Pharmacokinetic properties of a novel formulation of S-adenosyl-L-methionine phytate.

S-adenosyl-L-methionine (SAM), the main endogenous methyl donor, is the adenosyl derivative of the amino acid methionine, which displays many important roles in cellular metabolism. It is widely used as a food supplement and in some countries is also marketed as a drug. Its interesting nutraceutical and pharmacological properties prompted us to evaluate the pharmacokinetics of a new form of SAM, the phytate salt. The product was administered orally to rats and pharmacokinetic parameters were evaluated by comparing the results with that obtained by administering the SAM tosylated form (SAM PTS). It was found that phytate anion protects SAM from degradation, probably because of steric hindrance exerted by the counterion, and that the SAM phytate displayed significant better pharmacokinetic parameters compared to SAM PTS. These results open to the perspective of the use of new salts of SAM endowed with better pharmacokinetic properties.

Prenatal S-Adenosine Methionine (SAMe) Induces Changes in Gene Expression in the Brain of Newborn Mice That Are Prevented by Co-Administration of Valproic Acid (VPA).

In previous studies, we produced changes in gene expression in the brain of mice by early postnatal administration of valproic acid (VPA), with distinct differences between genders. The addition of S-adenosine methionine (SAMe) normalized the expression of most genes in both genders, while SAMe alone induced no changes. We treated pregnant dams with a single injection of VPA on day 12.5 of gestation, or with SAMe during gestational days 12-14, or by a combination of VPA and SAMe. In the frontal half of the brain, we studied the expression of 770 genes of the pathways involved in neurophysiology and neuropathology using the NanoString nCounter method. SAMe, but not VPA, induced statistically significant changes in the expression of many genes, with differences between genders. The expression of 112 genes was changed in both sexes, and another 170 genes were changed only in females and 31 only in males. About 30% of the genes were changed by more than 50%. One of the most important pathways changed by SAMe in both sexes was the VEGF (vascular endothelial growth factor) pathway. Pretreatment with VPA prevented almost all the changes in gene expression induced by SAMe. We conclude that large doses of SAMe, if administered prenatally, may induce significant epigenetic changes in the offspring. Hence, SAMe and possibly other methyl donors may be epigenetic teratogens.

Benefit of an association of an antioxidative substrate and a traditional chinese medicine on telomere elongation.

Telomere shortening is involved in age-related disorders, such as cancer and cardiovascular diseases. Recently, telomerase re-activation strategies have been proposed to counteract telomere shortening and its consequences. Here, we investigated the benefit of dietary supplementation with a mix of S-adenosyl-methionine (SAMe) and a polysaccharide extract of Astragalus (APS) on telomere length of circulating lymphocytes of healthy volunteers. Blood lymphocytes of a cohort of 26 healthy volunteers who were administrated the mix of SAMe and APS in a food supplement for one year were collected. In vitro treatment of blood lymphocytes of healthy volunteers with the mix was also performed. A cohort of 150 healthy volunteers was used as a control. Telomere length was measured by Q-FISH. The micronucleus assay was performed to detect genotoxicity of the mix. The telomeres of circulating lymphocytes of the cohort of 26 donors supplemented with the mix were significantly longer than those of matched controls (p < 10-4). This elongation was essentially observed in the lymphocytes of older donors. Similarly, in vitro treatment of circulating lymphocytes with the mix significantly increased telomere length and decrease the proportion of cells with short telomeres. Here, we observed an increase in telomere length after in vivo and in vitro administration of a mix with SAMe and APS.  The benefit of dietary supplementation with this mix opens a new horizon for the battle against aging and could be used in the treatment of chronic age-related disorders.

Phase II evaluation of S-adenosyl-L-methionine (SAMe) for the treatment of hot flashes.

PURPOSE: Hot flashes are a significant source of symptom burden that negatively impacts quality of life (QOL). For women who have contraindications to, or are unwilling to consider, estrogens or antidepressants for bothersome hot flashes, there are limited effective pharmacologic or complementary and alternative medicines. METHODS: This single-arm phase II trial studied the efficacy of S-adenosyl-L-methionine (SAMe) for the treatment of hot flashes. Eligible women were required to have reported ≥14 hot flashes per week for ≥1 month. The patients were treated with SAMe at a dose of 400 mg twice daily to evaluate whether a reduction in hot flash score appeared to be better than the historical placebo response of approximately 25%. The women kept a daily hot flash diary during a baseline week and then daily during weeks 2-7. The primary endpoint was the change from baseline to week 7 in hot flash score and hot flash frequency. Secondary endpoints included toxicity analyses and the effect of SAMe on QOL. RESULTS: From October 28, 2010 to January 30, 2012, 43 women were treated with SAMe. The decrease in mean percent of baseline hot flash score and frequency was 35.4 and 32.6%, respectively. When compared to the historical placebo response of 25%, the effect of SAMe on hot flash score was not statistically significant (p = 0.09). Treatment was well tolerated with expected grade 1/2 gastrointestinal toxicity and no negative effect on QOL. CONCLUSIONS: The use of SAMe does not appear to significantly reduce hot flashes more than would be expected with a placebo.

S-Adenosyl Methionine in the Therapy of Depression and Other Psychiatric Disorders.

Preclinical Research S-adenosyl methionine (SAM) is a major methyl donor and as such exerts its influence on CNS function through methylation reactions, such as methylation of several catecholamine moiety-containing neurotransmitters, epigenetic changes through methylation of DNA, RNA, RNA-binding proteins and histones, and phospholipid methylation. Based on available evidence, SAM is currently recommended as a next-step (second-line) treatment option following inadequate treatment response to a first-line antidepressant. It shows significant promise in the treatment of pediatric and perinatal depression, as well as Alzheimer's disease, but to make this a recommendation further clinical trials are needed. SAM is safe to use in most patients, but is contraindicated in those with bipolar disorder. Concerns considering the possible increase of homocysteine levels (and cardiovascular complications) due to long-term SAM therapy need to be further addressed in clinical trials taking into account individual`s ability to metabolize homocysteine and his/her folate status. Drug Dev Res 77 : 336-346, 2016. © 2016 Wiley Periodicals, Inc.

[Protective effects of S-adenosylmethionine against CCl4 - and ethanol-induced experimental hepatic fibrosis].

In this study the effects of S-adenosylmethionine (SAM) on experimental hepatic fibrotic rats induced by carbon tetrachloride (CCl(4)) and ethanol and the relevant potential mechanisms were explored. Hepatic fibrotic rat models were established with CCl(4) diluted in olive oil being drunk with 10% ethanol in water. SAM was used both for prevention and treatment. Histological evaluation was carried out by hematoxylin-eosin (HE) and Masson staining of hepatic samples. Serum biochemical assays showed that alanine aminotransferase (ALT) was increased and albumin (ALB) was decreased by CCl(4) and ethanol, and both effects were suppressed by preventing and treating use of SAM. The model control rats got significantly higher scores in fatty degeneration, lobular inflammation, and hepatocyte ballooning. A significant improvement was observed in the SAM-prevented rats and SAM-treated rats, which was consistent with the change of fibrosis scoring in each group. Smad3 was induced by CCl(4) and ethanol in the model control group, which was significantly down regulated by SAM. SAM reduced both total Smad3 and phospho-Smad3 in vitro. SAM had a protective effect on hepatic fibrosis in rats induced by CCl(4) combined with ethanol and the down-regulation of activity and expression of Smad3 were involved in the potential mechanisms.

[Comparative results of use liver protecting drugs for prophylaxis of the liver failure after extensive resections of the liver]. / Sravnitel'nye rezul'taty primeneniya gepatoprotektorov dlya profilaktiki pechenochnoi nedostatochnosti pri obshirnykh rezektsiyakh pecheni.

After 100 extensive resections of a liver for excision of metastasises of a colorectal cancer, the different drugs protecting a liver were used for prophylaxis of a liver failure. MATERIAL AND METHODS: Patients were distributed on 2 equivalent groups. Patients of the first group received Ademetionin in a dosage 400 mg 2 times a day within 7 days. Patients of the second group received Remaxol in a dosage 400 ml within 7 days once a day. RESULTS: Frequency of cases of an acute liver failure in the first group of patients was 38%, in the second group of patients - 20% (p<0.05). Patients of the second group had milder course of an acute liver failure (by criteria of ISGLS, 2011) in comparison with patients of the first group. Postoperative bed - days in the first group of patients lasted 13 (11-15) days, in the second group of patients - 11 (10-13) days (p<0.05). There was no postoperative lethality.

[Optimization of infusion therapy in patients with ovarian cancer].

We investigated the clinical observations and the results of a comprehensive survey of 70 patients with ovarian cancer stage III-IV aged 30 to 70 years with the presence of endotoxemia. Integral assessment of prognosis and severity of the condition was performed according to SAPS II and SOFA. Infusion program included a preliminary correction of hypovolemia prior to surgery on the operating table in equal parts, HES and balanced crystalloid solutions, with in- creased infusion of 15% of blood volume based on the method of anesthesia. In the early postoperative period, infusion programs were complemented by various embodiments of metabolic correction. Patients of group-1 (n = 35) received remaxol in a dose of 800 mI/day. Patients of group-2 (n = 35) received ademethionine (heptral) 800 mg/day. Analysis of the results revealed that premorbid background in patients with ovarian cancer stage III-IV was characterized by hypovolemia, phenomena hepatopathy, and endotoxemia, and mixed forms of hypoxia of varying severity. Differentiated approach to the choice of pathogenesis-based perioperative infusion according to premorbid condition, anesthesia and blood loss contributed to the elimination of hypovolemia, favored efficient oxygen delivery and consumption, the ade- quacy of tissue oxygenation. Remaxol inclusion in the perioperative infusion programs in patients with ovarian cancer enhanced their clinical efficiency, reduced cytolytic and cholestatic syndromes, recovered of protein and synthetic liver function, reduced the appearance of mixedforms of hypoxia and endogenous intoxication.

[Meta-analysis of ursodeoxycholic acid and S-adenosylmethionine for improving the outcomes of intrahepatic cholestasis of pregnancy].

OBJECTIVE: To conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) that have assessed the effect and safety of ursodeoxycholic acid (UDCA), S-adenosylmethionine (SAMe) and UDCA-SAMe combination therapies for intrahepatic cholestasis of pregnancy (ICP). METHODS: Using searching protocols and assessment methods recommended by the Cochrane Collaboration to reduce bias in systematic reviews, the databases of Medline, EMBASE, Cochrane Central Register of Controlled Trials (CCRT), China National Knowledge Infrastructure (CNKI), Chinese BioMedical Literature (CBM) and Wanfang China Online Journals were searched to identify relevant RCTs published from database inception to December 2011. RESULTS: Ten RCTs (of 727 pregnant women) were included in the study and represented a low risk for bias. Compared to the patients who received UDCA monotherapy, those who received UDCA-SAMe combination therapy had significantly lower rates of Cesarean section (odds ratio (OR) =0.45, 95% confidence interval (CI):0.24-0.86), preterm birth (OR=0.36, 95% CI:0.20-0.63), and fetal asphyxia (OR=0.27, 95% CI:0.13-0.56) (all P less than 0.05); however, the UDCA-SAMe therapy did not provide better rates of amniotic fluid pollution (OR=0.38, 95% CI:0.14-1.01) or better new bom weight (mean difference (MD) =397.36, 95% CI:-96.17-890.89). Compared to the patients who received SAMe monotherapy, those who received UDCA-SAMe combination therapy had significantly lower rates of preterm birth (OR=0.39, 95% CI:0.21-0.73), fetal asphyxia (OR=0.23, 95% CI:0.07-0.75), and amniotic fluid pollution (OR=0.41, 95% CI:0.20-0.85) (all, P less than 0.05); however, the UDCA-SAMe therapy did not provide better rates of Cesarean section (OR =0.62, 95% CI:0.27-1.44) or better new bom weight (MD =445.95, 95% CI:-143.51-1035.42). Comparison of the two monotherapies (UCDA vs.SAMe) showed no statistical differences in rates of Cesarean section (OR=0.91, 95% CI:0.47-1.78), preterm birth (OR =0.79, 95% CI:0.49-1.38), fetal asphyxia (OR=0.90, 95% CI:0.38-2.12), and amniotic fluid pollution (OR=1.14, 95% CI:0.61-2.13), as well as of new born weight (MD =-62.86, 95% CI:-157.81-32.09). Six studies reported no side effects.None of the included studies reported use of allocation concealment or blinding. CONCLUSION: UDCA-SAMe combination therapy is better than either UDCA or SAMe monotherapy for improving the outcome of ICP without adverse effects. Large-scale trials with adequate sample sizes and higher quality study design are needed to further confirm the efficiency and safety of UDCA and SAMe for treating ICP.

[The hepatotropic activity of runihol and ademethionine against experimental liver damage caused by first-line antituberculosis drugs].

Experiments on 62 male albino outbred rats investigated the impact of 14-day use of the oral hepatotropic agents ademethionine and runihol in different doses in liver damage caused by a antituberculosis combination (HRZ). HRZ-induced liver damage was shown to be accompanied by the development of cytolysis and cholestasis. The test drugs in the doses under study had a mixed effect, by reducing the magnitude of biochemical manifestations of these syndromes. Both drugs favored the recovery of the structure of the liver and the reduction of the extent of carbohydrate, protein, and fat dystrophies of the organ. As in previous investigations, ademethionine was found to have enhanced activity of alterative processes in the liver.

[Results of analysis of clinical effectiveness of cytoprotectors used in therapy of widespread forms of psoriasis].

The authors report comparative analysis of the efficacy of cytoprotectors and basal therapy used to treat widespread forms of psoriasis. Combination of both modalities including remaxol and ademetionine increases the effectiveness of the treatment by 23% as appears from the decrease of PASI of 89.6% patients from 23.6 +/- 2.2 to 5.7 +/- 2.2 scores.

[Effect of hepatic functional activity of the liver and endogenous intoxication in patients with ovarian cancer].

The analysis of the clinical observations and the results of the study 70 patients with ovarian cancer stage III-IV, aged 30 to 70 years. After various programs chemotherapy underwent surgical treatment stage under general anesthesia. Investigated hematological indices of intoxication, protein-synthetic liver function, transaminase, C-reactive protein, hemostasis in the perioperative period. Analysis of the results revealed that the original premorbid background characterized by severe hepatic dysfunction, endogenous intoxication, activation of the systemic inflammatory response. The introduction of the treatment of patients with ovarian cancer Remaxol promotes more pronounced and rapid reduction in the degree of metabolic disorders, endogenous intoxication and systemic inflammatory response, compared with ademethionine.

[Alcoholic liver disease: possibilities of diagnosis, treatment and rehabilitation in multidisciplinary hospital].

Tactics of alcoholic liver disease treatment is defined in accordance with lesion level. Differentiated approach to these patients can significantly improve the efficiency of diagnosis, treatment and rehabilitation. At the stage of cirrhosis it is necessary to focus on prevention and treatment of complications. Patients with compensated cirrhosis and subcompensated improved survival achievable Propafenone S-ademetionine (geptral, Geptor). The article presents the results of our study demonstrating a significant decrease in serum bilirubin in patients on background intravenous S-ademetionine. Practicability of stage system creation of medical rehabilitation of patients with alcoholic cirrhosis is approved.

S-Adenosylmethionine (SAMe) for Central Nervous System Health: A Systematic Review.

Background/Objectives: S-adenosylmethionine (SAMe) is a natural compound used to improve mood-related symptoms. Our aim was to determine the efficacy, safety, and optimal dose of SAMe in Central Nervous System (CNS) signs (e.g., mood, behavior). Methods: We conducted a PRISMA-based systematic review by searching PubMed, CINAHL, and Web of Science using MeSH search terms. Articles were independently reviewed by two researchers (with a third resolving conflicts) during title/abstract screening and full-text review. Data were extracted in the same approach, with a quality assessment of included articles. Results: Out of 1881 non-duplicated studies, 36 were included in the review focusing on CNS signs (mood, behavior, sleep). Most studies (n = 32) achieved a 4 or 5 out of 5 points, indicating high study quality. Overall, SAMe was effective in 24 of 36 studies, with adverse events mostly consisting of mild, transient gastrointestinal disturbances. Conclusions: Many patients in these studies did experience improvements in CNS signs from using SAMe alone or in combination with existing therapy. However, future studies are needed to further understand the long-term effects of SAMe in the CNS.

Early diagnosis of adenylosuccinate lyase deficiency using a high-throughput screening method and a trial of oral S-adenosyl-l-methionine as a treatment method.

AIM: The aim of this study was to develop a high-throughput urine screening technique for adenylosuccinate lyase (ADSL) deficiency and to evaluate S-adenosyl-l-methionine (SAMe) as a potential treatment for this disorder. METHOD: Testing for succinyladenosine (S-Ado), a marker of ADSL deficiency, was incorporated into a screening panel for urine biomarkers for inborn errors of metabolism using electrospray tandem mass spectrometry. Liquid chromatography-mass spectrometry and high-performance liquid chromatography were used to confirm and monitor the response of metabolites to oral SAMe treatment. RESULTS: Increased levels of S-Ado were detected in a 3-month-old male infant with hypotonia and seizures. ADSL gene sequencing revealed a previously described c.-49T>C mutation and a novel c.889_891dupAAT mutation, which was likely to disrupt enzyme function. After 9 months of SAMe treatment, there was no clear response evidenced in urine metabolite levels or clinical parameters. INTERPRETATION: These results demonstrate proof of the principle for the high-throughput urine screening technique, allowing earlier diagnosis of patients with ADSL deficiency. However, early treatment with SAMe does not appear to be effective in ADSL deficiency. It is suggested that although SAMe treatment may ameliorate purine nucleotide deficiency, it cannot correct metabolic syndromes in which a toxic nucleotide is present, in this case presumed to be succinylaminoimidazole carboxamide ribotide.

A pilot study of S-adenosylmethionine in treatment of functional abdominal pain in children.

CONTEXT: Functional abdominal pain (FAP) is one of the most common functional gastrointestinal disorders (FGIDs) in children. Currently, medical practitioners widely use tricyclic antidepressants to treat FAP. Those antidepressants, however, have been associated with an increased risk of suicidal ideation, and the accompanying side effects often limit the benefits. S-adenosylmethionine (SAM-e) is a dietary supplement that has efficacy as an antidepressant and as a treatment for chronic pain. OBJECTIVE: The research team hypothesized that during SAM-e exposure (1) participants' pain reports would significantly improve over time, (2) participants' reported quality of life would significantly improve over time, and (3) toxicity measures (liver-function tests and mania and depression scales) would not change significantly. DESIGN: The research team performed an open-label, doseescalation trial of oral SAM-e among children with FAP. Participants came to the research facility for measurements at baseline and after 2 wk, 1 mo, and 2 mo. The research team monitored participants for potential toxicities (liver toxicity, mania, and depression) throughout the trial. SETTING: The trial was conducted at the University of California, San Diego. PARTICIPANTS: The research team recruited children and adolescents with FAP via advertisement at several community general pediatric clinics and at the research team's subspecialty pediatric gastrointestinal clinic at a tertiary care center. The eight resulting participants were children with a median and mean age of 14 y. INTERVENTION: To treat persistent abdominal pain, all participants received SAM-e at an initial dose of 200 mg/d, with escalation to a maximum dose of 1400 mg/d over the period of 2 mo. OUTCOME MEASURES: The primary outcomes were the participants' self-reports of pain and quality of life. The research team used the multidimensional measure for recurrent abdominal pain (MM-RAP), Wong-Baker FACES Pain Rating Scale, and the PedsQL for those measurements. The team used repeated measures analyses to analyze the data. RESULTS: Six participants completed the study. The research team demonstrated an improvement in self-pain reports over the 2-mo follow-up period (P = .004). The median dose of SAM-e that participants took at the 2-mo follow-up period was 1400 mg (interquartile range: 950-1400 mg) daily. Liver function tests and assessments for mania and depression did not change over the study period. CONCLUSIONS: Oral SAM-e demonstrates promise in reducing abdominal pain among children with FAP, with minimal toxicity. The research team needs to conduct larger, placebo-controlled trials to support its initial findings.

[Mechanism of hepatocyte apoptosis in experimental toxic liver injury].

One of the causes of drug hepatopathy is hepatocyte apoptosis, the mechanisms of which are still unclear. The experiments were performed in 24 Wistar rats to study the role of hepatoprotectors in the regulation of hepatocyte apoptosis in liver damage induced by administration of antituberculosis drugs (ATD). The level of apoptosis (TUNEL) was evaluated, and the expression of apoptosis-associated molecules was detected by immunohistochemistry and Western blotting. It was shown that a signaling cascade induced by ATD involved the activation of cell surface receptors (CD95) and caspase-8, i.e. apoptosis was mediated by extrinsic pathway. In addition,ATD induced p53 oncosuppressor synthesis with further activation of caspase-3 effector. Runihol administration during ATD treatment administration improved the condition of the liver, despite some apoptosis stimulating effect, mediated by an intrinsic pathway. It was found that runihol blocked both FAS- and p53-dependent pathways. Ademethionine during drug intoxication acts as a hepatoprotector, blocking extrinsic and p53-dependent pathways.

[Antioxidant properties of remaxol, reamberin, and ademetionine in patients with drug-induced liver injury on the background of antituberculous therapy].

The antioxidant properties of remaxol, reamberin and ademetionine have been studied in comparison to 5 % glucose solution in a group of 120 patients with drug-induced liver injury. It is established that the inclusion of this drugs in the composition of complex therapy contributed to restoration of the antioxidant potential of the cells, which was manifested by increased activity of glutathione peroxidase and superoxide dismutase and integral indices of antioxidant protection (total antioxidant capacity and total antioxidant status) with a relative stabilization of the level of glutathione-S-transferase. Maximum pharmacotherapeutic effect with respect to all of the studiea indices has been achieved by the use of remaxol.

[Comparative efficacy of clinical use of reamberin, remaxol and ademethionine in patients with tuberculosis of the respiratory organs and liver drug-injury].

The efficacy ofreamberin, remaxol, S-adenosyl-L-methionine (ademethionine) and 5% glucose solution was estimated in the treatment of patients with tuberculosis of the respiratory organs and drug hepatotoxicity signs confirmed by higher activity of liver indicative enzymes and nitrogen oxide levels. Remaxol showed a pronounced positive effect on the cytolytic syndrome signs, evident from lower activity of alanine aminotransferase and aspartate aminotransferase. At the same time ademethionine was superior to remaxol in the effect on the cholestatic signs and inferior in the effect on the cytolytic signs. By the effect on the activity of alanine aminotransferase and aspartate aminotransferase, reamberin was inferior to remaxol and superior to ademe-thionine, its effect on the cholestasis markers level vs. the other drugs being superior only to that of 5% glucose solution. As compared to reamberin, ademethionine and 5% glucose solution, remaxol promoted higher integral indices of the host antioxidant protection (total antioxidant capacity and total antioxidant status), that partially explained the drug pronounced hepatoprotective effect.

[Metabolic correction of dyslipidemia in patients with nonalcoholic fatty liver disease as a new therapy policy].

AIM: To study the impact of infusion therapy with the metabolic modulator remaxol on lipid metabolic parameters and target organ (liver, kidney) function in metabolic syndrome (MS). SUBJECTS AND METHODS: The investigation enrolled 90 patients (54 men and 36 women) with primary nonalcoholic steatohepatitis that was associated with insulin-resistance and MS; their age was 21 to 77 years. Every day the study group patients (n = 50) took as a component of combination therapy the metabolic hepatoprotective modulator remaxol intravenously in a dropwise manner in a dose of 400 ml once daily; the comparison group patients (n = 40) received ademetionine 400 mg diluted in 400 ml of isotonic sodium chloride. The duration of infusion therapy was 11 days. RESULTS: Infusion therapy with remaxol caused a pronounced blood lipid composition-regulating effect, by reducing the level of major atherogenic lipids (total cholesterol, triglycerides) and improving liver function and renal nitrogen-excreting and filtration function in patients with Stage IV diabetic nephropathy in the presence of MS. CONCLUSION: Therapy with the metabolic hepatoprotective modulator remaxol ensures reliable metabolic control and multifactorial correction of risk factors of organ lesions in MS: cardio-, hepato-, and nephroprotection.