Evaluation of the influence of different types of seats on postural control in individuals with paraplegia.

STUDY DESIGN: Cross-sectional study. OBJECTIVES: To assess the importance of proprioceptive and vision information on different types of wheelchair seats with regard to postural control in paraplegic individuals during static posture. SETTING: Centre of Rehabilitation at the University Hospital/FMRP-USP and Rehabilitation Outpatient Clinic at University Hospital/UNICAMP, Brazil. METHODS: This study involved 11 individuals with paraplegia. All individuals were submitted to an evaluation of static balance with their eyes open and closed in three different types of seats: wheelchair seat, foam seat and gel seat. Balance evaluation was performed by using the Polhemus system, in which body displacements and anteroposterior and mediolateral speeds were assessed in a static seated position in the different types of seats. Data were analyzed using analysis of variance. The differences were considered at P<0.05. RESULTS: No statistical differences were found between the three types of seats in terms of displacements and anteroposterior and mediolateral speeds, or between seats with individuals keeping their eyes open or closed (P>0.05). However, it was observed that body displacements were more prominent toward an anteroposterior than a mediolateral direction. CONCLUSION: This study suggests that individuals with paraplegia tend to exhibit a more anteroposterior body displacement than a mediolateral one, with no significant differences between the types of seats in both situations of eyes open and closed.

Pharmacokinetics of dicrofenac after its intrarectal and intracolostomal administration to rabbits with rectal resection or colostoma construction.

We investigated the pharmacokinetics of diclofenac, one of the important analgesics in palliative care, after its intrarectal and intracolostomal administration to rabbits with rectal resection or colostoma construction. In rectal-resected rabbits, its bioavailability after rectal administration was significantly lower than that in normal rabbits, and furthermore that after intracolostomal administration was significantly lower than that in rectal-resected rabbits. This decreased bioavailability in rabbits with rectal resection and colostoma construction was thought to be due to the increased first-pass effect. With increase in the dose up to 1.5-fold, the plasma concentrations in both rectal-resected and colostoma-constructed rabbits increased to the normal rabbit level. These results indicate that the bioavailability of diclofenac sodium after its rectal and intracolostomal administration decreases, and that an increased dose can restore the decreased plasma concentration. There was no difference in the plasma concentration with diclofenac sodium suppositories between administration into the normal rectum and the remaining rectum following colostoma construction, and the remaining rectum was found to be a useful administration route for suppositories. Therefore, it was indicated that when administering diclofenac sodium suppositories to rectal-resected and colostoma-constructed patients, the dose should be increased, because the pharmacokinetics of diclofenac was similar in rabbits and human.

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.

Reversal effects of antifungal drugs on multidrug resistance in MDR1-overexpressing HeLa cells.

In this study, the antiproliferative effects of vinblastine (VLB), paclitaxel (TXL), doxorubicin (DXR), daunorubicin (DNR) and 5-fluorouracil (5-FU) were assessed in the human cervical carcinoma cell line HeLa-Ohio (HeLa) and Hvr100-6 cells, established by growing the parental HeLa cells in the presence of progressively greater concentrations of VLB in the culture medium. Flow cytometric analysis indicated the induction of MDR1 (P-glycoprotein) in Hvr100-6 cells with no alterations in levels of multidrug resistance-associated protein (MRP). Resistance to VLB, TXL, DXR and DNR was found in Hvr100-6 cells with relative resistances of ca. 300, 4000, 50 and 200, respectively, whereas no resistance was found to 5-FU. The reversal effects of antifungal drugs, fluconazole, itraconazole, ketoconazole, miconazole and amphotericin B on multidrug resistance were also assessed using Hvr100-6 cells. Itraconazole was found to have potent reversal effect on the resistance to VLB and TXL, but the others had no such effect. This reversal effect of itraconazole was concentration-dependent, with dose modifying factors of 3.2, 10.1 and 435.7 at 0.1, 0.25 and 0.5 microM of itraconazole, respectively. In addition, this reversal effect of itraconazole was explained by the inhibition of accumulation of the anticancer drugs.

Factors influencing the prediction of steady state concentrations of digoxin.

The prediction error in the Bayesian analysis program for digoxin was evaluated in Japanese patients, and factors influencing the accuracy were investigated. Serum concentrations of digoxin were monitored two times and were compared with the predicted values obtained by using the Bayesian analysis program. The prediction error at the first time was 43.1%. Although this estimation error was reasonably restored at the second time of monitoring, the prediction error remained at 26.6%. These data suggested that unknown factors not included in the program affected the serum concentration of digoxin. Retrospective research of the digoxin serum concentrations in the patients suggested the coadministration of the drugs, which were the P-glycoprotein modulators, as well as the unexpected alteration of the serum creatinine, were the important factors influencing the prediction of the drug serum concentrations. We next examined the inhibitory effect of quinidine, verapamil and spironolactone on the transcellular transport of digoxin by using human P-glycoprotein overexpressing LLC-GA5-COL150 cells. Quinidine, verapamil and spironolactone could inhibit the transcellular transport of digoxin by 50%. In addition, the reduction of the renal clearance by 50%, which could possibly be caused by this inhibition, led to the increase of 36% in the steady state through concentrations of digoxin in the physiological pharmacokinetic model. In conclusion, the prediction of long-term serum concentration-time profiles of digoxin, based on the Bayesian analysis, will be disturbed by the coadministration of the P-glycoprotein modulators and the unexpected alteration of the serum creatinine.

[Primary pineal embryonal carcinoma occurring in a middle aged man].

A case of a primary pineal embryonal carcinoma occurring in a middle aged man is reported. A 42-year-old man suffering from headache and nausea was referred to our department. A neurological examination revealed that he had Parinaud's sign. Head CT and MRI showed a tumor in the pineal region. He was operated on using the occipital trans-tentorial approach. The tumor was partially removed and an intra-operative specimen was used to diagnose a kind of germ cell line tumor. However, the tumor was diagnosed afterwards as a pure embryonal carcinoma. Three courses of PE chemotherapy followed by 30 Gy of whole craniospinal irradiation and 30 Gy of extended local irradiation were completed. An MRI showed the tumor to be in complete remission. Despite careful follow-up with chemotherapy every three months, a re-operation and linac radio-surgery, the tumor recurred, and disseminated. The patient died due to an intra-tumoral hemorrhage. A pure primary pineal embryonal carcinoma occurring in a middle-aged person has never been reported previously in detail.

The novel anticancer drug KRN5500 interacts with, but is hardly transported by, human P-glycoprotein.

The interaction of the novel anticancer drug KRN5500, a spicamycin derivative, with human P-glycoprotein (P-gp) was analyzed from the viewpoint of cellular pharmacokinetics, i.e. by means of [3H]azidopine photoaffinity labeling, cellular accumulation and transcellular transport experiments. In this study, P-gp-overexpressing LLC-GA5-COL150 cells, porcine kidney epithelial LLC-PK1 cells transformed with human MDR1 cDNA, were used, since this cell line constructs monolayers with tight junctions, and would provide sufficient information for analyzing the cellular pharmacokinetics. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that the growth-inhibitory effect of KRN5500 in LLC-GA5-COL150 cells was comparable to that in LLC-PK1 cells (IC50 = 79.4 and 72.7 nM, respectively), but the inhibition of [3H]azidopine binding by KRN5500 was concentration-dependent in the membrane fraction of LLC-GA5-COL150 cells. The cellular accumulation of [14C]KRN5500 after its basal application in LLC-GA5-COL150 cells was slightly lower than that in LLC-PK1 cells, and was restored by the multidrug resistance (MDR) modulator SDZ PSC 833. The basal-to-apical transport of [14C]KRN5500 in LLC-GA5-COL150 cells was also slightly higher than that in LLC-PK1 cells, and was inhibited by SDZ PSC 833. However, the basal-to-apical transport of [14C]KRN5500 in LLC-GA5-COL150 cells was only a little higher than the apical-to-basal transport. Consequently, these results demonstrated that KRN5500 interacted with, but was hardly transported via, P-gp. These observations suggested that KRN5500 may be useful even for the treatment of tumors exhibiting P-gp-mediated MDR.

Interaction of docetaxel ("Taxotere") with human P-glycoprotein.

The interaction of docetaxel ("Taxotere") with P-glycoprotein (P-gp) was examined using porcine kidney epithelial LLC-PK1 and LLC-GA5-COL150 cells, overexpressing human P-gp selectively on the apical plasma membrane by transfection of human MDR1 cDNA into the LLC-PK1 cells. The basal-to-apical transport of [14C]docetaxel in LLC-GA5-COL150 cells significantly exceeded that in LLC-PK1 cells, but the apical-to-basal transport was decreased in LLC-GA5-COL150 cells. The intracellular accumulation after its basal or apical application to LLC-GA5-COL150 cells was 4- to 20-fold lower than that of LLC-PK1 cells. Multidrug resistance (MDR) modulators, i.e., cyclosporin A and SDZ PSC 833, inhibited the basal-to-apical transport and increased the apical-to-basal transport of [14C]docetaxel in LLC-GA5-COL150 cells, but verapamil affected only apical-to-basal transport. The intracellular accumulation after basal or apical application to LLC-GA5-COL150 cells was also increased by these three MDR modulators. These observations demonstrated that docetaxel is a substrate for human P-gp, suggesting that docetaxel-drug interactions occur via P-gp. The inhibition of [14C]docetaxel transport by the MDR modulators, as well as daunorubicin and vinblastine, was also found in LLC-PK1 cells, which endogenously express P-gp at lower levels, and concentrations showing similar levels of inhibition were lower than those in the case of LLC-GA5-COL150 cells. These observations indicate that it is necessary to consider the pharmacokinetic and pharmacodynamic interactions of docetaxel via P-gp.

Cellular pharmacokinetic aspects of reversal effect of itraconazole on P-glycoprotein-mediated resistance of anticancer drugs.

The reversal effect of itraconazole on P-glycoprotein (P-gp)-mediated resistance of vinblastine, daunorubicin and doxorubicin was analyzed from a cellular pharmacokinetic point of view, namely by [3H]azidopine photoaffinity labeling, intracellular accumulation and transcellular transport experiments. The LLC-GA5-COL150 cells, which expressed human P-gp selectively on the apical membrane due to transfection of MDR1 cDNA into the porcine kidney epithelial cells (LLC-PK1 cells), was used here, since this cell line constructs the monolayer with tight junction, being able to characterize the cellular pharmacokinetics. In LLC-GA5-COL150 cells, itraconazole caused a reversal from resistance as shown by a growth inhibition assay. [3H]Azidopine photoaffinity labeling demonstrated that itraconazole, vinblastine, daunorubicin and doxorubicin showed higher binding ability for P-gp compared with digoxin, suggesting the following results were via P-gp. The intracellular accumulation of [3H]vinblastine, [3H]daunorubicin and [14C]doxorubicin after their application on the basal and apical sides was increased by itraconazole. These changes were similar to the dose modifying factors determined by the growth inhibition assay. However, their basal-to-apical transport was hardly affected by itraconazole, and this was explained by the fact that itraconazole inhibited P-gp, and subsequently increased their intracellular concentration and then the non-P-gp mediated transport from the intracellular space to apical side. The apical-to-basal transport of [3H]vinblastine, [3H]daunorubicin and [14C]doxorubicin was increased by itraconazole, and this was reasonably explained by the inhibition of P-gp, and partly also by the increase of their intracellular concentration via the inhibition of P-gp.

Inhibitory effects of a cyclosporin derivative, SDZ PSC 833, on transport of doxorubicin and vinblastine via human P-glycoprotein.

The inhibitory effects of SDZ PSC 833 (PSC833), a non-immunosuppressive cyclosporin derivative, on the P-glycoprotein (P-gp)-mediated transport of doxorubicin and vinblastine were compared with those of cyclosporin A (Cs-A). The transcellular transport of the anticancer drugs and PSC833 across a monolayer of LLC-GA5-COL150 cells, which overexpress human P-gp, was measured. Both PSC833 and Cs-A inhibited P-gp-mediated transport of doxorubicin and vinblastine in a concentration-dependent manner and increased the intracellular accumulation of doxorubicin and vinblastine in LLC-GA5-COL150 cells. The values of the 50%-inhibitory concentration (IC50) of PSC833 and Cs-A for doxorubicin transport were 0.29 and 3.66 microM, respectively, and those for vinblastine transport were 1.06 and 5.10 microM, respectively. The IC50 of PSC833 for doxorubicin transport was about 4-fold less than that for vinblastine transport, suggesting that the combination of PSC833 and doxorubicin might be effective. PSC833 itself was not transported by P-gp and had higher lipophilicity than Cs-A. These results indicated that the inhibitory effect of PSC833 on P-gp-mediated transport was 5- to 10-fold more potent than that of Cs-A, and this higher inhibitory effect of PSC833 may be related to the absence of PSC833 transport by P-gp and to the higher lipophilicity of PSC833.

Intraventricular, cystic, atypical meningioma.

A 37-year-old male presented with a very rare cystic meningioma in the trigone of the left lateral ventricle. Neurological examination revealed mild conduction aphasia and right hemisensory disturbance. Computed tomography and magnetic resonance imaging showed a solid, enhancing tumor in the left trigone which had multiple cystic components located anteriorly and superiorly. The tumor was totally resected via a parietal, transventricular approach. Histological examination revealed an atypical meningioma with cellular pleomorphism and prominent nucleoli. Both the solid component and the cyst wall consisted of tumor cells.

Transport mechanisms of anthracycline derivatives in human leukemia cell lines: uptake of pirarubicin, daunorubicin and doxorubicin by K562 and multidrug-resistant K562/ADM cells.

We studied the uptake mechanisms of anthracycline derivatives, pirarubicin (THP), daunorubicin (DNR) and doxorubicin (ADR), in K562 and multidrug-resistant K562/ADM cells, which overexpress a multidrug efflux pump P-glycoprotein (P-gp). The uptake of THP, DNR and ADR by K562 or K562/ADM cells was time-, temperature- and concentration-dependent. The THP and ADR uptake by the parental cells was not affected by treatment with 4 mM 2,4-dinitrophenol (DNP) alone or DNP plus a P-gp specific inhibitor, cyclosporin A (CyA, 10 microM), while the DNR uptake in the DNP treatment group was significantly greater than that in the control group. There was no difference in the uptake of THP between DNP-pretreated K562 cells and DNP plus CyA-pretreated K562/ADM cells. The uptake of DNR or ADR was almost equal in both types of cell treated with DNP alone. Every kinetic constant for THP, DNR and ADR uptake by the sensitive cells was approximately equal to that in the resistant cells, respectively, under the above conditions. THP uptake was noncompetitively inhibited and stimulated on simultaneous treatment and preloading, respectively, of DNR or ADR in each type of cell. ADR showed noncompetitive inhibition of DNR uptake by either type of cell. Therefore, it was suggested that a common carrier-mediated transport system was involved in the uptake of THP, DNR and ADR, and that their binding sites in the carrier might be different from one another in both K562 and K562/ADM cells.

Transport mechanism of anthracycline derivatives in human leukemia cell lines: uptake and efflux of pirarubicin in HL60 and pirarubicin-resistant HL60 cells.

We studied the transport mechanism of pirarubicin (THP) in HL60 and its THP-resistant (HL60/THP) cells, which showed no expression of mdr1 mRNA on Northern blot analysis. Under physiological conditions, the uptake of THP by both types of cell was time- and temperature-dependent. The amount of drug transport in the resistant cells was significantly less than that in the parent cells within 3 min of incubation. THP uptake was significantly higher in the presence than in the absence of 4 mM 2,4-dinitrophenol (DNP) in glucose-free Hanks' balanced salt solution in both HL60 and HL60/THP cells and the increases were approximately equal. In the presence of DNP, the uptake of THP by both types of cell was concentration-dependent, and there were no significant differences in the apparent kinetic constants (Michaelis constant (Km), maximum velocity (Vmax) and Vmax/Km) for THP uptake between HL60 and HL60/THP cells. Additionally, THP transport was competitively inhibited by its analogue doxorubicin. The efflux of THP from HL60/THP cells was significantly greater than that from HL60 cells, and the release from both types of cell was completely inhibited by decreasing the incubation temperature to 0 degrees C and by treatment with DNP in glucose-free medium. In contrast, the P-glycoprotein inhibitors verapamil and cyclosporin A did not inhibit THP efflux. However, genistein, which is a specific inhibitor of multidrug resistance-associated protein (MRP), increased the THP remaining in the resistant cells, and the value was approximately equal to that of the control group in the sensitive cells. These results suggest that THP is taken up into HL60 and HL60/THP cells via a common carrier by facilitated diffusion, and then pumped out in an energy-dependent manner. Furthermore, the accelerated efflux of THP by a specific mechanism, probably involving MRP, other than the expression of P-glycoprotein, resulted in decreased drug accumulation in the resistant cells, and was responsible, at least in part, for the development of resistance in HL60/THP cells.

[Treatment of acute cholecystitis by direct-puncture bile aspiration with ultrasound-image control].

We carried out ultrasound guided direct-puncture bile aspiration (DPBA) in 58 patients with acute cholecystitis. Symptoms and laboratory findings of acute cholecystitis were rapidly improved after DPBA. NO serious complications were seen during and after the DPBA procedure. It was concluded that DPBA is practical and safe treatment of acute cholecystitis. Furthermore long follow up study revealed that this therapeutic method would be useful and reliable for elder patients and patients with systemic complication.

Transforming growth factor-beta-induced gene expression of monocyte chemoattractant JE in mouse osteoblastic cells, MC3T3-E1.

A recent study demonstrated that PDGF-inducible JE is an inflammatory cytokine that directs chemotactic activity of monocytes. Accumulation of monocyte/macrophage lineage cells at site of bone tissue sites is very important for formation of multinucleate osteoclasts, which mediate bone resorption. Since transforming growth factor-beta (TGF-beta) is a potent regulator in bone remodeling, we examined whether TGF-beta induced JE gene expression in mouse osteoblastic cells, MC3T3-E1. TGF-beta induced a maximum JE mRNA expression at 3 hr after initiation of the cytokine treatment. This maximal expression was observed in when TGF-beta was used at a concentration of 1 ng/ml. The chemotactic activity for human monocytes was detected in conditioned medium of TGF-beta-treated cells, and the chemotactic activity was neutralized by anti-JE serum treatment.

Resolution of diffuse granulomatous fibrosis of the liver with antituberculous chemotherapy.

A 71-yr-old man with pulmonary tuberculosis developed jaundice, and an ultrasound examination suggested hepatolithiasis. The liver was markedly enlarged and of stony consistency. Two 2.5-cm biopsy specimens of the liver each disclosed diffuse fibrosis with giant cells; practically no normal parenchyma was seen. Ultrasonography and computed tomography disclosed multiple intrahepatic calcifications, and percutaneous cholangiography revealed stenosis of the right hepatic duct. One year after treatment with antituberculous drugs, liver biopsy specimens taken from the same areas of the liver showed nearly normal histology.

Membranous obstruction of the portal vein. A case report.

Membranous obstruction of the portal vein has not been previously reported. This 56-yr-old Indonesian man with a history of a tropical fever 5 yr earlier presented with variceal bleeding. Transhepatic obliteration of the varices was attempted, but the catheter placed in the right portal branch would not pass beyond the porta hepatis. Another catheter was inserted into the portal trunk under ultrasound guidance. Simultaneous opacification through the two catheters demonstrated a complete membranous obstruction of the portal vein at the porta hepatis and a portal-superior mesenteric-venous axis that had lost communication with incoming veins and the left portal branch, most likely because of multiple thrombosis. Other angiographic procedures also revealed marked hepatopetal collaterals (cavernous transformation) entering the liver through the hilum. Liver biopsy showed acute posttransfusion hepatitis superimposed upon portal fibrosis. The possible mechanism for membrane formation in relation to thrombosis is discussed.