[The efficacy of radiotherapy based combined therapy for unresectable locally invasive bladder cancer and its associated factors analysis].

Objective: Retrospective analysis of the efficacy and influencing factors of bladder preservation integrated therapy for unresectable invasive bladder cancer confined to the pelvis was done, also including the bladder function preservation and adverse effects analysis. Methods: Sixty-nine patients with unresectable locally invasive bladder cancer who received radiotherapy-based combination therapy from March 1999 to December 2021 at our hospital were selected. Among them, 42 patients received concurrent chemoradiotherapy, 32 underwent neoadjuvant chemotherapyand 43 with transurethral resection of bladder tumors (TURBT) prior to radiotherapy. The late adverse effect of radiotherapy, preservation of bladder function, replase and metastasis and survival were followed-up. Cox proportional hazards models were applied for the multifactorial analysis. Results: The median age was 69 years. There were 63 cases (91.3%) of uroepithelial carcinoma, 64 of stage Ⅲ and 4 of stage Ⅳ. The median duration of follow-up was 76 months. There were 7 grade 2 late genito urinary toxicities, 2 grade 2 gastrointestinal toxicities, no grade 3 or higher adverse events occurred. All patients maintained normal bladder function, except for 8 cases who lost bladder function due to uncontrolled tumor in the bladder. Seventeen cases recurred locally. There were 11 cases in the concurrent chemoradiotherapy group with a local recurrence rate of 26.2% (11/42) and 6 cases in the non-concurrent chemoradiotherapy group with a local recurrence rate of 22.2% (6/27), and the difference in local recurrence rate between the two groups was not statistically significant (P=0.709). There were 23 cases of distant metastasis (including 2 cases of local recurrence with distant metastasis), including 10 cases in the concurrent chemoradiotherapy group with a distant metastasis rate of 23.8% (10/42) and 13 cases in the non-concurrent chemoradiotherapy group with a distant metastasis rate of 48.1% (13/27), and the distant metastasis rate in the non-concurrent chemoradiotherapy group was higher than that in the concurrent chemoradiotherapy group (P=0.036). The median 5-year overall survival (OS) time was 59 months and the OS rate was 47.8%. The 5-year progression-free survival (PFS) time was 20 months and the PFS rate was 34.4%. The 5-year OS rates of concurrent and non-concurrent chemoradiotherapy group were 62.9% and 27.6% (P<0.001), and 5-year PFS rates were 45.4% and 20.0%, respectively (P=0.022). The 5-year OS rates of with or without neoadjuvant chemotherapy were 78.4% and 30.1% (P=0.002), and the 5-year PFS rates were 49.1% and 25.1% (P=0.087), respectively. The 5-year OS rates with or without TURBT before radiotherapy were 45.5% and 51.9% (P=0.233) and the 5-year PFS rates were 30.8% and 39.9% (P=0.198), respectively. Multivariate Cox regression analysis results showed that the clinical stage (HR=0.422, 95% CI: 0.205-0.869) was independent prognostic factor for PFS of invasive bladder cancer. The multivariate analysis showed that clinical stages (HR=0.278, 95% CI: 0.114-0.678), concurrent chemoradiotherapy (HR=0.391, 95% CI: 0.165-0.930), neoadjuvant chemotherapy (HR=0.188, 95% CI: 0.058-0.611), and recurrences (HR=10.855, 95% CI: 3.655-32.638) were independent prognostic factors for OS of invasive bladder cancer. Conclusion: Unresectable localized invasive bladder cancer can achieve satisfactory long-term outcomes with bladder-preserving combination therapy based on radiotherapy, most patients can retain normal bladder function with acceptable late adverse effects and improved survival particularly evident in patients with early, concurrent chemoradiotherapy and neoadjuvant chemotherapy.

[Endovascular implantation of iodine-125 seeds strand and portal vein stenting followed by transcatheter arterial chemoembolization combined therapy with sorafenib for hepatocellular carcinoma with main portal vein tumor thrombus].

OBJECTIVE: To compare the therapeutic effect of portal vein stenting and endovascular implantation of iodine-125 seeds strand followed by transcatheter arterial chemoembolization combined with or without sorafenib in patients for hepatocellular carcinoma (HCC) with main portal vein tumor thrombus (MPVTT). METHODS: A total of 53 patients with HCC complicated by MPVTT who received portal vein stenting and endovascular implantation of iodine-125 seeds strand followed by transcatheter arterial chemoembolization combined without (group A, n=38) or with (group B, n=15) sorafenib in Affiliated Yancheng Hospital of Southeast University Medical College during January 2010 and August 2015 were analyzed retropectively.Overal survival, progress free survival and procedure-related adverse event were compared between the two groups. RESULTS: The technical success rate was 100% for placement of (125)I seeds strand and stent in the obstructed main portal vein.No serious procedure-related adverse events occurred. Median survival time of group A and B were 12.1 and 14.8 months, respectively (P=0.037). Additionally, Median progress free survival time of group A and B were 2.8 and 4.0 months, respectively (P=0.002). CONCLUSIONS: Endovascular implantation of iodine-125 seeds strand and portal vein stenting followed by transcatheter arterial chemoembolization combined with sorafenib could improve the survival time, the progress free survival time of patients with HCC complicated by MPVTT.

Oral bioavailability and pharmacokinetics of elimination of 9-hydroxybenzo[a]pyrene and its glucoside and sulfate conjugates after administration to male and female American lobsters, Homarus americanus.

The pharmacokinetics of [(3)H]-9-hydroxybenzo[a]pyrene (9-OH-BaP), a highly lipophilic primary metabolite of benzo(a)pyrene, were examined after intrapericardial (iv) or oral doses of 50 or 200 microg/kg to intermolt American lobsters, Homarus americanus. Combining data for all lobsters, the average terminal elimination half-life of parent 9-OH-BaP was 97.3 h after iv and 56.5 h after oral administration, considerably less than found previously for benzo(a)pyrene (720 h). The oral bioavailability of parent 9-OH-BaP, calculated from the area under the hemolymph concentration curve, was 15.9%. The low bioavailability and variable elimination rates were attributed to extensive first-pass conjugation and sequestration in the hepatopancreas. BaP-9-sulfate was the major metabolite. Hemolymph concentrations of BaP-9-sulfate increased up to one day after the dose, and then decreased, with a terminal elimination half-life of 45 h. BaP 9-beta-D-glucoside was a minor metabolite in most hemolymph and tissue samples; an exception was hemolymph from the iv high-dose group. Concentrations of 9-OH-BaP and metabolites in the edible muscle tissue were similar to those in hemolymph, and 9-OH-BaP residues at 10 to 16 days after the dose were 3 to 12 ng/g muscle. Sulfotransferase and UDP-glucosyltransferase (UGT) activities with 9-OH-BaP were found in the antennal gland, intestinal mucosa, and hepatopancreas (UGT only). Sulfatase activity with BaP-9-sulfate, found in both the hepatopancreas and the antennal gland, was thought to contribute to metabolite cycling. These studies showed that 9-OH-BaP was readily conjugated to sulfate and glucose in the lobster, and that despite their high lipophilicity, 9-OH-BaP and conjugates were excreted from the lobster hemolymph and tissues much more rapidly than benzo[a]pyrene.

Intrasynaptosomal free calcium and nitric oxide metabolism in central nervous system oxygen toxicity.

BACKGROUND: Central nervous system (CNS) oxygen (O2) toxicity is complex, and the etiology of its most severe manifestation, O2 convulsions, is yet to be determined. A role for nitric oxide (NO) has been proposed, although recent data have indicated that NO is synthesized from L-arginine by an enzyme, NO synthase (NOS). The enzyme is dependent on free calcium (Ca2+) concentration, therefore increases in intracellular Ca2+ may constitute the physiological and pathophysiological mechanisms for stimulating the synthesis of NO. METHODS: In this study, the intrasynaptosomal free calcium concentration ([Ca2+]i) was measured by the fluorescence of fura-2/AM, and cGMP (as an indirect marker of NO levels) was by radioimmunoassay (RIA) in the rat hippocampus after hyperbaric oxygen (HBO) exposure. We also investigated the effects of daurisoline (DSL, calcium channel blocker) and N-nitro-L-arginine (LNNA, NOS inhibitor) on the above biochemical parameters and the development of oxygen toxicity. RESULTS: The results show that when the rats were exposed to HBO at 0.5 MPa the intrasynaptosomal Ca2+ and cGMP levels increased by two and three times, respectively, whereas with the use of DSL prior to HBO, the accumulation of [Ca2+]i and cGMP dropped to 56% and 60%, correspondingly. In the rats medicated with LNNA prior to HBO. [Ca2+]i and cGMP levels dropped to 70% and 36% of the HBO group. At the same time, the appearance of CNS oxygen toxicity was delayed and the survival rate increased. The protective effects of LNNA were reversed by L-arginine pretreatment. These findings suggest that the neuronal Ca2+ overload during HBO exposure is a major factor in the pathogenesis of CNS O2 toxicity, and cGMP-NO pathways may be directly involved in HBO-induced seizures.

Pharmacokinetics of 2-naphthol following intrapericardial administration, and formation of 2-naphthyl-beta-D-glucoside and 2-naphthyl sulphate in the American lobster, Homarus americanus.

1. Following a 0.25-mg/kg intrapericardial dose of the phenolic compound, 2-naphthol, to the American lobster, Homarus americanus, a two-compartment model best described the disposition of parent [14C]-2-naphthol in the haemolymph. Male and female lobsters had similar alpha-phase half lives of 26 +/- 19 min (mean +/- SD, n = 4) and 29 +/- 15 min respectively. The beta-phase half lives were significantly longer in males, 63.9 +/- 30.9 h, than in females, 30.6 +/- 6.8 h (p < 0.05). The total body clearance for females was 26.4 +/- 6.5 ml x h-1 x kg-1 and was higher than that of males, 11.1 +/- 5.9 ml x h-1 x kg-1 (p < 0.05). 2. 2-Naphthol was converted to 2-naphthyl-beta-D-glucoside (major metabolite) and 2-naphthyl sulphate (minor metabolite) such that at 24 h 39-60.6% of the radioactivity in haemolymph was 2-naphthyl-beta-D-glucoside, 38.6-58.9% 2-naphthol and 0.5-4% 2-naphthyl sulphate. 3. The 2-naphthol-derived radioactivity was > 99% bound to haemolymph proteins at 1 min and > 90% bound at 1 day after the dose, indicating that both 2-naphthol and 2-naphthyl-beta-D-glucoside were highly protein bound. 4. 2-Naphthyl-beta-D-glucoside was slowly eliminated from haemolymph in both males and females, with elimination half lives of 34-78 h. 2-Naphthyl-beta-D-glucoside was the major metabolite in urine samples collected at 5 days after the dose. Hepatopancreas and antennal gland contained glucosidase activities, and the long half life of 2-naphthyl-beta-D-glucoside could be explained by conjugation deconjugation cycling. 5. 2-Naphthyl sulphate was eliminated from haemolymph with a half-life < 10 h and was excreted in urine.

The bioavailability of ginkgolides in Ginkgo biloba extracts.

A new Ginkgo biloba leaf extract, BioGinkgo 27/7, was prepared using a method that enriches ginkgolide B. The bioavailability of ginkgolides in these extracts was assessed in rabbits in comparison with a commercially available standardized 24/6 extract. It was found that, after a single dose, a higher concentration of ginkgolides was maintained for a longer period of time with these extracts than was found with commercial extract prepared by existing methods.

Biotransformation, hepatopancreas DNA binding and pharmacokinetics of benzo[a]pyrene after oral and parenteral administration to the American lobster, Homarus americanus.

It has been shown that American lobsters, (Homarus americanus) environmentally exposed to polycyclic aromatic hydrocarbons do not develop tumors or neoplastic changes although finfish exposed under identical conditions do develop cancer. In this study, environmentally relevant doses (nominally 50 micrograms/kg) of a radiolabelled model procarcinogen, benzo[a]pyrene (BaP), were administered i.v. or p.o. to lobsters and the fate of the radiolabel examined. Parent BaP was rapidly distributed from hemolymph into tissues after i.v. administration. Following oral administration, hemolymph concentrations of BaP rose slowly and reached levels similar to those found after i.v. administration by 48 h after the dose. The tissue distribution of BaP residues was determined at 3 days, 2 weeks and 4 weeks after the p.o. dose and 2 weeks after the i.v. dose. There was no route-related difference in tissue concentrations of BaP residues at 2 weeks. At all times, most of the retained BaP residues were in hepatopancreas (25-75% administered dose) or muscle (8-42% administered dose). Greater than 93% of the radioactivity in muscle was parent BaP at all studied times and the mean concentration of BaP residues in muscle was constant over the period of study. Although most of the radioactivity in hepatopancreas was BaP, metabolites were found and BaP residues declined with time. DNA isolated from hepatopancreas showed extremely low levels of BaP-metabolite binding, 0.016 +/- 0.013 pmol BaP equivalents/mg DNA, mean +/- S.D., n = 11. These studies show that BaP from dietary sources is retained for long periods by edible lobster tissues and suggest that a major reason for the resistance of American lobsters to polycyclic aromatic hydrocarbon-induced cancers is the very slow phase 1 metabolism to reactive metabolites.

The electrophysiological effects of alcoholized rhubarb solution in feline heart in vivo.

The effects of Chinese medicine, alcoholized rhubarb, on cardiac electrophysiology and contractile force were studied by using monophasic action potential (MAP) techniques with an improved pressure-electrical transducer epicardial electrode and/or an endocardial pressure-contact electrode catheter in 27 feline hearts in vivo. The results of the experiments were as follows: 1) Alcoholized rhubarb solution (1.5 g/kg) caused a greater increase in the MAP amplitude (from 18.8 +/- 0.62 mV to 26.7 +/- 3.87 mV, p < 0.01), in the MAP maximum rate of rise of phase 0 (from 1.7 +/- 0.13 V/sec to 2.6 +/- 0.43, p < 0.01), and in the MAP duration at 50% and 90% repolarization (from 194.3 +/- 14.00 msec to 216.3 +/- 6.30 msec and from 238.8 +/- 21.41 msec to 280.5 +/- 14.68 msec, respectively, p < 0.01), and a decrease in the heart rate (from 130.8 +/- 12.10 bpm to 110.8 +/- 10.35 bpm, p < 0.01) in the epicardial monophasic action potentials after rhubarb solution administration for 1 min. 2) The ventricular contractile force of the feline heart in vivo was also significantly increased (11.1 +/- 0.52 g to 14.0 +/- 1.41 g, p < 0.01) by rhubarb solution. 3) A dose-dependent relation of alcoholized rhubarb solution was found and indicated that lower doses (1.0-1.5 g/kg) had an excitatory effect, while a higher dose (2.0 g/kg) had inhibitory or toxic effects on the intact feline heart. The present study provides evidence that Chinese rhubarb solution has electrophysiological effects on the feline heart in vivo.

Rapid, dose-dependent elimination of phenol across the gills, and slow elimination of phenyl sulfate in the urine of phenol-dosed lobsters, Homarus americanus.

Although lobsters are known to metabolize lipophilic organic compounds by monooxygenation, little is known of the fate of the hydroxylated metabolites. Single doses of [14C]phenol, 0.019 to 2.8 mg/kg, were administered intrapericardially to groups of lobsters. Hemolymph was sampled serially from appendage joints and analyzed for radioactivity and chemical composition. Separate groups of lobsters were dissected at 0.5, 4, and 24 hr after the 0.1-mg/kg dose to collect urine and tissue samples. Tank water was collected at 0.5 hr and analyzed. Phenol concentrations decreased rapidly in hemolymph (alpha t1/2 = 8.7 min, beta t1/2 = 14.0 min) and part of the dose was excreted through gills into tank water as parent phenol in the first 30 min. The percentage of each dose excreted through the gills increased with increasing dose up to greater than 90% at greater than 2 mg/kg. The phenol that was not excreted through gills was rapidly conjugated with sulfate in the antennal glands and possibly other sites. In both male and female lobsters, phenyl sulfate was eliminated from hemolymph much more slowly than parent phenol. The terminal elimination half-life of phenyl sulfate was slower in females (t1/2 = 11.9 hr) than in males (t1/2 = 6.3 hr). The [14C] present in urine collected 24 hr after the dose consisted primarily of phenyl sulfate (greater than 97%) with traces of phenyl beta-D-glucoside (0.1-3%). Thus, in the lobster, metabolism of phenol to polar conjugates did not enhance elimination from the animal.

[Neolignans from Piper polysyphorum C.DC].

Piper polysyphorum C.DC (Piperaceae) is indigenous to the southern part of China. In the course of screening for inhibitors of platelet activating factor (PAF), the nonpolar fraction was found to exhibit PAF inhibitory activity. One new neclignan named polysyphorin and three new enantiomeric forms of (+)-virolongin, (+)-grandisin and (+)-lancifolin D were isolated. Two known neolignans, wallichinine and hancinone D were also obtained from the same sources. The structure determination was based upon spectroscopic analysis (UV, IR, CD, MS, 1HNMR, 13CNMR, COSY) and derivative preparation. The structure for polysyphorin was established as threo-delta 7'-7-hydroxy-3,4,5,3',5'-pentamethoxy-8-O-4' -neolignan. It is a racemic enantiomer. The PAF inhibitory activities were reported.

[The isolation and identification of PAF inhibitors from Piper wallichii (Miq.) Hand-Mazz and P. hancei Maxim].

Platelet activating factor (PAF) is a highly potent endogenous phospholipid mediator, involved in various inflammatory and cardiovascular disorders. As part of a research program dealing with PAF inhibitors isolated from Piper plant species, we have isolated kadsurenone (I), denudatin B (II), and N-isobutyl-deca-trans-2-trans-4-dienamide (III) from Piped wallichii (Miq.) Hand-Mazz. and P. hancei Maxim. In a continuing search for potential PAF inhibitor from plants, using PAF induced platelet aggregation as a guide, a new neolignan named hancinone D (IV) was isolated from P. hancei maxim. By X-ray analysis it was identified as a racemate. The X-ray analysis led to a revision of the previously made structure assignment of hancinone C. Another new neolignan named wallichinine (V), which was identified as an analogue of (IV), along with the known compounds hancinone C (VI), galgravin (VII), dihydropiperlonguminine (VIII) and crotepoxide (IX) were isolated from P. wallichii (Miq.) Hand-Mazz. The structure determination was based upon spectroscopic analysis. All of the compounds were for the first time obtained from both plants. In the test of platelet aggregation caused by PAF, I, II, V, VI, VII showed inhibitory activity, whereas III, IV, VII, IX showed no activity.

Resibufogenin-induced delayed afterdepolarization in rabbit heart in situ.

The pharmacological effects of resibufogenin (RGB), an effective cardiotonic obtained from a famous traditional Chinese medicine, on the electrical activity of the rabbit heart (n = 12) in situ were studied by using a new technique of recording monophasic action potential (MAP). RBG (0.3 mg/kg IV) induced DAD in 3/12 animals. DAD appeared within the first 0.5 to 1 min after RBG and lasted about 20-30 min. The position of DAD was in the end of phase 3 of MAP. The DADs of rabbit epicardium showed a transient, regular and phasic depolarization process. The triggered arrhythmias were not recorded in these experiments, as amplitudes of DAD were lower and did not reach the threshold. The results indicate that DADs are induced by RBG at first time in situ in rabbits. The characteristics of DAD were similar to those previously described in single cardiac fibers in vitro.