Each film coated tablet contains:
S-Adenosyl-L-Methionine Distulfate p-toluenesulfonate
eq. to s-adenosyl L-Methionine ion 200 mg
S-Adenosyl-L-Methionine Disulfate p-toluenesulfonate
eq: to S-Adenosyl-L-Methionine ion 400 mg
is basically a nutritional supplement containing S-Adenosyl-L-methionine (SAMe) or ademetionine, a naturally occurring molecule found in virtually all body tissues and fluids. It acts as a methyl group donor in many transmethylation reactions and therefore is involved in the synthesis or metabolism of a wide range of compounds that maintain normal cell function. S-Adenosyl-L-methionine disulfate p-toluensulfonate is a stable form of ademetionine. Similar stable formulations of ademetionine have been used for the treatment of depression, liver disorders, and osteoarthritis.
SAMe is formed from the essential amino acid methionine and adenosine triphosphate. Chemical name of the compound is (S)-5-[(3-Amino-3-carboxypropyl) methylsulphonio]-5' deoxyadenosine hydroxide. Its molecular formula is C15 H22 N6 O5 S and molecular weight is 398.4. Structural formula of SAMe is as under.
SAMe is found every living cell, where it functions as a donor of methyl groups in >100 different reactions catalyzed by methlytransferase enzymes. SAMe also serves as a precursor molecule to the aminopropylation pathway, which leads to the synthesis of glutathionine.
SAMe is a major methyl donor in the brain that is involved in the pathways for synthesis of hormones, neurotransmitters, nucleic acids, proteins, and phospholipids. SAMe is required for the synthesis of norepinephrine, dopamine, and serotonin, and also plays a role in other intracellular metabolic pathways.
SAMe is the initiartor of three important metabolic pathways- transmethylation, transulfuration and aminopropylation.
The transmethylation pathway involves the transfer of methyl groups from SAMe to a broad range of molecules such as phospholipids, nucleic acids, proteins and porphyrins. When SAMe induces methylation of liver plasma membrane phospholipids, the result is enhanced membrane fluidity which maintains membrane structure and function, which in turn improves the structure and function of the liver tissue. Alcohol induced liver dysfunction can deplete SAMe and result in interference with the transmethylation pathway and promote liver plasma membrane injury. SAMe is the precursor to all methylated compounds. These mechanisms are needed for optimal liver function and can be depleted when the liver is stressed.
SAMe is a methyl donor and by release of methyl groups initiates transulfuration which generates sulfur compounds. This source of endogenous sulfur has many positive benfits in hepatic function by enhancing liver detoxification. SAMe increases the Sulfation of hepatotoxic endogenous bile acids.
SAMe is also precursor of essential amino acids and peptides including cysteine, taurine and glutathione. All of these are needed for optimal liver function and when depleted cause serious problems in liver function. Taurine is implicated in the process of bile acid conjugate with taurine, this increases their volubility and reduces the accumulation of toxic bile acids in the hepatocyte. An impairment of the transulfuration pathway can lead to a cysteine and taurine, deficiency which may cause nutrional defects particularly in people with liver dysfunction. Cysteine deficiency can lead to reduced production of the essential peptide glutathione.
Glutathione acts as an intracellular detoxifying agent and is important in maintaining hepatic function. Glutathione protects this liver by neutralizing free radicals, which have a deleterious effect on all tissues in the body.
SAMe also has applications in optimizing joint structure and function, by stimulating proteoglytes synthesis. Proteoglycans are needed for optical joint function. Evidence has shown that SAMe is a precursor of endogenous sulfated products, which are in turn used to sulfate glycosaminoglycans.
SAMe has the ability to stimulate proteoglycan synthesis and secretion in cultured chondrocytes, which are important for cartilage repair. Oral dosing of SAMe induces a significant increase in synovial fluid concentration of this molecule. It is also involved in aminopropylation reactions to form polyamides as a stabilizing effect on proteoglycans. It also has protective effects on the gastric mucosa, and will not harm the mucosa as some NSAID'S can. SAMe also works as a scavenger of toxic oxygen species in the body, including the joint tissues, which can benefit joint structure and function.
S-Adenosylmethionine (SAMe) is present in many tissues, including the central nervous system (brain and spinal cord). In the CNS, as in the rest of the body, a major function of SAMe is to donate methyl groups in the reactions synthesizing various crucial compounds, including neurotransmitters (e.g., epinephrine) and phospholipids. For example, SAMe facilitates the conversion of phosphatidylethanolamine to phosphatidylcholine, which forms part of the inner lipid layer of the plasma membrane. In so doing, it increases membrane fluidity. This fluidity is necessary for the exchange of chemical messages (neurotransmitters) between brain cells. Thus, SAMe supports the synthesis of neurotransmitters, and also facilitates their function as chemical messengers in the brain.
SAMe is synthesized from the amino acid L-methionine through a metabolic pathway called the one-carbon cycle, which relies, in part, on adequate concentrations of the vitamins folate and B12. Deficiencies of both of these vitamins have also been linked to depression. For example, between 10% and 30% of depressed patients may have low folate concentrations, and these patients appear to respond less well to antidepressants. Vitamin B12 is converted to methylcobalamin, which is also involved in the synthesis of the various central nervous system neurotransmitters. Vitamin B12 deficiency may result in an earlier age of onset of depression. The common mediator of this effect may be reduced SAMe. Correction of folate and vitamin B12 deficiencies may alleviate depressive symptoms and augment of the response to antidepressant therapy, perhaps because of the resultant increase in SAMe concentrations.
SAMe relation to mood is suggested by several lines of evidence. For instance, low SAMe concentrations have been observed in the cerebrospinal fluid of depressed persons. Conversely, there is a positive correlation between an increase in plasma SAMe concentrations and an improvement in depressive symptoms. The activity of the enzyme methionine adenosyltransferase, which is involved in the manufacture of SAMe, has been shown to be low in depressed schizophrenic patients but high in manic patients. This finding supports the role of SAMe as a mood-elevating agent.
SAMe has been studied in clinical trials to determine its mood elevating effect in depressed patients. A fewpublished clinical studies showed that parenteral (intervenous or intramuscular) SAMe is superior to placebo and is as effective as tricyclic antidepressants. Trials of oral SAMe suggest an efficacy comparable to the of tricyclic antidepressants. Trials of oral SAMe suggest an suggest an efficacy comparable to that of tricyclic antidepressants and superior to placebo at doses between 200 and 1600 mg/d.
SAMe may have a relatively faster onset of action than do conventional antidepressants. In one study, some patients improved within a few days and most did within 2 weeks. Likewise, 2 studies showed that the combination of SAMe and low-dose tricyclic antidepressants resulted in an earlier onset of action than did tricyclic antidepressants alone.
Several studies indicate that a CNS methyl group deficiency may play a role in the etiology of Alzheimer disease (AD0. Reduced SAMe concentrations were found in CSF and in several different brain regions of patients with AD. In addition, reduced and in several different brain regions of patients with AD. In addition, reduced phosphatidylcholine concentrations were found in postmortem brain tissue from AD patients, and significant changes in brain phospholipids that are dependent of SAMe metabolim were detected in vivo with 31p magnetic resonance spectroscopy in the early stages of AD. Deficiencies of folate and vitamin B12 are common in the elderly and can lead to decreased CNS SAMe concentrations. Several studies indicate that elevated blood homocsteine concentrations, considered to be a marker for folate deficiency, vitamin B12 deficiency, and impaired methylation, may be a risk factor for AD. It is therefore important to note that preliminary studies using either SAMe or alternative methyl group donors [such as betaine or folate and vityamin B12] can improve measures of cognitive function. These treatments may be able to restore methyl group metabolism and normalize blood homocysteine concentrations.
Reduced SAMe concentrations in CSF were also reported in patients with subacute combined degeneration of the spinal cord resulting from folate or vitamin B12 deficiency and in children with inborn errors of the methyl-transfer pathway who had demyelination, In these cases, treatment with methyl-group donors such as SAMe, methyltetrahydrofolate, betaine, and methionine was associated with remyelination and a clinical response. In 3 independent studies, reduced SAMe concentrations in CSF were found in HIV- infected patients; one study was conducted in children and the other 2 studies were conducted in adults. Although the cause of the decreased CSF SAMe Concentrations in HIV infection is not known. It was proposed that the resulting methyl-group deficiency may be pathogenic mechanism involved in the etiology of the vacuolar myelopathy that is often part of the AIDS dementia complex. Furthermore, HIV-related vacuolar myelopathy bears a sticking histologic resemblance to subacute combined degeneration of the spinal cord, which can accompany dolate and Vitamin B12 deficiencies.
The potential benefits of SAMe in treating osteoarthritis was discovered when patients enrolled in clinical trials of SAMe for depression reported marked improvement in their osteoarthritis symptoms. Nine clinical trails in Europe and 1 in the United states with a total of >22000 participants have confirmed the therapeutic activity of SAMe against osteoarthritis.
SAMe has effects similar to those of the non steroidal anti-inflammatory drugs, but its tolerability is higher. Experimental studies indicates that SAMe increase chondrocyte proteoglycan syntheticsis and proliferation rate. SAMe induces the synthesis of polyamines which might stabilize the polyanionic macromolecules if proteoglycans and protect them from attack by proteolytic and glycotic enzymes. Furthermore, in vitro studies show that SAMe can antagonize the tumor necrosis factor alpha-induced decrease in synovial cell proliferation and fibronectin mRNA expression. These findings indicate that in cultured synovial cells, SAMe restores basal conditions after cytokine-induced cell damages. In addition, oral administration of SAMe (400mg for 7d) to 4 subjects significantly increased SAMe concentration in synovial fluid by 3-4 fold compared with pretreatment values.
The potential benefits of Same in treating liver disease stems from several important aspects of Same metabolism. In mammals, as much as 80% of the methionine in the liver is converted into SAMe. Hepatic glutathione, which is dependent on methionine and SAMe metabolism, is one of the principal antioxidants involved in hepatic detoxification. Studies have shown that abnormal SAMe synthesis is associated with chronic liver disease, regardless of its etiology.
Experimental studies and clinical trails showed that parenteral and oral SAMe administration can increase glutathione concentration in red blood cell and in hepatic tissue and can effectively replenish replenish depleted glutathione pools in patients with liver disease.
Four double-blind trails have studies the use of SAMe for fibromyalgia, these of them finding it to be helpful. Most of these used SAMe given either intravenously oras an injection into the muscles, sometimes in combination with oral doses. However one double-blind study that used only oral SAMe also reported positive results. In this trail, 44 people with fibromyalgia took 800 mg of SAMe of placebo for 6 weeks. Compared to the group taking placebo, those taking SAMe had improvements in disease activity, pain at rest, fatigue, and morning stiffness, and in one measurement of mood. In other respects, such as the amount of tenderness in their tender points, the group taking SAMe did no better than those taking the placebo. Presently it is not clear whether SAMe in beneficial in fibromyalgia through its antidepressant effects, or by some other mechanism.
Following oral intake, SAMe is absorbed from the small intestine. It is better absorbed if taken on an empty stomach. The systemic bioavailability of SAMe after oral administration appears to be low. SAMe is mainly metabolized in the liver, with the methyl group being incorporated into stable pools such as proteins and phospholipids. Sixty percent of SAMe is incorporated into stable pools as cysteine , sulphate, glutathione ,etc .Orally administered SAMe follows the SAMe metabolic fate as the endogenous compound in the cells. It crosses the blood-brain barrier and slowly accumulates in the cerebrospinal fluid. It can also enter into synovial fluid of bony joints. The pharmacokinetic features of SAMe are similarly in healthy volunteers and chronic liver disease patients.
Pre Clinical Safety Data
Teratogenicity & Mutagenicity
There is no evidence that SAMe is teratogenic or mutagenic. However, because nucleic acid mrthylation pattern may change in cancer patients, use of SAMe in such patients warrants caution.
INTASAM 200/400 is used for mild to moderate depression, fibromyalgia, osteoarthritis, and alcoholic liver disease in adult patients.
Known hypersensitivity to SAMe or to any of the ingredients presents in INTASAM 200/400.
- Those undergoing gene therapy should avoid supplemental SAMe.
SAMe may cause lack of sleep if taken at night, therefore, avoid taking at night. People with bipolar disorder (manic-depressive illness) should not take SAMe since it may worsen manic episodes.
Large doses of SAMe may cause abnormally elevated mood. Start at a low dose and gradually increases it; do not exceed recommended doses.
SAMe should not be combined with other antidepressants without first consulting a doctor.
Persons taking SAMe may need to take a multivitamin that contains folic acid and vitamin B12 and B6.
Use in Special Population
Pregnancy and Lactation
Pregnant and brest-feeding women should not take SAMe.
Safety for use in young children, or those with severe kidney disease has not been established.
There are no reports of serious adverse events in persons SAMe in doses up to 1600 mg per day over long periods. Reported side effects includes allergy, mild gastrointestinal upsets (stomach pain, nausea, diarrhea, and flatulence), anxiety, a feeling of elation, restlessness, insomnia , and hypomania.
When these side effects occur, decrease the dose and then gradually increase the dose. Long-term effects are yet known.
Risk of serotonin syndrome can be there if SAMe is taken concomitantly with any of the following drugs: dextromethorphan (present in some cough formulations), pethidine, pentazocine, and tramadol.
SAMe may interact with antidepressant medications, increasing the potential for side effects including headache, irregular or acceterated heart rate, anxiety, and restlessness. Caution and medial supervision is advised for concomitant us.
SAMe may reduce its side effects and also its effectiveness over a period of time.
Medications for diabetes:
SAMe may reduce levels of blood sugar and may strengthen the effect of diabetes medications, which increases the possibility of hypoglycaemia.
No overdosage has been reported.
Store below 300 ℃ .
Protect from light and moisture. Keep out of reach of children.