Carlo Clerici

Equol: History, Chemistry, and Formation

Equol, first isolated from equine urine in 1932 and identified 50 years later in human urine as a metabolite of the soy isoflavones, daidzin and daidzein, is produced by intestinal bacteria in some, but not all, adults. This observation led to the term equol-producers to define those adults that could make equol in response to consuming soy isoflavones and the hypothesis that the health benefits of soy-based diets may be greater in equol-producers than in equol nonproducers. By virtue of a chiral center, equol occurs as a diastereoisomer and intestinal bacteria are enantiospecific in synthesizing exclusively the S-(-)equol enantiomer, an enantiomer that has selective affinity for the estrogen receptor-beta. Both enantiomers are of interest from a clinical and pharmacological perspective and are currently being developed as nutraceutical and pharmacological agents. The wide range of biological activities these enantiomers possess warrants their investigation for the treatment of a number of hormone-related conditions involving estrogen-dependent and androgen-related conditions. The following review describes the history, chemistry, and factors governing the intestinal bacterial formation of equol.

NCX-1000, a nitric oxide-releasing derivative of ursodeoxycholic acid, ameliorates portal hypertension and lowers norepinephrine-induced intrahepatic resistance in the isolated and perfused rat liver

BACKGROUND/AIMS We studied whether acute administration of NCX-1000, a nitric oxide (NO)-releasing derivative of ursodeoxycholic acid (UDCA), to animals with established liver cirrhosis decreases intrahepatic resistance and modulates hepatic vascular hypereactivity to norepinephrine (NE). METHODS Four-week bile duct ligated (BDL) cirrhotic and control, sham-operated, rats were treated orally with 28 mg/kg per day NCX-1000 or 15 mg/kg per day UDCA for 5 days. Isolated normal and cirrhotic livers were perfused with NE, from 10 nM to 30 microM, in a recirculating system. RESULTS NCX-1000 administration to BDL cirrhotic rats decreased portal pressure (P<0.01) without affecting mean arterial pressure and heart rate. In the isolated perfused liver system, administration of NE resulted in a dose-dependent increase of intrahepatic resistance. Vasoconstriction caused by 30 microM NE was reduced by 60% in animals treated with NCX-1000 (P<0.001), while UDCA was uneffective. The same portal pressure lowering effect was documented in cirrhotic and sham operated rats. Administration of NCX-1000 to BDL and sham operated rats resulted in a similar increase of nitrite/nitrate and cGMP concentrations in the liver. CONCLUSIONS By selectively delivering NO to the liver, NCX-1000 increases cGMP concentrations and effectively counteracts the effect of endogenous vasoconstrictors on the hepatic vascular tone.

Antroduodenojejunal motor activity in untreated and treated celiac disease patients

Background and Aim:  Patients with celiac disease may present with abnormal upper gut motor activity. However, it is not known if these abnormalities persist after the introduction of a gluten‐free diet. The present study aimed to compare antroduodenojejunal motor variables recorded in untreated celiac patients with those of celiac patients given a gluten‐free diet and healthy volunteers.

Effect of intraduodenal administration of 23-methyl-UDCA diastereoisomers on bile flow in hamsters

Abstract3α,7β-Dihydroxy-23-methyl-5β-cholan-24-oic acid (MUDCA) and its two diastereoisomers, α- and β-MUDCA, were infused intraduodenally in biliary fistula hamsters in order to evaluate the effect on bile flow and their hepatic biotransformation processes compared with the natural analog ursodeoxycholic acid (UDCA). In addition, the corresponding glycine conjugates were compared. The bile acids were administered at different doses (0.7–6 μmol/min/kg) over periods of 90 min. The results indicate that the racemic mixture exhibits a potent choleretic effect at both low and high doses, while the two individual diastereoisomers show this effect only at high doses. The presence of a C-23 methyl group in the side chain prevents hepatic amidation and alternative conjugations occur, such as glucuronidation, in order to facilitate their biliary secretion. Biotransformation of the methyl derivatives of UDCA occurred mainly by conversion to more polar glucuronide conjugates. There was little alteration to the molecule and, unlike UDCA, very little amidation occurred. These data indicate that the presence of a C-23 methyl group prevents the usual side-chain amidation common to the most naturally occurring bile acids and that glucuronidation is a requisite for efficient biliary excretion.

Amino acid derivatives of 5-ASA as novel prodrugs for intestinal drug delivery.

In an attempt to obtain site-specific delivery of 5-ASA in the intestinal tract, we have determined the extent of absorption and metabolism of a number of novel 5-ASA derivatives, namely, (N-l-glutamyl)-amino-2-salicylic acid (1), (N-l-aspartyl)-amino-2-salicylic-acid (2), 5-aminosalicyl-l-proline-l-leucine (3), and 5-(N-l-glutamyl)-aminosalicyl-l-proline-l-leucine (4), which are selectively cleaved by intestinal brush border aminopeptidase A and carboxypeptidases. These novel prodrugs, 5-ASA, and sulfasalazine were administered to adult Fisher rats (N=30) and to animals that had undergone prior colostomy (N=30). Urine and feces were collected at timed intervals for 48 hr and the metabolites, 5-ASA, andN-acetyl-5-ASA were measured by high-performance liquid chromatography. The absorption and metabolism of all compounds were essentially identical in colostomized and normal animals. 5-ASA exhibited a rapid proximal intestinal absorption as evidenced by the high cumulative urinary excretion (>65%) and low fecal excretion. Sulfasalazine, as expected, exhibited a lower urinary recovery (<35%) and higher fecal excretion of 5-ASA and its metabolite. The novel glutamate and aspartate derivatives (1 and2) behaved similarly to sulfasalazine, while administration of the proline-leucine derivative (3) resulted in urinary and fecal recovery values intermediate with respect to those observed with 5-ASA and sulfasalazine. 5-(N-l-Glutamyl)-aminosalicyl-l-proline-l-leucine yielded the highest fecal recovery of 5-ASA and itsN-acetyl derivative, indicating a more efficient delivery to the distal bowel. Amino acid derivatives of 5-ASA appear to be potentially useful prodrugs for the site-specific delivery of 5-ASA to different regions of the intestinal tract.

Novel Soy Germ Pasta Enriched in Isoflavones Ameliorates Gastroparesis in Type 2 Diabetes: A pilot study

OBJECTIVE To determine the effect of soy germ pasta enriched in biologically active isoflavone aglycons on gastric emptying in type 2 diabetic patients with gastroparesis. RESEARCH DESIGN AND METHODS This randomized double-blind, placebo-controlled study compared soy germ pasta with conventional pasta for effects on gastric emptying. Patients (n = 10) with delayed gastric emptying consumed one serving per day of each pasta for 8 weeks, with a 4-week washout. Gastric emptying time (t1/2) was measured using the [13C]octanoic acid breath test at baseline and after each period, and blood glucose and insulin concentrations were determined after oral glucose load. RESULTS Soy germ pasta significantly accelerated the t1/2 in these patients (161.2 ± 17.5 min at baseline vs. 112.6 ± 11.2 min after treatment, P = 0.009). Such change differed significantly (P = 0.009) from that for conventional pasta (153.6 ± 24.2 vs. 156.2 ± 27.4 min), without affecting glucose or insulin concentrations. CONCLUSIONS These findings suggest that soy germ pasta may offer a simple dietary approach to managing diabetic gastropathy.