and α_1B-adrenoceptors with pK _i values of 7.82 and 7.29, respectively. Z-350 inhibited rat prostatic steroid 5α-reductase non-competitively with a pIC₅₀ of 8.42. These results indicate that Z-350 is a α₁-adrenoceptor antagonist and is a steroid 5α-reductase inhibitor. It is expected that Z-350 will be a candidate drug for the treatment of benign prostatic hyperplasia. Received: 26 January 1999 / Accepted: 2 March 1999     

Simultaneous determination of grepafloxacin, ciprofloxacin, and theophylline in human plasma and urine by HPLC.

A specific and sensitive reversed-phase high-performance liquid chromatographic (HPLC) method has been developed and validated for the simultaneous determination of grepafloxacin, ciprofloxacin, and theophylline in human plasma and urine. This assay allows these drugs to elute and be resolved in a single chromatogram at 280 nm, using a linear gradient. The procedure involves liquid-liquid extraction. Separation was achieved on a C18 reversed-phase column. The quantification limits were 0.05 mg/L in plasma and 0.5 mg/L in urine for grepafloxacin and ciprofloxacin and 0.5 mg/L in plasma and urine for theophylline. Standard curves were linear (correlation coefficients >0.999) over the ranges 0.05 to 5 mg/L for grepafloxacin and ciprofloxacin in plasma, from 0.5 to 20 mg/L for theophylline in plasma, and from 0.5 to 500 mg/L for the three drugs in urine. The coefficients of variation for the three drugs were less than 10% for within- and between-day analyses. The recoveries averaged 94.5% for theophylline, 93% for ciprofloxacin, 93.7% for grepafloxacin, and 95.1% for the internal standard (IS). The assay can be used for pharmacokinetic studies of these drugs, to investigate the interaction of grepafloxacin and ciprofloxacin with theophylline, or for routine simultaneous monitoring of theophylline, grepafloxacin, and ciprofloxacin.     

The ultrastructure of parapapillary chorioretinal atrophy in eyes with secondary angle closure glaucoma

Background: The present study was performed to investigate the ultrastructure of deep retinal layers and choroid corresponding to the parapapillary chorioretinal atrophy in eyes with secondary angle-closure glaucoma. Methods: The glaucomatous eyes included two eyes enucleated due to iris ring melanoma with high intraocular pressure and one eye with neovascular glaucoma enucleated due to ocular pain. The control eyes included one eye enucleated due to choroidal malignant melanoma with normal intraocular pressure and one eye enucleated during surgery for supramandibular carcinoma. These eyes were studied with light and electron microscopy. Results: In the region of parapapillary chorioretinal atrophy of glaucomatous eyes, the retinal pigment epithelial cells showed degenerative changes, such as loss of basal in foldings and microvilli, degenerated mitochondria, vacuolar degeneration and irregular distribution of melanin granules. The photoreceptors were decreased in number in this area of glaucomatous eyes. The lumen of the choriocapillary vessels adjacent to the optic nerve was collapsed. Conclusion: These results elucidate the fine structures of deep retina and choroid in the region of parapapillary chorioretinal atrophy of glaucomatous eyes, and suggest that the reduced choroidal perfusion might be the pathogenetic mechanism of glaucomatous parapapillary chorioretinal atrophy.     

Availability and limitations of thallium-201 myocardial SPECT quantitative analysis: Assessment as daily routine procedure for ischemic heart disease

To determine the availability and limitations of the detection of ischemic lesions by stress thallium-201 myocardial SPECT as the daily routine procedure, we compared and evaluated the detectability of the quantitative analysis (%uptake and washout rate (WR)) and visual evaluation in 104 patients with effort angina and 17 normal subjects. Visual evaluation combined with WR analysis resulted in significantly higher sensitivity (88.0%) but lower specificity (60.2%) than the other methods. The sensitivity by visual evaluation was quite low in multivessel disease (MVD), and in the regions supplied by mild coronary stenosis or by the left circumflex artery. These were markedly improved by combining visual evaluation and WR analysis, but sensitivity in the MVD group was unsatisfactory even with this analytic method in comparison with the single vessel disease group. One of the causes of low sensitivity in the MVD group might be the "true negative": No induction of the ischemia in the regions of milder stenosis, or the regions supplied by the collateral coronary flow. We therefore conclude that the combination of visual evaluation as a qualitative analysis and WR analysis as a quantitative analysis, is the most useful daily routine procedure as a screening test for detecting ischemia.     

Lidocaine-metabolizing Activity after Warm Ischemia and Reperfusion of the Rat Liver In Vivo

The effect of warm ischemia on lidocaine-metabolizing activity was examined in vivo. Total liver ischemia was produced for 1 hr in Sprague-Dawley rats by clamping the portal vein and hepatic artery at the hilum. Livers were then reperfused, and liver microsomes were prepared before and 0, 2, 6, and 24 hr, and 3, 6, and 10 days after reperfusion. Microsomal lidocaine-metabolizing activity and cytochrome P-450 content were examined. Lidocaine N-deethylase activity was decreased from 2.25 ± 0.33 to 0.97 ± 0.21 nmol/mg protein/min (mean ± SD) 24 hr after reperfusion. This inhibition was prolonged, and activity gradually recovered after 10 days. The cytochrome P-450 content showed the same tendency. On the other hand, serum levels of alanine aminotransferase increased significantly 2 hr after reperfusion and returned to control levels 3 days after reperfusion. Liver blood flow recovered rapidly after unclamping and reached baseline levels within 6 hr. Our results suggest that after warm ischemia, prolonged hepatic dysfunction in drug metabolism, which cannot be detected by evaluating serum enzymes or liver blood flow, exists at the microsomal level.     

Use of YAG laser combined with mucosal suturing for the treatment of polypoid vocal cord]

To improve low-pitched voices in cases with polypoid vocal cords, YAG laser irradiation combined with a mucosal suturing technique was attempted in 9 female cases with severe polypoid changes in their vocal cords. A YAG laser beam (5 to 10 W) was used to irradiate the upper surface of the polypoid vocal cord. The polypoid content of the cord was gradually coagulated, and the free edge of the cord appeared to slide up toward the burned area. The polypoid content was then removed and squeezed through an open wound made in the burned area using a conventional method. Bleeding was successfully controlled using the laser. After the excessive mucosal margin was trimmed and the contour of the vocal cord was adjusted, the wound was closed by 7-0 monofilament absorbable suture. Suturing was relatively easy because the mucosal edge was also coagulated. Postoperative evaluations of voice quality revealed an improvement in the GRBAS scale of voice quality as well as an elevation in voice pitch and an upwards shift in the voice range in all cases.     

Medulloblastoma in an adult suggestive of external granule cells as its origin: A histological and immunohistochemical study

We describe a rare case of medulloblastoma in an adult woman with histological findings suggesting an origin for this neoplasm in the external granular layer or its remnants. The patient presented with cerebellar dysfunction, and neuroimaging revealed a right cerebellar mass lesion. Pathological examination of the operative specimen revealed a medulloblastoma with occasional areas of neuronal or glial differentiation. Zic protein was also detected immunohistochemically in the tumor cells. The tumor cells were mainly distributed in the subarachnoid space and extended to the cerebellar parenchyma through the perivascular space to form tumor nodules. A suggestive finding, as concerns the origin of this neoplasm, was that the tumor cells were also spread evenly along the subpial zone of the molecular layer, reminiscent of the cellular architecture of the fetal external granular layer.