Studies on interactions between traditional herbal and Western medicines. IV: lack of pharmacokinetic interactions between Saiko-ka-ryukotsu-borei-to and carbamazepine in rats.

The possibility of pharmacokinetic interactions between Saiko-ka-ryukotsu-borei-to extract powder (TJ-12), a widely used traditional Chinese herbal (Kampo) medicine, and carbamazepine (CBZ), an important anti-epileptic drug, was examined in rats. There were no significant differences in the serum protein binding of CBZ and carbamazepine- 10,11-epoxide (CBZ-E), its active metabolite, at two concentrations (1 and 10 Bg/ml) between twogroups pretreated orally with the vehicle andTJ-12 suspension (1 g/kg/d, p.o.) for 1 week. One-week repeated pretreatment with TJ- 12 (1 g/kg/d) did not influence liver weight, contents of cytochromes P450 and b5 in hepatic microsomes or the formation rate of CBZ-E from CBZ by its microsomes, while pretreatment with phenobarbital (80 mg/kg/d, i.p.) significantly increased these parameters. Neither a single nor 1-week repeated oral pretreatment with TJ-12 (1 g/kg/d) affected the plasma concentration-time profile and any pharmacokinetic parameter of CBZ or CBZ-E after oral administration of CBZ (50 mg/kg). These results indicated that oral co-administration of TJ-12 with CBZ has no effect ofthe pharmacokinetics of CBZ or CBZ-E in rats. Concomitant treatment with TJ- 12 and CBZ appears to be pharmacokinetically safe in humans.

Membrane transport and antitumor activity of pirarubicin, and comparison with those of doxorubicin.

We have compared the membrane transport and antitumor activity of pirarubicin with those of doxorubicin in M5076 ovarian sarcoma, which exhibits low sensitivity to doxorubicin. Pirarubicin was rapidly taken up by M5076 cells and the intracellular concentration of pirarubicin reached more than 2.5-fold that of doxorubicin. In terms of the 50% cell growth-inhibitory concentration in vitro, pirarubicin was more effective than doxorubicin. Thus, the intracellular concentration influenced the cytotoxicity of these anthracycline agents. On comparison of the nuclear uptake of pirarubicin and doxorubicin, the nucleus/cell ratio of pirarubicin was found to be about 40%, whereas that of doxorubicin reached more than 80%. As the intranuclear concentration of pirarubicin is dependent on nuclear transport, the increases in not only cell membrane transport, but also nuclear membrane transport contributed to the enhancement of the efficacy of pirarubicin. In M5076 solid tumor-bearing mice, pirarubicin reduced the tumor weight to 60% of the control level, although doxorubicin had no effect. These results were supported by the intracellular uptake of pirarubicin. Moreover, theanine, which inhibited the pirarubicin efflux from M5076 cells, increased by 1.3-fold the pirarubicin concentration in the tumor and enhanced the therapeutic efficacy of pirarubicin 1.7-fold. In conclusion, our results suggest that an increase in the concentration of an anthracycline derivative in tumor cells due to alteration of cell membrane transport results in enhancement of the antitumor activity.

Studies on interactions between traditional herbal and Western medicines. I. Effects of Sho-seiryu-to on the pharmacokinetics of carbamazepine in rats.

The effects of oral co- and pre-administration of Sho-seiryu-to extract powder (TJ-19, 1 g/kg), a widely used Kampo (traditional Chinese herbal) medicine, on the pharmacokinetics of an anti-epileptic drug, carbamazepine (CBZ), and its active metabolite (carbamazepine-10,11-epoxide, CBZ-E) after oral administration of CBZ (50 mg/kg) were examined in male rats. The simultaneous administration of TJ-19 significantly lengthened the time to reach the peak plasma concentration (Tmax), but did not influence the peak plasma concentration, area under the plasma concentration-time curve or terminal elimination half-life (t1/2). Each parameter for CBZ or CBZ-E with a single pretreatment with TJ-19 was not significantly different from that with the vehicle. Tmax and the elimination rate constant for CBZ were significantly increased by 1-week repeated pretreatment with TJ-19, by 83% (p<0.01) and 88% (p<0.001), respectively. t1/2 and the mean residence time from zero to infinity (MRT0-infinity) in the TJ-19 pretreatment group were significantly shortened, by 52 and 34% (p<0.005), respectively. No significant difference in the bound fraction of each drug at two concentrations (1 and 10 microg/ml) was observed between the control and TJ-19 pretreatment groups. These results indicate that simultaneous oral administration of TJ-19 delays the oral absorption of CBZ, while 1-week repeated pretreatment with TJ-19 accelerates the metabolism of CBZ in rats, without affecting the protein binding of CBZ.

Why is transurethral microwave thermotherapy (TUMT) positively effective?

Between 1992 and 1994, 157 patients with benign prostatic hyperplasia were treated with transurethral microwave thermotherapy (TUMT). In evaluating the efficacy of TUMT with the International PrOstate Symptom Score (I-PSS) in 121 patients, 18 (15%) showed excellent and 42 (35%) showed good response. In evaluation of QOL, the result was 43 patients (33%) excellent and 42 patients (35%) good response. In objective evaluation of uroflow in 93 patients, 12 (13%) showed excellent and 13 (14%) showed good response. The prostatic volume did not show a significant decrease after treatment. In terms of overall improvement, according to the criteria proposed at the 2nd International Consultation on BPH, the treatment was considered effective in 53 of 108 patients (48%). Histological examination of the prostate enucleated from a patient 7 months after TUMT revealed degenerative changes of nerve fibres on S-100 protein immunohistochemical staining, which were more extensive than those in smooth muscle cells on HE staining. In in vitro tests the isometric contraction force of the rabbit prostatic tissue was measured after exposure to different temperatures, ranging from 37 to 50 degrees C. No significant change was observed up to 45 degrees C vs. 37 degrees C. After exposure to 48 degrees C, the nerve mediated contractions became completely depressed, although phenylephrine or KCl induced contractions were only partially suppressed. After exposure to 50 degrees C, no contraction was induced by any type of stimuli. In conclusion, it is suggested that good symptomatic improvement after TUMT results from both neural and muscular damage to the prostate. As TUMT is not aiming at a relief of anatomical obstruction, 50 degrees C is thought to be a sufficient thermal condition to cause an irreversible damage to prostatic tissue, which will provide a relief from functional obstruction and urethral instability.

[How does thermotherapy effectively work on benign prostatic hyperplasia--an experimental study].

Isometric contractile force of rabbit prostatic tissue in response to electric field stimulation (EFS), KCl, and phenylephrine were measured at incubation temperature of 37 degrees C, before and after thermal exposure to 42 degrees C, 45 degrees C, 48 degrees C and 50 degrees C for 30 minutes. The contractile force in response to EFS decreased after thermal exposure above 45 degrees C, and the contractile force in response to KCL or phenylephrine decreased after thermal exposure above 48 degrees C. All the contractile response abolished after thermal exposure to 50 degrees C. The results indicate that the nerve is more hear-sensitive than the smooth muscle in the prostate. Histological examination revealed shrinkage of cell body and dark staining of nuclear chromatin of the smooth muscle cells after thermal exposure above 48 degrees C. The same histological change of the smooth muscle as well as degenerative change of the nerve cells was observed on the prostate 3-7 months after clinical thermotherapy. From these results, it is suggested that clinical effect of thermotherapy is brought about from both neural and muscular damage of the prostate. Since the least temperature to cause an irreversible tissue damage ranges from 48 degrees C through 50 degrees C, we believe it is ideal to heat the prostate around 50 degrees C to obtain a good clinical effect of thermotherapy on benign prostatic hyperplasia as a minimum invasive treatment.