Transmethyl: Indications, Administration, Side Effects, Contraindications, Precautions and Interactions

It is used for liver disorders, chronic liver disease, depression , fibromyalgia , osteoarthritis, and other conditions.

Transmethyl contains ademethionine as an active ingredient.

Transmethyl or S-adenosyl-L-methionine is a derivative of the amino acid methionine. Due to structural instability, stable salt forms of Transmethyl are required for use as an oral drug. The active ingredients are the salt, Transmethyl 1,4-butanedisulfonate (ademethionine SD4).

Transmethyl works by regulating hormones and neurotransmitters in the brain and liver.

History of Transmetil

S-adenosyl-L-methionine is a molecule that forms naturally in the body. It can also be done in the laboratory.

S-adenosyl-L-methionine is involved in the formation, activation, or breakdown of other chemicals in the body, including hormones, proteins, phospholipids, and certain medications.

S-adenosyl-L-methionine has been available as a dietary supplement in the US since 1999, but has been used as a prescription drug in Italy since 1979, in Spain since 1985, and in Germany since 1989.

In animal models, the relationship between intrahepatic depletion of S-adenosyl-L-methionine and liver fibrosis has been confirmed.

In vitro experiments showed that S-adenosyl-L-methionine increases the antiviral effect of interferon; therefore, S-adenosyl-L-methionine is regarded as the first esoteric sensitizer of interferon.

In the 1970s, S-adenosyl-L-methionine was used as an anti-inflammatory pain reliever to treat arthritis and depression.

Recently, S-adenosyl-L-methionine could also be used as a safe and effective drug to reduce jaundice, especially in patients with Chronic Hepatitis B.

However, similar studies using animal models showed that S-adenosyl-L-methionine could not improve liver cell necrosis and fibrosis.

Based on viral response research, S-adenosyl-L-methionine might be related to an early viral response, although S-adenosyl-L-methionine does not induce a sustained viral response.

In recent years, an increasing number of patients with chronic liver disease have been treated with S-adenosyl-L-methionine in different countries.

As a relatively new method for treating liver disease, a large number of clinical trials focusing on S-adenosyl-L-methionine have begun. However, a debate about S-adenosyl-L-methionine has been ongoing for years.

Results published in different countries in the last 20 years have indicated that there is no quantitative evidence, in the form of a comprehensive data analysis, on the efficacy of treating chronic liver diseases with S-adenosyl-L-methionine.

This document is therefore the first systematic review and quantitative analysis of the effectiveness and safety of S-adenosyl-L-methionine in the treatment of chronic liver diseases based on published randomized controlled trials (RCTs). in English).

Uses of Transmethyl

It has been established that S-adenosyl-L-methionine (SAMe) is the main methyl donor in methyltransferase reactions and that S-adenosyl-L-methionine supplementation restores hepatic glutathione stores (GSH) and attenuates liver injury.

Other findings suggest that S-adenosyl-L-methionine could be used as the basis of a drug regimen for improving liver function due to its safety.

Transmethyl (S-adenosyl-L-methionine) is a pleiotropic molecule that participates in multiple cellular reactions. This molecule participates in the following three types of reactions: transmethylation, transulfurization, and aminopropylation.

It has been established that S-adenosyl-L-methionine is the major methyl donor in methyltransferase reactions and that Transmethyl supplementation restores hepatic glutathione stores and attenuates liver injury.

Transmethyl also participates in many biochemical reactions in the human body, and acts as a key metabolite that regulates the growth, death, and differentiation of hepatocytes. In mammals, two genes (MAT1A and MAT2A) encode homologous MAT catalytic subunits.

However, Transmethyl biosynthesis is depressed in patients with chronic liver disease. Preclinical studies indicate that this depression could exacerbate liver injury; therefore, supplementation could represent a useful therapy.

Other uses of S-adenosyl-L-methionine (Transmethyl)

The body uses S-adenosyl-L-methionine to make certain chemicals in the body that play a role in pain, depression, liver disease, and other conditions.

People who do not produce enough S-adenosyl-L-methionine can naturally benefit from taking S-adenosyl-L-methionine as a supplement.

Some people take S-adenosyl-L-methionine by mouth to:

Depression, anxiety, heart disease, fibromyalgia, abdominal pain, osteoarthritis, bursitis, tendonitis, chronic back pain, dementia, Alzheimer’s disease, slowing down the aging process, chronic fatigue syndrome, improved mental performance, liver disease and illness Parkinson’s.

It is also taken by mouth to:

  • Attention deficit hyperactivity disorder, multiple sclerosis, spinal cord injury, seizures, migraine, lead poisoning, to break down a chemical in the body called bilirubin, or to help with disorders related to the accumulation of a chemical called porphyrin or its precursors.
  • Some women take S-adenosyl-L-methionine by mouth for PMS and a more serious form of PMS called PMDD. Some women also take S-adenosyl-L-methionine by mouth for hot flashes.
  • S-adenosyl-L-methionine is used intravenously (intravenously) for depression, osteoarthritis, AIDS-related nervous system disorders, fibromyalgia, liver disease, cirrhosis, and for a liver disorder that occurs in pregnant women. , which is called intrahepatic cholestasis.

S-adenosyl-L-methionine is injected as an injection for fibromyalgia, depression, and Alzheimer’s disease.

Physiological role of S-adenosyl-L-methionine

The S-adenosyl-L-methionine in Transmethyl is an important metabolically pleiotropic molecule that participates in multiple cellular reactions and influences numerous cellular functions.

Biochemically, it participates in three types of reaction: transmethylation, transulfurization, and aminopropylation. A comprehensive discussion of these metabolic pathways falls outside the scope of this review, however the key reactions will be briefly summarized.

S-adenosyl-L-methionine in Transmethyl is the methyl donor principle required for the methylation of nucleic acids, phospholipids, histones, biogenic amines and proteins.

Under standard conditions, most of the generated S-adenosyl-L-methionine is used in transmethylation reactions. Glycine-N-methyl transferase (GNMT) is the most abundant methyltransferase in the liver and is also present in the exocrine pancreas and prostate.

Regardless of the specific enzyme that mediates the reaction, a common product is S-adenosylhomocysteine ​​(SAH).

Removal of S-adenosylhomocysteine ​​by conversion to homocysteine ​​and adenosine in a reversible reaction catalyzed by S-adenosylhomocysteine ​​hydrolase (CE) is essential.

Since many S-adenosyl-L-methionine dependent methylation reactions are strongly inhibited by the accumulation of S-adenosylhomocysteine.

Homocysteine ​​is found at the intersection of the remethylation pathway and the transulfurization pathway through which homocysteine ​​can be processed to form the primary endogenous cellular antioxidant, glutathione.

In the former, homocysteine ​​is remethylated by methionine synthase (MS) in a process coupled to the folate or betaine methyltransferase (BHMT) cycle to re-form methionine.

Although it should be noted that the role of betaine methyltransferase is of much less importance in primates than in rodents.

Alternatively, the conversion of homocysteine ​​to crystallationin by crystalthionine β-synthase (CBS) begins the transulfurization pathway through which the methionine-derived sulfur atom in S-adenosyl-L-methionine is processed step by step into cysteine ​​and finally glutathione.

These pathways are self-regulated by the hepatic concentration of S-adenosyl-L-methionine, which acts as a potent inhibitor of methionine synthase and the activity of betaine methyltransferase and an activator of crystallationin β-synthase, so that Transmethyl in excess is preferentially partitioned into glutathione.

Folic acid and the cofactors vitamin B6 and B12 are necessary for the functioning of methionine synthase, crystalllationin β-synthase and betaine methyltransferase, respectively, therefore their availability will limit the enzymatic activity and, therefore, the levels of homocysteine ​​and liver methionine management.

The S-adenosyl-L-methionine in Transmethyl is also the precursor for the synthesis of polyamines that are necessary to preserve cell viability and proliferation.

In this case, S-adenosyl-L-methionine is decarboxylated by S-adenosyl-L-methionine decarboxylase and the aminopropyl group used to form polyamines, including the biologically active metabolite 5′-methylthioadenosine (MTA).

Transmethyl dosage

Treatment can be started with parenteral administration and continued orally or started orally.

Intrahepatic cholestasis : recommended dose: 10-25 mg / kg / day. Usual starting dose: 800 mg per day. Total daily dose: It should not exceed 1,600 mg.

Maintenance therapy : 800-1,600 mg / day.

Renal impairment : No studies have been performed in patients with renal impairment. Therefore, caution is advised when administering Transmethyl to these patients.

Hepatic impairment : pharmacokinetic parameters are similar in healthy volunteers and patients with chronic liver disease.

Administration : Transmetil should be swallowed whole and not chewed. For better absorption of the active ingredients and full therapeutic effects, Transmetil tablets should be taken with meals.

Transmethyl must be removed from the blister pack immediately before use. If the tablets are other than white or yellowish in color (due to holes in the foil), it is recommended that Transmethyl not be used.

Transmethyl interactions

Serotonin syndrome has been reported in patients taking transmethyl and clomipramine.

Therefore, although a possible interaction is postulated, caution is advised when administering Transmethyl concomitantly with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (such as clomipramine), and over-the-counter tryptophan and supplements based on herbs.

Side effects of Transmethyl

Clinical Trials : Transmethyl was studied in 2434 patients, of whom 1983 were exposed to Transmethyl with liver disease and 817 patients with depression, in controlled open-label trials of up to 2 years.

The following adverse reactions are based on 1667 patients in 22 clinical trials treated with Transmethyl, of whom 121 (7.2%) experienced a total of 188 adverse reactions.

Nausea, abdominal pain, and diarrhea were the most frequently reported adverse reactions. A causal relationship of the adverse event with the drug was not always evaluable.

Infections and infestations : urinary tract infection.

Psychiatric disorders : confusion, insomnia .

Nervous system disorders : dizziness, headache, paraesthesia.

Cardiac disorders: cardiovascular disorders.

Vascular disorders : hot flashes, superficial phlebitis.

Gastrointestinal disorders : abdominal distention and pain, diarrhea , dry mouth, dyspepsia, esophagitis, flatulence, gastrointestinal pain and bleeding, nausea, vomiting.

Hepatobiliary disorders : biliary colic, liver cirrhosis .

Skin and subcutaneous tissue disorders : hypihidrosis, pruritus , skin reactions.

Musculoskeletal and connective tissue disorders : arthralgia , muscle spasms.

General disorders and administration site conditions : Asthenia, chills, injection site reactions, influenza-like illnesses, malaise, peripheral edema, pyrexia.

Post Marketing Experience – Immune System Disorders – Anaphylactic Reaction.

Respiratory, thoracic and mediastinal disorders : laryngeal edema.

Skin and subcutaneous tissue disorders : injection site reactions (very rarely with skin necrosis), rash, angioedema.

Contraindications of Transmethyl

  • Hypersensitivity to Transmetil or to any of the components of Transmetil.
  • Patients with genetic defects affecting the methionine cycle and / or causing homocystinuria and / or hyperhomocysteinemia (such as β-synthase cystation deficiency, vitamin B12, metabolic defect).

In case of overdose

Cases of overdose with Transmethyl appear to be rare. Doctors should contact their local poison control centers. In general, patients should be monitored and provide supportive care.

Transmethyl Precautions

Ammonia levels should be monitored in patients with precirrhotic and cirrhotic states of hyperammonemia taking Transmethyl orally.

Because vitamin B12 and folate deficiencies can lower Transmethyl levels, at-risk patients like:

  • Anemia, liver disease, pregnancy or possible vitamin deficiencies due to other diseases or eating habits, for example vegans, these should have routine blood tests to check plasma levels.

If a deficiency is found, treatment with vitamin B12 and / or folic acid is recommended before or simultaneously with the administration of Transmethyl. Some patients may experience dizziness with the use of Transmetil.

Patients should be advised not to drive or operate machinery during treatment until they are reasonably certain that Transmethyl therapy does not affect their ability to participate in such activities.

Transmethyl is not recommended for use in patients with bipolar illness. There have been reports of patients who have switched from depression to hypomania or mania when treated with Transmetil.

There has been only one report from the literature on serotonin syndrome in a patient taking Transmethyl and Clomipramine.

Although a possible interaction is postulated, caution is advised when administering Transmethyl concomitantly with selective serotonin reuptake inhibitors, tricyclic antidepressants (such as Clomipramine), and over-the-counter and herbal supplements containing trytophan.

The efficacy of Transmetil in the treatment of depression was studied in short-term clinical trials (3-6 weeks duration).

The effectiveness of Transmetil in treating depression for long periods is unknown. There are many medications to treat depression, and patients should consult with their physician to determine the optimal therapy.

Patients should be encouraged to inform the physician if symptoms do not decrease or worsen during Transmethyl therapy.

Patients with depression are at risk for suicide and other serious events, and therefore should receive ongoing psychiatric support during treatment with Transmetil to ensure that symptoms of depression are appropriately addressed and treated.

There have been reports of transient or worsening anxiety in patients treated with Transmetil. In most cases, interruption of therapy was not necessary. In some cases, the anxiety resolved after a reduction in dose or discontinuation of therapy.

Interference with Hemocysteine ​​Immunoassays : Transmethyl interferes with homocysteine ​​immunoassays, which may show falsely elevated plasma homocysteine ​​levels in patients treated with Transmethyl.

In patients treated with Transmethyl, therefore, the use of non-immunological methods to measure plasma homocysteine ​​is recommended.

Effects on the ability to drive or operate machinery : Some patients may experience dizziness with the use of Transmetil.

Patients should be advised not to drive or operate machinery during treatment until they are reasonably certain that Transmethyl therapy does not affect the ability to participate in such activities.

Use in pregnancy and lactation : the use of high doses of Transmetil in women in the last 3 months of pregnancy did not produce any adverse effects. It is advisable to administer Transmetil in the first 3 months of pregnancy only if absolutely necessary.

Transmethyl should be used during breastfeeding only if the potential benefit justifies the potential risk to the baby.

Use in children : The safety and efficacy of Transmetil for use in children have not been established.

Use in the elderly : Transmetil clinical studies did not include a sufficient number of subjects ≥65 years of age to determine whether they respond differently from younger subjects.

Reported clinical experiences have not identified differences in responses between elderly and young patients.

In general, dose selection for elderly patients should be cautious, generally starting at the lower end of the dosage range, reflecting the greater frequency of decreased liver, kidney, or heart function, and concomitant disease or other drug therapy. .

Transmethyl (S-adenosyl-L-methionine) treatment for chronic liver disease

Intra-hepatic cholestasis

The efficacy of Transmethyl therapy has been examined in a variety of chronic liver conditions, although historically the greatest interest has been in the area of ​​intrahepatic cholestasis (IHC).

Intrahepatic cholestasis is a syndrome that develops from impaired bile flow at the sublobar level. This can occur due to:

Hepatocellular damage, including viral hepatitis, alcoholic hepatitis, or long-term use of total parenteral nutrition.

Canalicular membrane changes are often seen in drug-induced liver injury (eg oral contraceptives, antibiotics, etc.); genetic defects in bile transporters; obstruction of the canaliculi or ducts and ductopenia.

Alcoholic liver disease

The effects of Transmethyl supplementation in alcoholic liver diseases have been explored in various animal models and in various clinical trials.

In general, the results of preclinical studies have been positive. In isolated perfused liver, S-adenosyl-L-methionine attenuated ethanol toxicity by restoring total and mitochondrial glutathione in the liver.

Supplementation with S-adenosyl-L-methionine has been shown to reverse the depletion of S-adenosyl-L-methionine and glutathione; reduces liver fibrogenesis after exposure to carbon tetrachloride.

It restores the fluidity of the mitochondrial inner membrane of the hepatocyte and prevents the depletion of glutathione mediated by TNFα, improving steatosis, hepatocyte necrosis and elevations of alanine aminotransferase.

Nonalcoholic fatty liver disease

Transmethyl may influence the pathogenesis of nonalcoholic fatty liver disease through its role as a precursor of glutathione synthesis and also as a methyl donor in the synthesis of phosphatidylcholine, which is required for the assembly of very low lipoproteins. density and export of liver triglycerides.

The evidence for the role of methionine and S-adenosyl-L-methionine metabolism in the pathogenesis of NAFLD has been largely based on the study of pre-clinical models.

Long-term consumption of a diet deficient in methionine-choline (MCD) is associated with hepatic depletion of S-adenosyl-L-methionine and the development of histological fibrosis steatohepatitis.

Hepatitis viral

Several of the studies discussed so far have included a significant number of patients with viral hepatitis in the cohort and have indicated that Transmethyl may be effective in intrahepatic cholestasis of viral etiology.

An effect supported in a viral hepatitis cohort by an open study comparing S-adenosyl-L-methionine and traditional Chinese remedies for the treatment of jaundice.

However, the recent studies showing that Transmethyl may be an effective add-on therapy in the treatment of chronic hepatitis C (HCV) are arguably of greater interest.

Conclution

In conclusion, there is strong preclinical evidence that S-adenosyl-L-methionine has important physiological functions in health and that liver diseases of various etiologies can alter them.

Furthermore, it is clear that the hepatocellular concentration of S-adenosyl-L-methionine can influence various pathophysiological processes including:

Tissue oxidative stress, mitochondrial function, hepatocellular apoptosis, and malignant transformation, not to mention the intriguing data suggesting that chronic viral hepatitis can modulate interferon sensitivity through S-adenosyl-L-methionine.

These data suggest that S-adenosyl-L-methionine could offer substantial clinical benefits, however, very few large, high-quality clinical trials have been conducted to prove or disprove this.

In particular, Transmethyl can help improve liver function and, in the correct dose, could be used as the basis of a medication regimen. But Transmetil does not improve the outcome or reduce the occurrence of adverse events for chronic liver diseases.

And also, for certain diseases, such as cholestasis or viral hepatitis, the combination with other medications can be more effective than Transmethyl alone.

Therefore, the results of studies have limited clinical value. Furthermore, due to research problems on basic treatment with Transmetil, further study is required in the future.

Studies of new drugs for the treatment of certain liver diseases may also represent a more valuable research direction.