Double-blind, placebo-controlled pharmacodynamic studies with a nutraceutical and a pharmaceutical dose of ademetionine (SAMe) in elderly subjects, utilizing EEG mapping and psychometry.

In a double-blind, placebo-controlled crossover study, the effects of S-adenosyl-l-methionine (SAMe) on brain function measures of 12 normal elderly volunteers (6 m/6 f, aged 57-73 years, mean: 61 years) were investigated by means of EEG mapping and psychometry. In random order, the subjects were orally administered a pharmaceutical dose of 1600 mg SAMe, a nutraceutical dose of 400 mg SAMe and placebo, each over a period of 15 days, with wash-out periods of 2 weeks in between. EEG recordings, psychometric tests and evaluations of tolerability and side effects were carried out 0, 1, 3 and 6 h after drug administration on days 1 and 15. Multivariate analysis based on MANOVA/Hotelling T2 tests of quantitative EEG data demonstrated significant central effects of SAMe as compared with placebo after acute, subacute and superimposed drug administration of both the nutraceutical and the pharmaceutical dose. EEG changes induced by SAMe were characterized by an increase in total power, a decrease in absolute and relative power in the delta/theta and slow alpha frequencies, an increase in absolute and relative power in the alpha-2 and beta frequencies as well as an acceleration of the alpha centroid and the centroid of the total power spectrum. The delta/theta and the beta centroid showed variable changes over time. The dominant alpha frequency was accelerated, the absolute and relative power in the dominant alpha frequency attenuated after SAMe as compared with placebo. These acute and subacute pharmaco-EEG findings in elderly subjects are typical of activating antidepressants. Time-efficacy calculations showed that acute oral administration of SAMe in both the nutraceutical and the pharmaceutical dose induced the pharmacodynamic peak effect in the first hour with a subsequent decline. The 3rd and 6th hours still showed a significant encephalotropic effect after the 1600 mg dose. The maximum EEG effect was noted after 2 weeks of oral administration of both 1600 mg/die and 400 mg/die. The superimposed dose induced significant encephalotropic effects in the 3rd hour after 400 mg and in the 3rd and 6th hours after 1600 mg as compared with pre-treatment. Dose-efficacy calculations showed that the pharmaceutical dose of 1600 mg had a more pronounced effect on the CNS than the nutraceutical dose of 400 mg, with both doses being superior to placebo. Psychometric tests concerning noopsychic and thymopsychic measures as well as critical flicker fusion frequency generally demonstrated a lack of differences between SAMe and placebo, which reflects a good tolerability of the drug in elderly subjects. This was corroborated by the findings on side effects, pulse and blood pressure.

S-adenosylmethionine in the treatment of osteoarthritis. Review of the clinical studies.

S-Adenosylmethionine (SAMe), a physiologic compound that ranks with ATP as a pivotal molecule in biology, offers physicians an innovative approach to the treatment of osteoarthritis. Experimental investigations suggest that the administration of SAMe exerts analgesic and antiphlogistic activities and stimulates the synthesis of proteoglycans by articular chondrocytes with minimal or absent side effects on the gastrointestinal tract and other organs. The results of extensive clinical trials, which have enrolled about 22,000 patients with osteoarthritis in the last five years, support the clinical effectiveness and the optimal tolerability of SAMe administration. The intensity of therapeutic activity of SAMe against osteoarthritis is similar to that exerted by nonsteroidal anti-inflammatory drugs, but its tolerability is higher. Based on these findings, SAMe is proposed as the prototype of a new class of safe drugs for the treatment of osteoarthritis.

Spontaneous and polyclonal Ig secretion by circulating B cells after surgery.

Abnormalities of the immune response are commonly observed after surgery. In many cases, they are part of a physiologic rather than of a pathologic response to trauma. In this study we show that after elective surgery in otherwise healthy subjects the B cell compartment is deeply affected, as documented by the appearance, 7 days after the intervention, of circulating lymphoblastoid B cells spontaneously secreting in vitro IgG and IgA antibodies. Analogous lymphoblastoid B cells have been described after in vivo immunization and represent a sensitive marker of the B cell response against the immunizing antigen. To better understand the origin of the reaction, we have analyzed the specificity of the antibodies secreted in culture supernatants. We show that the antibody response is polyclonal, since low titers of antibodies against several different bacterial antigens--such as tetanus toxoid, pneumococcal capsular polysaccharides (PCPs), and the lipopolysaccharides (LPSs) of several enteropathogenic strains of Escherichia coli--are detected. This response seems to reflect the previous immunologic experience of the single patient and to be caused by antigens released from traumatized tissues or absorbed through breaches in skin or mucous membranes.

Effects of iron overload on bile secretion and hepatic porphyrin metabolism in ethinyl estradiol-treated rats.

We investigated the effects of ethinyl estradiol (5 mg/kg body wt daily for 5 days, orally) and/or iron sorbitol (50 mg/kg body wt daily for 5 days, i.m.) on bile flow, bile salt independent fraction (BSIF), hepatic delta-aminolevulinate synthase (ALA-S) and uroporphyrinogen decarboxylase (URO-D) in female rats. Ethinyl estradiol administration was associated with a significant decrease of bile flow and BSIF and an increase in URO-D activity in comparison to control values. Iron alone did not modify biliary parameters, but significantly increased the activity of ALA-S. Combined treatment with ethinyl estradiol plus iron partially corrected the reduction of BSIF and restored the activity of ALA-S and URO-D to control levels. Thus iron appears to exert a partially protective effect against ethinyl estradiol-induced cholestasis. No porphyrinogenic effect was observed.

Bile secretion and liver microsomal mixed function oxidase system in mice with griseofulvin-induced hepatic protoporphyria.

Administration of 2.5% griseofulvin in the diet to male CD1 mice produced protoporphyria and cholestasis. Protoporphyria became evident as early as after 10 days of treatment, whereas cholestasis, expressed in terms of total bile flow reduction, developed only after 45 days of griseofulvin. Bile flow impairment was due both to the length of treatment and to the severity of liver protoporphyria. Griseofulvin administration was also associated with a significant modification of the relative amounts of hepatic microsomal cytochromes P-450 and b5, a loss in concentration/mg of protein of cytochrome P-450 and a concomitant increase of b5. Despite these changes, the activity of aniline hydroxylase expressed per mg of microsomal protein, assessed in vitro, was not modified.

Red blood cells: a new major modality for acetaldehyde transport from liver to other tissues.

After alcohol ingestion, an amount of acetaldehyde much larger than previously appreciated by measurements in plasma is released from the splanchnic areas, travels reversibly bound to the red blood cells, and is taken up by extrahepatic tissues. The magnitude of this new modality for acetaldehyde transport is markedly enhanced in alcoholics and may contribute to acetaldehyde toxicity in extrahepatic tissues.

First pass metabolism of ethanol--a gastrointestinal barrier against the systemic toxicity of ethanol.

Both in men and rats, most of the ethanol ingested at a low dose is metabolized before it reaches the systemic circulation. Oxidation of ethanol (mainly in the stomach) accounts for the bulk of this effect. This "first pass" metabolism (FPM) may be viewed as a barrier which protects against the systemic toxicity of ethanol. This barrier can be overcome by large doses of ethanol. Its efficiency is also reduced by a decrease in gastric alcohol dehydrogenase (ADH) activity secondary to chronic alcohol consumption.

3-Hydroxy-3-methylglutaric acid (HMGA) reduces dietary cholesterol induction of saturated bile in hamster.

3-Hydroxy-3-methylglutaric acid (HMGA) is a competitive inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCoAR) and strongly reduces cholesterol biosynthesis both in vitro and in vivo. Since the effects of this compound on biliary lipid composition are hitherto unknown, we have investigated whether it prevents dietary cholesterol induction of saturated bile in the hamster. Female Golden Syrian hamsters have been divided into four groups and treated for 10 weeks as follows: I) Standard diet, containing 0.8 mg cholesterol/g food; II) Standard diet plus HMGA (100 mg/kg b.w./day per os); III) Lithogenic diet containing 2.4 mg cholesterol/g food; IV) Lithogenic diet plus HMGA as above. The results indicate that HMGA is effective in reducing both bile cholesterol supersaturation and hypercholesterolemia. Inhibition of hepatic cholesterogenesis at the level of mevalonate synthesis by HMGCoAR and reduction of intestinal cholesterol absorption may be responsible for these effects.

S-adenosyl-L-methionine protection against alpha-naphthylisothiocyanate-induced cholestasis in the rat.

The effect of S-adenosyl-L-methionine (SAMe) on cholestasis induced by alpha-naphthylisothiocyanate (ANIT) was studied in rats. SAMe significantly attenuated both bile flow impairment and elevated values of serum bilirubin, glutamic pyruvic transaminase and alkaline phosphatase in ANIT-treated animals. These results suggest that SAMe protects the rat liver against the toxic effects of ANIT.

Effects of phlebotomy on urinary porphyrin pattern and liver histology in patients with porphyria cutanea tarda.

Urinary porphyrin profiles and liver histology have been investigated in a group of adult alcoholics with porphyria cutanea tarda (PCT) before and after one year phlebotomy. Both parameters were evaluated during the same period in a group of patients who did not undergo specific therapy for PCT. All patients were advised to abstain from alcohol. At the end of the one year observation period there was a significant fall of urinary total porphyrins and in the uro/coproporphyrin ratio in treated patients compared to basal values whereas no changes were found in controls. Liver biopsy findings revealed a significant reduction of hepatic fatty degeneration and siderosis with no changes in inflammatory infiltrates and fibrosis in treated patients, so the progression of liver disease was similar to controls. These results show that clinical and biochemical remission of PCT can occur independently of the evolution of the concomitant liver disease.

Abnormal serum gamma-glutamyltranspeptidase in alcoholics. Clues to its explanation.

In order to investigate the reason for the elevation of serum gamma-glutamyltranspeptidase (GGT) after chronic alcohol consumption, the activity of this enzyme, together with the activities of aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase in serum (parameters of liver cell damage) and the excretion of D-glucaric acid (D-GA) in urine (parameter of microsomal enzymatic induction) were determined in 72 chronic alcoholics. Of these, 32 had no significant liver disease (1st group) and 40 had an overt liver disease varying from fatty liver to liver cirrhosis (2nd group). The GGT was elevated in only 62% of the patients of the first group, but in 95% of the second group. Of the latter group, patients with cirrhosis had significantly higher GGT mean levels than the patients with fatty liver. On the other hand, increased D-GA excretion was only found in 23% of the group 1 patients and in 44% of the group 2 patients. Moreover, in all patients there was a significant correlation between the values of GGT and aspartate aminotransferase, but not between GGT and D-GA. From these results, the GGT increase in chronic alcoholics, would seem to be better related to cellular damage than to enzymatic induction assessed on the basis of D-GA urinary excretion.

S-adenosylmethionine for the treatment of intrahepatic cholestasis of pregnancy. Results of a controlled clinical trial.

Previous studies have shown that S-adenosylmethionine (SAMe) counteracts oestrogen-induced bile secretion failure. In order to confirm this anticholestatic activity, we conducted a single-blind clinical trial comparing SAMe with placebo in the treatment of women with intrahepatic cholestasis of pregnancy (ICP). Thirty patients in the last trimester of pregnancy were randomly assigned to receive either SAMe (800 mg/day i.v.) or placebo until delivery for a mean period of 18 days. After SAMe, the women exhibited significantly (p less than 0.01) lower levels of total bile acids, serum conjugated bilirubin and aminotransferases with respect to pretreatment levels as well as to the corresponding values of the placebo group. In addition, SAMe significantly reduced pruritus whereas placebo was ineffective. No adverse reactions on mother or child were recorded during SAMe treatment, and the follow-up of these cases showed an incidence of premature labour (earlier than 37 weeks of gestation) in 2 out of 15 vs 5 out of 15 cases in the placebo group. In conclusion, these findings document that SAMe is more effective than placebo in ameliorating subjective and objective parameters of ICP.

A review of the studies on the clinical use of S-adenosylmethionine (SAMe) for the symptomatic treatment of intrahepatic cholestasis.

S-Adenosylmethionine (SAMe) proved to be effective in antagonizing bile secretion impairment induced by a wide range of hepatotoxins, including ethynylestradiol, taurolithocholate, chlorpromazine and alpha-naphthyl-isothiocyanate. The anticholestatic activity of SAMe may result from its role in the intermediate metabolism as this molecule is involved in transmethylation and transsulfuration reactions. Clinical experience, carried-out on more than 1,000 cholestatic patients, supports preclinical data. In particular, controlled clinical trials have documented that intravenous SAMe (800 mg/day) induced a significant decrease of biochemical parameters of cholestasis (serum total and conjugated bilirubin, serum total bile salts, and aminotransferases), as well as a significant improvement of pruritus in women with ICP compared with placebo. In addition, other studies provided the evidence that both parenteral (800 mg/day) and oral SAMe (1600 mg/day) significantly improves subjective (pruritus, fatigue, and general discomfort) and objective (serum total and conjugated bilirubin, and serum alkaline phosphatase) parameters of cholestasis in patients with intrahepatic cholestasis complicating chronic liver diseases compared with placebo. In all these trials, SAMe treatment has been well tolerated at the same extent as placebo. In conclusion, experimental and clinical investigations indicate that SAMe represents an effective and safe approach to the management of intrahepatic cholestasis.

Effects of methyltestosterone on bile secretion in female and male rats.

No adverse effect on bile secretion was noted in methyltestosterone-treated female rats. In male rats, methyltestosterone administration exerted a cholestatic effect, which is not only due to the decrease of bile salt excretion rate, but also to a possible interference of the steroid with bile salt micelle size.

Bile flow impairment of ventro-medial hypothalamus lesioned obese rats.

Cholesterol supersaturation of bile has been reported in human obesity. Since electrolytic lesions placed in the ventro-medial hypothalamus induce hyperphagia and obesity in the rat, bile flow and lipid composition have been studied two months after the induction of such stereotaxic lesions in a group of ten animals and in their sham-operated controls. Bile flow was significantly lower in obese rats than in controls. The bile flow reduction was attributed to a decrease of the bile acid independent fraction, since no variation in bile acid excretion rate and in bile to plasma ratio of [14C] erythritol was seen between the two groups. Whereas plasma cholesterol and triglycerides were higher in ventro-medial hypothalamus lesioned rats, biliary cholesterol and phospholipid excretion rates were similar in the two groups. These data indicate that stereotaxic lesions of ventro-medial hypothalamus in the rat significantly reduce bile flow, suggesting a correlation between active sodium transport at canalicular level and neuroendocrine hypothalamic function, but fail to induce qualitative alterations of bile lipid composition.

Double-blind placebo-controlled clinical trial of microporous cholestyramine in the treatment of intra- and extra-hepatic cholestasis: relationship between itching and serum bile acids.

In order to investigate the effectiveness of microporous cholestyramine in the pharmacological management of intra- and extrahepatic cholestasis, a double-blind placebo-controlled study was carried out in 10 patients. Microporous cholestyramine or placebo 3 g t.i.d. were given orally over a four-week period. The active drug resulted statistically superior to the placebo in reducing itching intensity (p less than 0.01) and serum bile acids (p less than 0.01). A positive linear relationship between itching and serum bile acids (p less than 0.01) was also demonstrated.

Effect of a concomitant treatment with ethynylestradiol and ascorbic acid on bile secretion in female hamsters.

The administration of large doses (5 mg/kg b.wt./day) of ethynylestradiol to adult female hamsters did not induce cholestasis or modifications of bile lipid composition. These findings are in contrast with the data of other authors who in different experimental conditions described the sensitivity of hamsters to the estrogen-induced hepatobiliary toxicity. Ascorbic acid alone or added to ethynylestradiol did not impair bile secretion. However, it significantly increased the plasma levels of radioactivity tested 24 hours after the oral administration of a tracer dose of radiolabelled ethynylestradiol. These results confirm previous data showing in humans the capability of ascorbic acid to favour the rise of plasma concentrations of ethynylestradiol.

[Bile secretion]. / La secrezione biliare

The canaliculus is the primary site for the formation of bile. Here, active secretion of bile acids creates an osmotic gradient between bile and blood, crossed passively by water and solutes. Numerous experimental data point to the existence of a canalicular bile fraction that is independent of the active transport of bile acids and related to active sodium secretion. The bile ducts are not mere conduits for the passage of bile, but can also change its volume and composition by means of both absorption and secretion. Nervous, vascular, hormonal and pharmacological factors serve to modify bile secretion. In most cases, however, their mechanism of action is virtually unknown.

Dissolution of bile duct stones with monooctanoin: in vitro study.

Mono-octanoin (Mo) is the drug of choice in the topical litholytic treatment of residual gallstones following cholecystectomy. Although this drug does not produce significant side effects, it requires a lengthy period of treatment (15-20 days). The purpose of this study was to verify the in vitro efficacy of the mixture Mo + 10% H2O vs pure Mo in human cholesterol stones. The findings indicate that this mixture can reduce dissolution time by 15.8% and increase the dissolution rate by 27.9% vs pure Mo. A further significant reduction (p = 0.0001) in dissolution times can be obtained by constant exchange of the solvent at the surface of the stone (stirring).

[A new therapeutic approach to retained biliary calculi. Results in 6 patients]. / Nuovo approccio terapeutico ai calcoli biliari residui. Risultati in sei pazienti.

A new three-phase therapeutical approach to retained biliary stones (RBS) is designed to shorten the long treatment times with Monooctanoin (Mo). In the first phase, the litholytic agent is infused to soften the stones. In the second one the calculi are crushed, and in the last complete elimination of the fragmentary stones into the duodenum is obtained after 1-2 flushings with ceruletide. In 6 patients a complete clearance of the stones was obtained (success 100%) together with a reduction in the litholytic agent dose (52%) and the infusion time (62%), in comparison with the results of using Mo. alone.