Biomedical subjects

Danilo Castellani

Publications and source records attributed to Danilo Castellani.

7 recordsLinked to original sources

PubMed2006

3alpha-6alpha-Dihydroxy-7alpha-fluoro-5beta-cholanoate (UPF-680), physicochemical and physiological properties of a new fluorinated bile acid that prevents 17alpha-ethynyl-estradiol-induced cholestasis in rats.

3alpha-6alpha-Dihydroxy-7alpha-fluoro-5beta-cholanoate (UPF-680), the 7alpha-fluorine analog of hyodeoxycholic acid (HDCA), was synthesized to improve bioavailability and stability of ursodeoxycholic acid (UDCA). Acute rat biliary fistula and chronic cholestasis induced by 17alpha-ethynyl-estradiol (17EE) models were used to study and compare the effects of UPF-680 (dose range 0.6-6.0 micromol/kg min) with UDCA on bile flow, biliary bicarbonate (HCO(3)(-)), lipid output, biliary bile acid composition, hepatic enzymes and organic anion pumps. In acute infusion, UPF-680 increased bile flow in a dose-related manner, by up to 40.9%. Biliary HCO(3)(-) output was similarly increased. Changes were observed in phospholipid secretion only at the highest doses. Treatment with UDCA and UPF-680 reversed chronic cholestasis induced by 17EE; in this model, UDCA had no effect on bile flow in contrast to UPF-680, which significantly increased bile flow. With acute administration of UPF-680, the biliary bile acid pool became enriched with unconjugated and conjugated UPF-680 (71.7%) at the expense of endogenous cholic acid and muricholic isomers. With chronic administration of UPF-680 or UDCA, the main biliary bile acids were tauro conjugates, but modification of biliary bile acid pool was greater with UPF-680. UPF-680 increased the mRNA for cytochrome P450 7A1 (CYP7A1) and cytochrome P450 8B (CYP8B). Both UDCA and UPF-680 increased the mRNA for Na(+) taurocholate co-transporting polypeptide (NCTP). In conclusion, UPF-680 prevented 17EE-induced cholestasis and enriched the biliary bile acid pool with less detergent and cytotoxic bile acids. This novel fluorinated bile acid may have potential in the treatment of cholestatic liver disease.

Animals↗

PubMed2006

Colonic propulsive and postprandial motor activity in patients with ulcerative colitis in remission.

BACKGROUND: Although it is known that colon motility is abnormal in ulcerative colitis, data are still scarce with regard to the underlying mechanisms. Recent evidence suggests that the propulsive activity is highly increased during the active phase of the disease, probably contributing to the diarrhoea. However, data are even scarcer in the quiescent phase of the disease. AIMS: To assess the colonic high-amplitude and low-amplitude propulsive activity and the colonic motor response to eating in patients with ulcerative colitis in remission. PATIENTS AND METHODS: Fourteen patients were recruited, all with the disease in remission as documented by clinical and endoscopic criteria. Twenty-four hour manometric recordings were obtained in these patients, and compared to those of 16 healthy controls. RESULTS: The high-amplitude propagated contractions were similar in both groups (5.8+/-2.6 events in ulcerative colitis patients and 5.5+/-0.8 in controls (P=0.13)), whereas patients tended to display a higher number of low-amplitude propagated events (134.4+/-34 vs. 60.9+/-16 in controls (P=0.058)). No differences were found in the colonic motor response to eating between patients and controls. CONCLUSIONS: Colonic propulsive activity in ulcerative colitis in remission is almost normal, even though the low-amplitude propagated activity tends to be similar to that observed in patients with the irritable bowel syndrome, thus possibly contributing to the persistence of abdominal symptoms in a subgroup of patients.

Adult↗

PubMed2005

Normal aspects of colorectal motility and abnormalities in slow transit constipation.

Human colonic motility is a relatively difficult topic to investigate. However, the refinement of manometric techniques in recent years enabled us to study both the proximal and distal segments of the viscus. The present paper reviews our knowledge about normal aspects of colorectal motility in man and the abnormalities found in slow transit constipation (STC), one of the most frequent and difficult to treat subtypes of constipation. An internet-based search strategy of the Medline and Science Citation Index was performed using the keywords colon, colonic, colorectal, constipation, slow transit, motility, rectal, rectum in various combinations with the Boolean operators AND, OR and NOT. Only articles related to human studies were used, and manual cross-referencing was also performed. Most of colonic motor activity is represented by single nonpropagated contractions, rarely organized in bursts; this activity is maximal during the day, especially after waking and following meals. In addition, a specialized propagated activity with propulsive features is detectable, represented by high- and low-amplitude propagated contractions. In the severe form of constipation represented by the slow transit type, the above motor activity is completely deranged. In fact, both basal segmental activity (especially in response to meals) and propagated activity (especially that of high amplitude) are usually decreased, and this may represent a physiologic marker of this disorder. Human colonic motor activity is quite a complex issue, still only partly understood and investigated, due to anatomic and physiological difficulties. In recent years, however, some more data have been obtained, even in proximal segments. These data have helped in elucidating, although only in part, some pathophysiological mechanisms of chronic constipation, and especially of the STC subtype.

Colon↗

PubMed2005

Protective effects of 6-ethyl chenodeoxycholic acid, a farnesoid X receptor ligand, in estrogen-induced cholestasis.

The farnesoid X receptor (FXR), an endogenous sensor for bile acids, regulates a program of genes involved in bile acid biosynthesis, conjugation, and transport. Cholestatic liver diseases are a group of immunologically and genetically mediated disorders in which accumulation of endogenous bile acids plays a role in the disease progression and symptoms. Here, we describe the effect of 6-ethyl chenodeoxycholic acid (6-ECDCA or INT-747), a semisynthetic bile acid derivative and potent FXR ligand, in a model of cholestasis induced by 5-day administration of 17alpha-ethynylestradiol (E(2)17alpha) to rats. The exposure of rat hepatocytes to 1 microM 6-ECDCA caused a 3- to 5-fold induction of small heterodimer partner (Shp) and bile salt export pump (bsep) mRNA and 70 to 80% reduction of cholesterol 7alpha-hydroxylase (cyp7a1), oxysterol 12beta-hydroxylase (cyp8b1), and Na(+)/taurocholate cotransporting peptide (ntcp). In vivo administration of 6-ECDCA protects against cholestasis induced by E(2)17alpha. Thus, 6-ECDCA reverted bile flow impairment induced by E(2)17alpha, reduced secretion of cholic acid and deoxycholic acid, but increased muricholic acid and chenodeoxycholic acid secretion. In vivo administration of 6-ECDCA increased liver expression of Shp, bsep, multidrug resistance-associated protein-2, and multidrug resistance protein-2, whereas it reduced cyp7a1 and cyp8b1 and ntcp mRNA. These changes were reproduced by GW4064, a synthetic FXR ligand. In conclusion, by demonstrating that 6-ECDCA protects against E(2)17alpha cholestasis, our data support the notion that development of potent FXR ligands might represent a new approach for the treatment of cholestatic disorders.

Animals↗

PubMed2005

S-equol, a potent ligand for estrogen receptor beta, is the exclusive enantiomeric form of the soy isoflavone metabolite produced by human intestinal bacterial flora.

BACKGROUND: The discovery of equol in human urine more than 2 decades ago and the finding that it is bacterially derived from daidzin, an isoflavone abundant in soy foods, led to the current nutritional interest in soy foods. Equol, unlike the soy isoflavones daidzein or genistein, has a chiral center and therefore can occur as 2 distinct diastereoisomers. OBJECTIVE: Because it was unclear which enantiomer was present in humans, our objectives were to characterize the exact structure of equol, to examine whether the S- and R-equol enantiomers are bioavailable, and to ascertain whether the differences in their conformational structure translate to significant differences in affinity for estrogen receptors. DESIGN: With the use of chiral-phase HPLC and mass spectrometry, equol was isolated from human urine and plasma, and its enantiomeric structure was defined. Human fecal flora were cultured in vitro and incubated with daidzein to ascertain the stereospecificity of the bacterial production of equol. The pharmacokinetics of S- and R- equol were determined in 3 healthy adults after single-bolus oral administration of both enantiomers, and the affinity of each equol enantiomer for estrogen receptors was measured. RESULTS: Our studies definitively establish S-equol as the exclusive product of human intestinal bacterial synthesis from soy isoflavones and also show that both enantiomers are bioavailable. S-equol has a high affinity for estrogen receptor beta (K(i) = 0.73 nmol/L), whereas R-equol is relatively inactive. CONCLUSIONS: Humans have acquired an ability to exclusively synthesize S-equol from the precursor soy isoflavone daidzein, and it is significant that, unlike R-equol, this enantiomer has a relatively high affinity for estrogen receptor beta.

Animals↗

PubMed2004

Pseudo-pseudo-obstruction.

Chronic intestinal pseudo-obstruction is a clinical syndrome characterised by symptoms and signs of intestinal obstruction in the absence of a mechanical lesion of the intestinal lumen. The diagnosis is often difficult and relies on clinical, radiological and manometric grounds. We present here a case in which such a diagnosis was suspected, but a thorough in-depth evaluation revealed that the symptoms were due to a treatable cause--abdominopelvic adhesions.

Abdominal Pain↗

PubMedDate not supplied

Treatment with all-trans retinoic acid plus tamoxifen and vitamin E in advanced hepatocellular carcinoma.

BACKGROUND: Low serum retinol and hepatic tocopherol levels correlate with hepatocellular carcinoma (HCC) risk. Antiestrogen tamoxifen seems useful in HCC patients. A pilot study was performed to evaluate the effect of all-trans retinoic acid associated with tamoxifen and vitamin E on patients with advanced HCC. PATIENTS AND METHODS: Fifteen consecutive patients with advanced HCC were included in the study. Patients were evaluated for survival, quality of life, liver function, tumor mass, toxicity related to the treatment and retinoid receptors in liver biopsies. RESULTS: The median survival of our patients was 22 months. Pain and asthenia were improved in the majority of patients. Every patient with baseline elevated liver enzymes showed an improvement in liver function. RAR-alpha, RXR-alpha, RAR-beta and RAR-gamma receptors were demonstrated in 100%, 73%, 47% and 40%, respectively. CONCLUSION: A combination therapy of all-trans retinoic acid, tamoxifen and vitamin E increases the survival rate and ameliorates the clinical outcome in patients with inoperable HCC.

Aged↗