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The influence of mast cell activation on the secretion of prolactin has been studied in rats receiving lysophosphatidylserine, a natural occurring phospholipid with secretagogue activity in these cells. After the i.v. injection of lysophosphatidylserine (10 mg/kg) a plasma prolactin peak correlates with an increased blood histamine level. Following the secretory event, which is inhibited by the H1 anti-histamine tripelenamine, plasma prolactin level drops below the basal line. Repeated lysophosphatidylserine administrations induce mast cell desensitisation, thus reducing also the pituitary response. Under these conditions a decrease in prolactin basal level is still observed, although the pituitary stores of this hormone are preserved. Control tests in vitro with lysophosphatidylserine, show that the diacyl lysophosphatidylserine derivative amplifies the inhibitory effect of dopamine on prolactin secretion from isolated pituitaries. The data suggests that lysophosphatidylserine induces prolactin secretion through mast cell activation. After this event, the reacylation of this phospholipid into lysophosphatidylserine in the pituitary membrane may enhance the inhibitory control by dopamine.

The synthesis, binding affinity for estrogen receptor subtypes (ER alpha and ER beta) and pharmacological activity on rat uterus of a new class of potent ligands, characterized by a 3-phenylbenzopyran scaffold with a basic side chain in position 4, are reported. Some of these compounds, endowed with very high receptor affinity, showed potent inhibition of agonist-stimulated uterine growth, with no or limited proliferative effect. Binding affinity mostly depended on the nature and position of substituents at the 3-phenyl ring, while the uterine activity seems to be affected by basic chain length. Compound 9c (CHF4227) showed excellent binding affinity and antagonist activity on the uterus. The docking of benzopyran derivatives explained the structure-affinity relationships observed for 3-phenyl substitution: a small, hydrophobic 4'-substituent could interact with a small accessory binding cavity, while di-substitution at 4' and 3' led to some ER alpha selectivity. This selectivity can be ascribed to differences in amino acid composition and side chain conformation in the region accommodating the 3-phenyl ring at human ER alpha and ER beta ligand-binding domain.

We have identified a new benzopyran derivative, 3-(4-methoxy) phenyl-4-[[4-[2-(1-piperidinyl)ethoxy]phenyl]methyl]-2H-1-benzopyran-7-ol hydrochloride (CHF 4227), with improved in vivo estrogen agonist/antagonist effects. CHF 4227 binds with high affinity to the human estrogen receptor-alpha and -beta (dissociation constant K(i) = 0.017 and 0.099 nM, respectively). In immature rats, oral administration of CHF 4227 for 3 days inhibited the uterotrophic action of 17alpha-ethynyl estradiol (EE2) (ED(50) = 0.016 mg/kg. day); raloxifene was 25 times less potent as estrogen antagonist (ED(50) = 0.39 mg/kg. day), whereas both compounds were found to be devoid of uterotrophic activity. In line with its estrogen antagonist effect, CHF 4227 significantly prevented the development of dimethylbenz[a]anthracene (DMBA)-induced mammary tumors, the incidence being reduced from 87.5 to 26.3% 6 months after DMBA administration. In ovariectomized (OVX) rats treated orally for 4 weeks, CHF 4227 completely inhibited OVX effects on bone density (ED(50) = 0.003 mg/kg. day) and on serum osteocalcin levels. The protective effects on bone were comparable with those achieved with EE2, whereas raloxifene was less efficacious and 100 times less potent. CHF 4227 reduced serum cholesterol (ED(50) = 0.007 mg/kg. day) and had little to no stimulatory effects on uterine weight, uterine peroxidase activity, and endometrium epithelial thickness. In conclusion, CHF 4227 compares favorably in efficacy and potency with raloxifene in preventing bone loss and in antagonizing EE2 stimulation of the uterus. This profile along with the minimal uterine stimulation suggests a therapeutic advantage to CHF 4227 over EE2 or raloxifene for the treatment of postmenopausal women.

We have discovered a new, nonsteroidal, estrogen agonist/antagonist, 3-phenyl-4-[[4-[2-(1-piperidinyl)ethoxy]phenyl] methyl]-2H-1-benzopyran-7-ol (CHF 4056). The aim of this study was to determine the effects of CHF 4056 on a series of parameters (body weight, uteri, serum cholesterol, and bones) that were previously shown to be sensitive to estrogens and to selective estrogen receptor modulators (SERMs). CHF 4056 is a benzopyran derivative that binds with high affinity to the human estrogen receptors alpha and beta (dissociation constant K(i) of 0.041 and 0.157 nM, respectively). In immature rats, CHF 4056 induced a full estrogen antagonism (half-maximal efficacious dose = 0.33 mg/kg x day p.o.) coupled with a lack of uterine stimulatory activity, whereas the structurally related SERM levormeloxifene demonstrated a maximal partial agonist effect of approximately 65% that of 17alpha-ethynyl estradiol (EE2). In ovariectomized (OVX) rats, CHF 4056 (0.1-1 mg/kg x day p.o. for 4 weeks) significantly reduced OVX-induced bone loss in the lumbar spine L1-4 and OVX-induced increase in serum osteocalcin. These protective effects on bone tissue were comparable with those of 0.1 mg/kg x day EE2. In the same experimental conditions, serum cholesterol was significantly lower in the CHF 4056-treated animals, compared with vehicle-treated OVX rats. In line with the results observed in immature rats, also in OVX rats CHF 4056 diverged dramatically from EE2 and levormeloxifene in its lack of significant estrogenic effects on uterine tissue. In conclusion, CHF 4056 is a new SERM that produces beneficial effects on bone and cholesterol levels, while maintaining antagonist effects on the uterus.

Cysteine-containing leukotrienes (cysteinyl-LTs) are potent bronchoconstrictors and play a key role in asthma. We found that histamine and LTD4 markedly constrict strips of human bronchi (HB) with similar efficacy. However, in human airway smooth-muscle (HASM) cells, LTD4, at variance with histamine, elicited only a small, transient change in intracellular calcium ion concentration. HASM cells express both Ca2+-dependent and -independent isoforms of protein kinase C (PKC) (i.e., PKC-alpha and PKC-alpha ). Western blot analysis showed that PKC-alpha is activated by histamine and, to a lesser extent, by LTD4, whereas only LTD4 translocates PKC-alpha. This translocation was specifically inhibited by the LTD4 antagonist pobilukast. Phorbol-dibutyrate ester (PDBu) (a PKC activator) contracted HB strips to the same extent in the presence as in the absence of extra- and intracellular Ca2+. In the absence of Ca2+, LTD4 contracted HB strips to the same extent as did PDBu, suggesting the involvement of a Ca2+-independent PKC in LTD4-mediated signal transduction. PDBu-induced desensitization and the PKC inhibitor H7 abolished the slow and sustained LTD4-triggered contraction of HB strips in the absence of Ca2+, although H7 did not greatly affect the response in the presence of the ion. Thus, in human airways, we identified a novel LTD4 transduction mechanism linked to bronchial smooth-muscle contraction, which is partly independent of Ca2+ and involves the activation of PKC-alpha.

The rareness of the illness and the infrequency of infectious complications have led the authors to report a case which has come to their attention. After a brief exam of the etiopathogenesis and pathologic anatomy of these hepatic forms of cyst and the following considerations on their clinical aspects, which range from complete lack of symptoms to the compression of nearby organs (gall ducts, stomach, kidney) due to an increase in their volume, to occurrence of complications (rupture, haemorrhage, suppuration), the authors evaluate the therapeutic problem. Emptying and internal drainage being nowadays discarded and everyone agree on the necessity of excising the whole cystic wall with the minimum loss of hepatic parenchyma, the most indicated operation is total cystectomy. As such an operation is not always feasible because of the adherences of the cyst to the hepatic parenchyma; partial cystectomy can be practiced, leaving in situ part of the cystic wall. If the cyst is complicated by rupture, haemorrhage or suppuration, typical or atypical hepatic resection is recommended. The reported case concerns a patient in good general conditions, bearer of a large left hepatic lobe cyst, complicated by suppuration, with normal liver function, who has been submitted to ablation of the third hepatic segment according to the Ton That Tung transparenchymal technique. Finally the authors point out the possibility of a new conservative therapeutic approach, practiced in a few centres, consisting in echo or CT guided percutaneous needle suction and sclerosis of the cyst with 95% pure alcohol.

The authors report their experience in the treatment of hemorrhagic duodenal ulcers in 19 patients (17 men, 2 women) between 1972 and 1977. They compare the results obtained with the two methods adopted, namely gastric resection and local hemostasis of the ulcer followed by troncular or selective vagotomy, or selective proximal vagotomy and pyloroplasty. The results so analyzed speak definitely in favor of the latter procedures as opposed to gastrectomy.

After a brief survey of the world literature on echinococcus cysts in the pancreas, a case is described. The peculiar clinical picture as well as treatment are underlined.

The Author reviews 102 cases of primary choledochotomy treated during a 14 years period of biliary surgery; he examines immediate and follow-up results. The excellent results are ascribed parthy for the exactues of indication, parthy to transduodenal sphincteroplasty that had been combined with aforesaid operation in 76% of cases.

3 cases of non-neoplastic gastrojejunocolic fistula are reported. These were treated by mass resection of the fistulous route with the stomach, small intestine and colon segments involved, followed by immediate restoral of intestinal continuity. After examining the aetiopathogenetic aspects of this disease and reporting the various therapeutic proposals, careful preoperative study is considered vital to clarify the cause of the fistula (hypervagotomy, gastrinoma, hyperparathyroidism). On this basis, surgery is then adapted to avert the danger of recurrence.

In a group of 48 patients with chronic pancreatitis the authors investigated the variations of blood insulin content after stimulation with starch and maltose, and compared these changes with the correspondind glycemia values. The two curves, practically matching in normal subjects, tend to diverge considerably in patients with chronic pancreatitis. According to the authors, since the assessment of exocrine pancreas function by common laboratory methods is none too satisfactory, this method may yield better appreciation of extant damage to the pancreas.

The use of non-absorbable suture material during the surgery of the choledochus can be a cause of choledocholithiasis. An interesting case of a female patient who underwent author's observation for recurrent cholangitis with partial pathological obstruction of the common bile duct after cholecystectomy (1948) and choledochotomy for choledocholithiasis (1977) is reported.

The Authors considers 49 cases of perforated duodenal ulcers in free peritoneum, observed in 6 years from 1972 to 1977. They are quite exclusively males (9 : 1), aged from 22 to 80 years, observed from over 4 to 72 hours from effective perforation. After the bare necessities of their hydroelectrolitics balancing, 20 cases came to a simple suture, 29 to an ulcer excision, vagotomy and pyloric plastics. No post operative complications were noted in the two groups: mortality has been of 2 patients in the first group and of no one in the second; pathological ulcerous relaps have been of 47% in the first group and 0 in the second one, with from over 15 months to 6 years controls. By clinical, radiological and andoscopical examinations the AA, concludes that the best therapy treatment in perforated duodenal ulcers--except very particular cases--consists at the same time in the treatment of ulcerous pathology and its complications, with vagotomy completed by piloric plastics sec. Judd, and ulcer's excision.

The present study was undertaken in order to better characterize the functional state of anterior pituitary gland in young and old rats by using prolactin secretion and incorporation of radioactive phosphate into phosphatidylinositol (PI) as markers. The in vitro incorporation of radiolabeled phosphate into anterior pituitary PI was significantly (p less than 0.01) greater in young (3-5 months) than in aged (24-25 months) male Sprague-Dawley rats. No significant difference was found in the incorporation by pituitary tissue of 32P into phosphatidylcholine (PC) and phosphatidylethanolamine (PE). Also, the extent of prolactin secretion from isolated pituitary was significantly greater in young than in aged rats, while the prolactin pituitary content was significantly higher in aged animals. In vitro dopamine (DA) decreased the incorporation of 32P into PI, both in young and old pituitary glands, and inhibited prolactin secretion into the incubation medium. Brain cortex-phosphatidylserine (BC-PS), a pharmacologically active purified phospholipid, capable of stimulating the dopaminergic system in the hypothalamus and of decreasing prolactin secretion both in humans and rats in vitro and in vivo, inhibited the incorporation of labeled phosphate into PI of pituitary glands from either young or old rats, but did not alter the prolactin secretion from the glands incubated in vitro. Baseline prolactin plasma levels did not differ significantly between young and old rats either when blood was collected from the trunk after decapitation or underwent sampling from chronically cannulated rats.(ABSTRACT TRUNCATED AT 250 WORDS)