Effects of pretreatment with SKF-525A on triphenyltin metabolism and toxicity in mice.

The effects of cytochrome P-450 inhibition by alpha-phenyl-alpha-propylbenzeneacetic acid 2-[diethylamino]-ethyl ester hydrochloride (SKF-525A), which inhibits the activity of a number of cytochrome P-450s, on triphenyltin metabolism and toxicity in mice were studied. At 24 h after triphenyltin administration, the triphenyltin levels in the tissues of SKF-525A-pretreated mice were about three times of those in the tissues of SKF-525A-untreated mice and the ratio of metabolites to parent triphenyltin in the tissues of SKF-525A-pretreated mice was lower than those in the tissues of SKF-525A-untreated mice. These data indicate that the pretreatment of SKF-525A decelerated the triphenyltin metabolism and increased triphenyltin accumulation in the tissues of mice. Although triphenyltin did not affect plasma glucose levels of in the SKF-525A-untreated mice, the triphenyltin produced marked hyperglycemia in SKF-525A-pretreated mice. These results suggest that the inhibition of cytochrome P-450 system enzymes by SKF-525A affects the metabolism and toxicity of triphenyltin and has a key role in inducing the hyperglycemic action of triphenyltin, i.e. by increasing triphenyltin accumulation in the mice.

Effects of pretreatment with cytochrome P-450 inducers, especially phenobarbital on triphenyltin metabolism and toxicity in hamsters.

The effects of cytochrome P-450 (CYP) induction by phenobarbital (PB), CYP 2B, 2C, and 3A inducer in mammalians, on triphenyltin metabolism and toxicity in hamsters were studied. A single dose of 50 mg/kg of triphenyltin chloride was given by gavage to hamsters after pretreatment with or without PB for 3 days continuously at a daily dose of 80 mg/kg intraperitoneally (i.p.). Although the triphenyltin produced marked but reversible hyperglycemia and hypertriglyceridemia in PB-untreated hamsters, the pretreatment of hamsters with PB, which increased levels of CYP, suppressed the diabetogenic effects compared with PB-untreated hamsters. Furthermore, we investigated whether the mitigation of triphenyltin-induced diabetogenic toxicity by PB pretreatment is due to an alteration of triphenyltin metabolism. Triphenyltin and its metabolites in liver, kidneys, pancreas and brain were determined by gas chromatography periodically for 96 h after triphenyltin administration in both groups of hamsters. The initial triphenyltin levels in the tissues of PB-pretreated hamsters were about half of those in the tissues of PB-untreated hamsters and PB pretreatment accelerated metabolism of triphenyltin at early stage in hamsters. We also examined the other CYP 1A and 2A inducers, beta-naphthoflavone (B-NF) and 3-methylcholanthrene (MC). The PB pretreatment showed the strongest suppression of the toxicity at 24 h after the triphenyltin intubation, compared with the effects of B-NF and MC. In addition, the maximum proportion of diphenyltin to parent triphenyltin in pancreas was observed in PB-treated hamsters. These findings suggest that the induction of CYP system enzymes affects the metabolism and toxicity of triphenyltin in hamsters. Especially, based on effects of PB and other CYP inducers, PB induction has a key role in suppressing the diabetogenic action of triphenyltin, i.e. by decreasing triphenyltin accumulation in the hamsters.

Advanced endocrine cell carcinoma of the gallbladder: a patient with 12-year survival.

Gallbladder carcinoid is a rare disease. In previous reports, classical carcinoid, an entity with a good prognosis, has not been distinguished from endocrine cell carcinoma, a tumor associated with marked cell atypia and mitosis, and a poor prognosis. The patient was a 66 year old woman who presented to our hospital with a chief complaint of jaundice. Pre-operatively, she was diagnosed as having advanced gallbladder carcinoma invading the liver and the hepatic hilus. The patient underwent right hepatic trisegmentectomy with en bloc resection of the caudate lobe and extrahepatic bile ducts, extended lymph node clearance and left hepaticojejunostomy. Histopathological examination showed positive Grimelius staining, marked mitosis, and intense atypism, hence, the tumor was diagnosed as an endocrine cell carcinoma. Twelve years after surgery, the patient is healthy, without any sign of recurrence. We present this novel case of long-term survival and review the literature.

Influence of hyperlipidemia and smoking on age-related changes in caloric response and pure-tone hearing.

To examine the influence of hyperlipidemia and smoking on age-related changes in caloric response and pure-tone hearing, a caloric test and pure-tone audiometry were performed in 14 healthy volunteers and in 78 tinnitus patients without subjective hearing loss. The patients were from 24 to 84 years of age, and were divided into 4 groups: the no-risk group (N group), the smoking alone group (S group), the hyperlipidemia alone group (L group), and the smoking plus hyperlipidemia group (S-L group). Slow phase eye velocity of the caloric nystagmus (SPEV) and average hearing level at high frequencies were compared between the N groups and the other groups. There was a significant difference in SPEV only between the N and S-L groups, but not in the hearing level. This suggests that age-related changes in the caloric response be promoted by atherosclerosis, unlike presbycusis.

Subchronic study of the metabolism of triphenyltin in hamsters.

In previous studies we investigated the metabolism of tin compounds in rats and hamsters following single oral treatments with triphenyltin. The objective of this study was to provide information on the metabolism of triphenyltin in hamsters subchronically treated with dietary triphenyltin for 180 d. Groups were fed diets containing 3 different triphenyltin concentrations: 1.28, 28.82 or 54.77 ppm. The 28.82 and 54.77 ppm groups gained less body weight than the control and 1.28 ppm groups. However, none of the animals showed characteristic symptoms. We detected triphenyltin and its metabolites in the tissues of dosed hamsters. Highest tin concentrations were in livers and kidneys, as diphenyltin and inorganic tin respectively; no significant amounts of triphenyltin were found. Triphenyltin was metabolized relatively rapidly in the hamsters. There was more tin relative to the administered triphenyltin in the livers of the low dietary group compared to the high dietary triphenyltin group. This suggests that low concentrations of triphenyltin are easily absorbed from the gastrointestinal tract. While we previously demonstrated that acutely dosed triphenyltin produced marked hyperglycemia in hamsters, this was not found in the hamsters repeatedly dosed with dietary triphenyltin in the present study.

Comparative study of the metabolism of triphenyltin in hamsters and rats after a single oral treatment with triphenyltin chloride.

Our previous work has shown that triphenyltin compound induces the diabetogenic effects, such as hyperglycemia and hypertriglyceridemia, on hamsters, but not on rats. In the present study, it is examined whether the species differences in the metabolic fate of triphenyltin exist for susceptibility between hamsters and rats. Triphenyltin chloride was orally dosed to hamsters and rats, and triphenyltin and its metabolites, mono- and diphenyltin, and inorganic tin, in liver, kidney, pancreas, brain, and blood were determined by gas chromatography periodically for 96 h after the treatment. Triphenyltin levels in the tissues of both species were almost maxima within 24 h after treatment. Although there were relatively high levels of triphenyltin in the tissues of hamsters dosed with triphenyltin chloride, compared with those in the rats, the proportion of metabolites to triphenyltin were lower than those in the rats. In particular, hamsters were more susceptible than rats to the pancreatic accumulations of triphenyltin and good correlation exists between the tin concentrations in the pancreas and the plasma glucose levels in triphenyltin-treated hamsters. These findings suggest that the dearylation of absorbed triphenyltin in hamsters is slower than that in rats and that triphenyltin-induced hyperglycemic action depends upon the amount of tin compounds absorbed into the pancreas. Furthermore, most of the tin compounds in the brains of both species were triphenyltin. This result shows that the metabolism of triphenyltin in the brains of both species was different from that in other tissues.

Gas chromatographic determination of inorganic tin in rat urine after a single oral administration of stannous chloride and mono-, di-, and triphenyltin chloride.

A method is described for the determination of inorganic tin by gas chromatography with flame photometric detection. The inorganic tins, stannous and stannic, were extracted with hydrochloric acid and n-hexane-benzene in the presence of 0.05% tropolone, and both inorganic tins were pentylated to tetrapentyltin with a Grignard reagent prior to gas chromatography. The absolute limit of detection for tetrapentyltin was 3 pg as tin. The recovery of stannous chloride added to rat urine samples was 80.2 +/- 2.4% (mean +/- S.D., n = 8). The application of this method to the study of urinary excretion of inorganic tin and organotin compounds in rats following oral administration of tin compounds is presented. The urinary excretion of tin compounds was observed over a period of 96 h following administration of stannous chloride or phenyltin compounds. Most of the inorganic tin was excreted into urine within 24 h after administration of stannous chloride. In the experiments on organotin administration, the level of the excretion as total tin for monophenyltin reached a maximum ca. 0-24 h after administration, whereas the maxima for di- and triphenyltin were found after 24-48 h and 48-72 h, respectively. The predominant excretion product of these tin compounds found in urine was monophenyltin.

Application of gas chromatographic determination of organotin compounds to basic research on the metabolism of triphenyltin chloride in rats.

This paper describes the application of gas chromatographic determination of organotin compounds to basic research on the metabolism of triphenyltin chloride in rats. Phenyltin compounds were extracted (as chloride) from rat-liver homogenates and subcellular fractions with hydrochloric acid and n-hexane-benzene (3:2, containing 0.05% tropolone). These organotin compounds were pentylated with a Grignard reagent prior to capillary gas chromatography. The absolute detection limits were in the range of 3.6 to 4.4 pg as tin. The absolute recoveries of phenyltin compounds added to homogenized whole liver and each subcellular fraction sample ranged from 73.9 to 97.4%. The intracellular distribution of triphenyltin and its metabolites in the liver was observed for 72 h after a single oral dose of triphenyltin chloride was given to rats. The tri-, di-, and monophenyltin compounds in the fractions reached maximal amounts about 6, 48, and 72 h after administration, respectively. Also, the concentrations of monophenyltin compounds in the liver were typically lower than to those of di- and triphenyltin compounds. The highest contents of di- and triphenyltin compounds per protein were found in the microsomal fractions.

Comparison of sulphur-mode and tin-mode flame photometric detectors for the gas chromatographic determination of organotin compounds.

A comparison of sulphur-mode (393 nm) and tin-mode (610 nm) flame photometric detectors for the gas chromatographic determination of butyl- and phenyltin compounds is described. The chromatographic peaks of the butyl- and phenyltin compounds were well separated, and high sensitivity was achieved in both modes; however, the tin-mode was more specific for tin compounds than the sulphur-mode. The absolute detection limits with the sulphur-mode and the tin-mode were 3.9-7.6 pg and 2.6-5.1 pg as tin, respectively. The application of the tin-mode gas chromatographic method to the determination of organotin compounds in fish is presented. For this application, organotins are extracted (as chloride) with hydrochloric acid and n-hexane-benzene (3:2, containing 0.05% tropolone) and the extracts are pentylated by a Grignard reagent prior to gas chromatography. The absolute recoveries of butyl- and phenyltin compounds added to fish samples ranged from 68.5 to 84.4% (the coefficients of variation were less than 6.6% for all substances, n = 8). Significant amounts of three organotin compounds (di- and tributyltin and triphenyltin) in fish samples were detected by this method. This technique may have application for other organotin compounds and the monitoring of butyl- and phenyltin compounds in the environment.

Simultaneous determination of butyltin and phenyltin compounds in oysters by capillary gas chromatography.

A method is described for the simultaneous determination of butyl- and phenyltin compounds in oyster samples. The organotin compounds were extracted (as chlorides) from oyster homogenates with hydrochloric acid and benzene in the presence of 0.05% tropolone. These compounds were converted into pentyl derivatives with pentyl Grignard reagent and then analysed by capillary gas chromatography with a flame photometric detector equipped with a 393-nm filter. The recoveries of six organotin compounds added to oyster samples ranged from 71 to 74%. The detection limits of butyl- and phenyltin compounds were in the 5-9 pg range as tin. We detected significant amounts of three organotin compounds (di- and tributyltin and triphenyltin) in oyster samples.

Clinical study on bacteria detected in the upper and lower respiratory tracts in patients with sinobronchial syndrome.

The authors examined bacteria to confirm the pathogenesis of sinobronchial syndrome (SBS). There were several theories such as the pus-descending, the pus-ascending, the coinciding theory and so on. Detection of bacteria was performed in SBS patients, empyema patients with no lower respiratory disease, and healthy adults. Considering SBS bacteriologically from the obtained results, the authors consider that internal infections of aerobic gram-negative bacteria of the normal flora mainly including Haemophilus influenzae possibly develop in two directions, downward and upward (into nasal cavities) from the pharynx, and so the pathogenesis of SBS might not be explained satisfactorily by either the ascending or the descending theory alone.

[Simultaneous determination of tributyltin and its metabolites, dibutyltin and monobutyltin, in biological materials by capillary gas chromatography].

Determination of tributyltin and its metabolites, dibutyltin and monobutyltin, in biological materials was made by capillary gas chromatography (C-GC) using a flame photometric detector (FPD). Butyltin compounds (BuTC) were extracted (as bromides) from tissue homogenates with hydrobromic acid and ethyl acetate. These compounds were converted to pentyl derivatives with pentyl Grignard reagent and then analysed by C-GC. The recoveries of each BuTC added to tissues were 96-99% for monobutyltin, 87-93% for dibutyltin and 90-93% for tributyltin. The detection limit of BuTC was 4-5 pg as tin. This method was applied to the analysis of BuTC in the liver and kidney of rats orally administered tributyltin chloride. Time course of three BuTC showed that the maximum value appeared 24 h after administration of the tin compound, which was followed by a rapid decrease. The order of the concentration of BuTC in both organs was dibutyltin greater than tributyltin greater than monobutyltin. The rate of dealkylation was more rapid in liver than in kidney.

[Determination of dibutyltin compounds in polyvinyl chloride resin by capillary gas chromatography].

Dibutyltin compounds (DBTC) in polyvinyl chloride resin (PVC) were examined by capillary gas chromatography using a flame photometric detector (FPD). DBTC was extracted with a carbon tetrachloride-methanol (2:1) mixture under reflux. The extract was mixed with a hydrobromic acid solution. Dibutyltin dibromide was converted to dibutyldipentyltin (DBDPeT) by the Grignard reaction with pentylmagnessium bromide and then subjected to gas chromatography. A linear correlation between the amount of tin and peak height was observed in the range of 7.8 to 250 pg of tin on log-log paper. Recoveries of DBTC added to PVC were 92.6-108.1%. The results show that this procedure is more useful and sensitive (the detection limit is 3-4 pg, as tin) than previous methods reported.

Follow-up study of reconstructed auricle in microtia: comparison of the results of the rib cartilage framework and the silicone rubber framework methods.

Plastic surgery for microtia had achieved fairly consistent good results since TANZER (Plast. Reconstr. Surg. 23: 1-15, 1959) and recently the modified methods have become popular. The authors did plastic surgery of auricles with the rib cartilage framework method from 1968 until 1986, and with the silicone rubber framework method from 1975 until 1986, and observed each postoperative course for 2 to 10 years. The operative results and the merits and the demerits of each method are reported here. The subjects were 49 ears for the rib cartilage framework method (17 of the former period, 1968-1977, and 32 of the latter, 1978-1986), and 20 ears for the silicone rubber framework method. The operation was performed in 3 stages according to the modified Tanzer's method. The results of operations were subjectively assessed as "satisfied," "fairly satisfied," "a little unsatisfied," and "unsatisfied." The results were as follows: 1) in the rib cartilage framework method, there were 21 satisfied cases (43%), 17 fairly satisfied cases (35%), and 5 unsatisfied cases (10%); 2) there were 8 satisfied cases (40%), 5 fairly satisfied cases (25%), and 6 unsatisfied cases (30%) in the silicone rubber framework method. From the aspect of postoperative management, the rib cartilage framework method is now better but the authors expect the silicone rubber framework method will be improved and used more extensively in the future.