Endoscopic sphincterotomy for stenosis of the sphincter of Oddi.

BACKGROUND: Sphincter of Oddi dysfunction (SOD) is one of the causes of postcholecytectomy syndrome and biliary pain. Endoscopic sphincterotomy (EST) is recommended in some cases for patients refractory to conservative treatment. By the Milwaukee classification, patients with biliary pain can be divided into three groups. Group I patients show all the objective signs suggestive of a disturbed bile outflow-i.e., elevated liver function tests, dilated common bile duct (CBD), and delayed contrast drainage during endoscopic retrograde cholangio pancreatography (ERCP). Group II patients have biliary-type pain along with one or two of the criteria from group I. Group III patients have only biliary pain, with no other abnormalities. This study confirms the effectiveness of EST for the relief of symptoms in group I patients (papillary stenosis). METHODS: Between 1989 and 1999, we treated eight patients clinically diagnosed as having group I papillary stenosis by EST. Their ages ranged from 52 to 73 years. In addition to biliary pain, all patients were found to have dilated CBD, elevated enzyme levels, and delayed contrast drainage at ERCP. None of the patients had CBD stones or other causes of obstruction. Sphincter of Oddi manometry was not performed. RESULTS: EST was successfully performed in eight patients. Each patient had a very large papilla. A false orifice was found in one patient. In five patients, endoscopic cannulation of the bile duct was very difficult. The use of a long, tapered catheter and guidewire papillotomy was necessary in four patients. A precut papillotomy was performed in one patient. All patients achieved resolution of their symptoms after EST. There were no complications. The average length of the follow-up period was 26 months. CONCLUSIONS: SOD is a real entity that continues to pose a diagnostic dilemma. EST is an effective and safe modality for the treatment of papillary stenosis (group I patients). SOD manometry is not necessary before EST in group I patients.

Reduced serum dehydroepiandrosterone levels in diabetic patients with hyperinsulinaemia.

OBJECTIVE: To elucidate the interaction between insulin and dehydroepi-androsterone (DHEA) concentrations, we evaluated serum DHEA and DHEA-sulphate (DHEA-S) levels in diabetic patients with hyperinsulinaemia. PATIENTS AND DESIGN: Twenty-four subjects with non-insulin dependent diabetes mellitus, 12 hyperinsulinaemic subjects (fasting serum insulin concentrations > or = 10 mU/ml (71.8 pmol/l)) and 12 non-hyperinsulinaemic subjects, and 10 normal control subjects were studied. Serum DHEA, DHEA-S, cortisol and ACTH levels were investigated in these subjects. Moreover, their serum DHEA levels were compared during hyperinsulinaemic-euglycaemic clamp and after ACTH stimulation. MEASUREMENTS: Serum insulin, cortisol, ACTH, DHEA and DHEA-S concentrations were evaluated by RIA. Serum glucose was determined by the glucose oxidase method. RESULTS: Diabetic patients with hyperinsulinaemia showed significantly lower levels of serum DHEA and DHEA-S than controls. After ACTH stimulation, these patients also showed significantly lower DHEA levels. During the hyperinsulinaemic-euglycaemic clamp, serum DHEA concentrations of diabetic patients with hyperinsulinaemia remained low and did not decline further, although those of control subjects and non-hyperinsulinaemic diabetic patients showed a significant decline of serum DHEA levels. Even after ACTH stimulation during the clamp, serum DHEA in hyperinsulinaemic patients was still significantly lower than in controls. CONCLUSIONS: In diabetic patients with hyperinsulinaemia, baseline DHEA levels are chronically and maximally suppressed compared to control subjects and non-hyperinsulinaemic diabetic patients, and thus not decreased further by exogenous insulin infusion during hyperinsulinaemic-euglycaemic clamp.

Wistar fatty rat is obese and spontaneously hypertensive.

The purpose of this study was to determine whether genetically obese Wistar fatty rats have higher blood pressure than their lean littermates and if so to elucidate the mechanism of this obesity-related hypertension. We measured blood glucose and plasma insulin levels, blood pressure, and catecholamine and sodium excretions in age-matched female Wistar fatty and lean rats. After 12 weeks of age, the body weight of Wistar fatty rats was significantly greater than that of their lean counterparts. Fasting blood glucose and plasma insulin concentrations were higher in the fatty than the lean rats throughout the observation period (8 to 24 weeks of age). Systolic blood pressure of fatty rats measured by the tail-cuff method was similar to that of lean rats at 8 weeks of age (135 +/- 2 [mean +/- SEM] versus 134 +/- 3 mm Hg) but significantly higher at 16 (158 +/- 2 versus 136 +/- 3 mm Hg, P < .01) and 24 (166 +/- 5 versus 142 +/- 2 mm Hg, P < .01) weeks of age. Urinary norepinephrine excretion was significantly increased in the fatty rats at both 16 (1755 +/- 173 versus 977 +/- 128 ng/24 h, P < .05) and 24 (1907 +/- 283 versus 737 +/- 173 ng/24 h, P < .01) weeks of age. The ratio of urinary norepinephrine excretion to body weight was also significantly increased in the fatty rats. These results show that with increasing body weight Wistar fatty rats develop hypertension, which may be attributable to an increased sympathetic nerve activity.(ABSTRACT TRUNCATED AT 250 WORDS)

No hypocalcemic action of Stannius corpuscle homogenates in rats.

1. Serum Ca level of goldfish administered with homogenate of the corpuscles of Stannius (CS) taken from 1/3 seawater-acclimated goldfish was significantly lower than that of the control goldfish up to 2 hr after administration. 2. Serum Ca, Mg, Pi, Na and K levels of rats administered with CS homogenates of freshwater eels, 1/3 seawater-acclimated goldfish, or seawater-inhabited wrasse were not statistically different from those of control rats during the 3 hr investigation. 3. It was concluded that in rats, CS homogenates did not decrease the serum mineral levels under the present conditions.

Goldfish calcitonin: purification, characterization, and hypocalcemic potency.

A novel teleost calcitonin was isolated from the goldfish, Carassius auratus, and its amino acid sequence was determined to be H-Cys-Ser-Ser-Leu-Ser-Thr-Cys-Val-Leu-Gly- Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Val-Gly- Ala-Gly-Thr-Pro-NH2. The structure of goldfish calcitonin (gCT) was similar to that of salmon calcitonin (sCT) but differed from the latter at positions 3, 27, and 29. The hypocalcemic activity of gCT was estimated to be 3,470 IU/mg by the standardized rat bioassay method, compared with a value of 3,500 IU/mg for sCT. After administration of gCT to young goldfish, the serum Ca concentration was significantly lower in some cases than in controls. However, in other cases no such difference was recognized.

Synthesis and antitumor activity of new amphiphilic alkylglycerolipids substituted with a polar head group, 2-(2-trimethylammonioethoxy)ethyl or a congeneric oligo(ethyleneoxy)ethyl group.

A new series of amphiphilic 1-octadecyl glycerolipids (eleven compounds, 1a-k) were designed and synthesized, in which the 3-phosphocholine portion of platelet-activating factor (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine, PAF) was replaced by the 2-(2-trimethylammonioethoxy)ethyl group and congeneric groups having oligo(ethyleneoxy)ethyl bridges of various lengths at position 3, together with modification at position 2 (lower alkyl, acetonyl, acetoacetyl, carboxymethyl and pyrimidin-2-yl groups). These ether lipids, characterized by a nonphosphorus lysoglycerolipid structure, showed potent antitumor activity in vitro (human promyelocytic leukemia cells, HL-60, and human epidermoid carcinoma cells, KB) and in vivo (mouse sarcoma S180 and mouse mammary carcinoma MM46). Maximal in vitro potency was obtained with 1-O-octadecyl-2-O-(2-pyrimidinyl)-3-O-[2-(2-trimethylammonioethoxy )ethyl] glycerol (1g; IC50 values for both HL-60 and KB were 0.32 microgram/ml, indicating a higher activity than alkyl-lysophospholipid, ET18-OMe). Several appropriately 2-substituted 1-octadecylglycerolipids with the 3-[2-(2-trimethylammonioethoxy)ethyl] group (e.g., methyl, 1b; butyl, 1f; 2,2,2-trifluoroethyl, 1j; and acetonyl, 1k) showed a potent life-span-prolonging effect on mice with ascites sarcoma S180 and on those with mammary carcinoma MM46, when administered intraperitoneally at 16.5 and 12.5 mg/kg/d, respectively. Compounds 1b and 1k showed definite tumor growth inhibition against solid sarcoma S180 in mice, whether given p.o. or i.v. at 16.5 mg/kg/d. Studies on the structure-activity relationships indicate that the metabolic stability to phospholipase C or related enzymes is at least partly responsible for the potent antitumor activity of this series of ether lipids.

Synthesis and antitumor activity of new alkylphospholipids containing modifications of the phosphocholine moiety.

New antitumor alkylglycerophospholipids, in which primarily the phosphocholine moiety of the platelet activating factor (PAF) molecule was modified, were synthesized from 1-alkyl-2-substituted glycerols by introducing polar head phosphoryl groups having methylene bridges of various lengths (from 2 to 14 carbons). They were tested for PAF agonistic activity and antitumor properties. In a series of 1-octadecyl-2-acetoacetylglycerophospholipids (1a-f), an increase in the length of the methylene bridge separating the phosphate and trimethylammonio group in the polar head side chain at position 3 of the glycerol backbone resulted in a progressive decrease in PAF agonistic activity and a characteristic change in antitumor activity against human promyelocytic leukemia cells (HL-60). Maximal potency was obtained with the compound having a decamethylene bridge (1e, IC50 value = 1.5 microgram/ml). Thus, alkylphospholipids possessing a decamethylene bridge and a variety of substituents at position 2 (1g-n) were synthesized. They showed potent inhibitory activity with IC50 values ranging from 0.4 to 1.9 micrograms/ml, depending on the nature of the 2-substituent in the phospholipid molecule. In in vivo tests of the present series of alkylglycerophospholipids (1a--n), using mice bearing sarcoma 180 and mice with mammary carcinoma MM46 (both cells and compounds were given i.p.), 1-octadecyl-2-acetoacetyl-3-glyceryl omega-trimethylammoniodecyl phosphate (1e) showed the most potent life-prolonging effect. The structure-activity relationships are discussed.

Studies on antianaphylactic agents. 7. Synthesis of antiallergic 5-oxo-5H-[1]benzopyrano[2,3-b]pyridines.

5-Oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylic acids 23 and their tetrazole analogues 24 were synthesized from 4-oxo-4H-1-benzopyran-3-carbonitriles 3 or 2-amino-4-oxo-4H-1-benzopyran-3-carboxaldehydes 4. When administered intravenously, they exhibited antiallergic activity in a reaginic PCA test in rats. In the carboxylic acid series, the activity was influenced by the substituents at the 2-position and increased substantially in the following order: Me, OMe less than NH2 less than OH, H less than NHOMe. On the other hand, in the tetrazole series, 2-unsubstituted derivatives showed the highest activity. Regardless of the kinds of substituents at positions 2 and 3, compounds bearing an alkyl group, especially an isopropyl group at the 7-position, were superior in activity to the corresponding unsubstituted compounds. Among these alkyl derivatives, 3-carboxylic acid derivatives, i.e., 23c (7-ethyl), 23g (2-amino-7-isopropyl), 23r [2-(methoxyamino)-7-isopropyl], and a 3-tetrazole derivative 24c (7-isopropyl), were 41-184 times as potent as disodium cromoglycate. They also exhibited remarkable activity when administered orally; clinical studies on 23g (AA-673) are in progress.

Studies on antianaphylactic agents. 6. Synthesis of some metabolites of 6-ethyl-3-(1H-tetrazol-5-yl)chromone and their analogues.

The metabolites of 6-ethyl-3-(1H-tetrazol-5-yl)chromone (AA-344) (1), an orally effective antiallergic agent, and their analogues were synthesized to confirm the proposed structures and to determine their activity in the rat passive cutaneous anaphylaxis (PCA) test. A glucuronic acid metabolite (6) was assigned the structure 24b, 1-deoxy-1-[5-(6-ethylchromon-3-yl)tetrazol-1-yl]-beta-D-glucopyranuronate, by the comparison of 13C NMR, mass spectra, and TLC of isomeric compounds. In 13C NMR spectra, the shift difference of the tetrazole ring carbons between a pair of isomers was more remarkable than that of the glycosidic carbons. Therefore, the former is a useful criterion for distinguishing between such isomers. Some of the metabolities and analogues were active when administered intravenously, and two metabolites (2 and 3) were also effective upon oral administration.

Studies on antianaphylactic agents. 4. Synthesis and structure-activity relationships of 3-(4-oxo-4H-1-benzopyran-3)acrylic acids, a new series of antiallergic substances, and some related compounds.

The syntheses of trans-3-(4-oxo-4H-1-benzypyran-3)acrylic acid and a number of analogs shown to be highly active in antiallergic bioassays are described. These compounds are of possible value in the treatment of asthma. The structural requirements for biological activity are discussed with reference to the type of the substituents on the chromone ring or positions of linkage of the acrylic acid on the pyrone ring.