Valproic acid recipe. Pharmacological group of the substance: Valproic acid. Instructions for use

Composition and release form of the drug

Extended-release film-coated tablets white or almost white, oval, biconvex; on a cross section, white or almost white.

Excipients: silicon dioxide - 50 mg, hypromellose 4000 - 176 mg, ethylcellulose - 12 mg, sodium saccharinate - 10 mg, colloidal silicon dioxide - 4 mg.

Film shell composition: Opadry II white 730 mg, including polyvinyl alcohol - 46.9%, macrogol 4000 - 23.6%, talc - 17.4%, titanium dioxide 12.1%
Weight of coated tablet: 765 mg.

30 pcs. - bottles (1) - cardboard packs.
100 pieces. - bottles (1) - cardboard packs.

pharmachologic effect

Antiepileptic drug. It is believed that the mechanism of action is associated with an increase in the content of GABA in the central nervous system, which is due to inhibition of GABA transaminase, as well as a decrease in the reuptake of GABA in brain tissue. This apparently leads to a decrease in excitability and convulsive readiness motor areas of the brain. Promotes improvement mental state and the mood of patients.

Pharmacokinetics

Valproic acid is quickly and almost completely absorbed from the gastrointestinal tract, bioavailability when taken orally is about 93%. Food intake does not affect the degree of absorption. Cmax in the blood is reached after 1-3 hours. The therapeutic concentration of valproic acid in the blood plasma is 50-100 mg/l.

C ss is achieved on days 2-4 of treatment, depending on the intervals between doses. Plasma protein binding is 80-95%. Concentration levels in cerebrospinal fluid correlate with the size of the fraction not bound to proteins. Valproic acid penetrates the placental barrier and is excreted breast milk.

Metabolized by glucuronidation and oxidation in the liver.

Valproic acid (1-3%) and its metabolites are excreted by the kidneys. T1/2 with monotherapy and in healthy volunteers is 8-20 hours.

When combined with other drugs, T1/2 may be 6-8 hours due to the induction of metabolic enzymes.

Indications

Epileptic seizures: generalized, focal (focal, partial) with simple and complex symptoms, minor. Convulsive syndrome with organic diseases brain Behavioral disorders associated with epilepsy. Manic-depressive psychosis with a bipolar course that cannot be treated with lithium or other medications. Febrile seizures in children, baby tic.

Contraindications

Severe liver dysfunction; severe violations pancreatic functions; porphyria; hemorrhagic diathesis; severe thrombocytopenia; I trimester of pregnancy; lactation (breastfeeding); increased sensitivity to valproic acid.

Dosage

Individual. For oral administration in adults and children weighing more than 25 kg, the initial dose is 10-15 mg/kg/day. Then the dose is gradually increased by 200 mg/day at intervals of 3-4 days until clinical effect. Average daily dose is 20-30 mg/kg. For children weighing less than 25 kg and newborns, the average daily dose is 20-30 mg/kg.

Frequency of administration: 2-3 times/day with meals.

IV (in the form of sodium valproate) is administered at a dose of 400-800 mg or dropwise at a rate of 25 mg/kg for 24, 36 and 48 hours. If simultaneous use orally and intravenously is necessary, the first administration is carried out by intravenous infusion at a dose of 0.5-1 mg/kg/hour 4-6 hours after the last oral dose.

Maximum doses: when taken orally for adults and children weighing more than 25 kg - 50 mg/kg/day. Use at a dose of more than 50 mg/kg/day is possible subject to monitoring the concentration of valproate in the blood plasma. If the plasma concentration is more than 200 mg/l, the dose of valproic acid should be reduced.

Side effects

From the side of the central nervous system: possible trembling of hands or arms; rarely - changes in behavior, mood or mental state, diplopia, nystagmus, spots before the eyes, impaired coordination of movements, dizziness, drowsiness, headache, unusual agitation, restlessness or irritability.

From the outside digestive system: possible mild cramps in the abdomen or in the stomach area, loss of appetite, diarrhea, digestive disorders, nausea, vomiting; rarely - constipation, pancreatitis.

From the blood coagulation system: thrombocytopenia, prolongation of bleeding time.

From the side of metabolism: unusual decrease or increase in body weight.

From the gynecological status: violations menstrual cycle.

Dermatological reactions: alopecia.

Allergic reactions: skin rash.

Drug interactions

At simultaneous use neuroleptics, antidepressants, MAO inhibitors, benzodiazepine derivatives, ethanol increase the inhibitory effect on the central nervous system.

With the simultaneous use of drugs that have a hepatotoxic effect, hepatotoxicity may increase toxic effect.

With simultaneous use, the effects of antiplatelet agents (including) and anticoagulants are enhanced.

With simultaneous use, the concentration of zidovudine in the blood plasma increases, which leads to increased toxicity.

When used simultaneously with, the concentration of valproic acid in the blood plasma decreases due to an increase in the rate of its metabolism caused by the induction of microsomal liver enzymes under the influence of carbamazepine. Valproic acid potentiates the toxic effect of carbamazepine.

With simultaneous use, metabolism slows down and its T1/2 increases.

When used simultaneously with mefloquine, the metabolism of valproic acid in the blood plasma increases and the risk of developing seizures increases.

When used simultaneously with meropenem, a decrease in the concentration of valproic acid in the blood plasma is possible; with primidone - increased concentration of primidone in blood plasma; with salicylates - it is possible to enhance the effects of valproic acid due to its displacement by salicylates from its connection with blood plasma proteins.

When used simultaneously with felbamate, the concentration of valproic acid in the blood plasma increases, which is accompanied by manifestations of toxic effects (nausea, drowsiness, headache, decreased platelet count, cognitive impairment).

When used simultaneously with phenytoin during the first few weeks, the total concentration of phenytoin in the blood plasma may decrease due to its displacement from plasma protein binding sites by sodium valproate, induction of microsomal liver enzymes and acceleration of phenytoin metabolism. Next, the metabolism of phenytoin is inhibited by valproate and, as a result, the concentration of phenytoin in the blood plasma increases. Phenytoin reduces plasma concentrations of valproate, probably by increasing its metabolism in the liver. It is believed that phenytoin, as an inducer of liver enzymes, may also increase the formation of a minor, but hepatotoxic, metabolite of valproic acid.

With simultaneous use, valproic acid displaces its binding to plasma proteins, resulting in an increase in its concentration in the blood plasma. Phenobarbital increases the rate of metabolism of valproic acid, which leads to a decrease in its concentration in the blood plasma.

There are reports of increased effects of fluvoxamine when used simultaneously with valproic acid. When used concomitantly with fluoxetine, some patients experienced an increase or decrease in the concentration of valproic acid in the blood plasma.

With the simultaneous use of cimetidine and erythromycin, it is possible to increase the concentration of valproic acid in plasma due to a decrease in its metabolism in the liver.

special instructions

Use with caution in patients with pathological changes in the blood, organic brain diseases, a history of liver disease, hypoproteinemia, and renal dysfunction.

In patients receiving other anticonvulsants, treatment with valproic acid should be initiated gradually, reaching a clinically effective dose after 2 weeks. Then the gradual withdrawal of other anticonvulsants is carried out. In patients not treated with other anticonvulsants, clinical effective dose should be achieved in 1 week.

It should be borne in mind that the risk of side effects from the liver is increased during combination anticonvulsant therapy.

During treatment, it is necessary to regularly monitor liver function, picture peripheral blood, the state of the blood coagulation system (especially during the first 6 months of treatment).

Children are at increased risk of developing severe or life-threatening hepatotoxicity. In patients under 2 years of age and in children receiving combination therapy, the risk is even higher, but decreases with increasing age.

Impact on the ability to drive vehicles and operate machinery

During treatment you should be careful when driving Vehicle and other activities requiring high concentration attention and rapid psychomotor reactions.

Pregnancy and lactation

Valproic acid is excreted in breast milk. Concentrations of valproate in breast milk have been reported to be 1-10% of maternal plasma concentrations. Application during breastfeeding contraindicated.

Women childbearing age During the treatment period, it is recommended to use reliable methods of contraception.

Use in childhood

For impaired renal function

Use with caution in case of impaired renal function.

For liver dysfunction

Contraindicated in case of liver dysfunction, acute and chronic hepatitis. Use with caution if you have a history of liver disease.

It should be borne in mind that the risk of side effects from the liver is increased during combination anticonvulsant therapy. During treatment, liver function should be regularly monitored.

Formula: C8H16O2, chemical name: 2-Propylvaleric acid (and the form of calcium, magnesium or sodium salt).
Pharmacological group: neurotropic drugs/antiepileptic drugs; neurotropic drugs / mood stabilizers.
Pharmachologic effect: muscle relaxant, antiepileptic, sedative.

Pharmacological properties

Valproic acid, by inhibiting the enzyme GABA transferase, increases the concentration of gamma-aminobutyric acid in the central nervous system, which leads to a decrease in the level of convulsive readiness and the excitability threshold of the motor areas of the brain. After oral administration, valproic acid dissociates to valproate ion, which is absorbed into the blood plasma. Food reduces the rate of absorption. The maximum concentration of valproic acid in the blood plasma is achieved within 1 to 4 hours. The therapeutic level of valproic acid in the blood is 50 - 100 mcg/ml (depending on the permeability of the blood-brain barrier in each individual patient, it can be significantly lower or higher). Valproic acid is approximately 90% bound to plasma proteins. Valproic acid is metabolized in the liver: the main part is glucuronidated, the remaining is oxidized either in the mitochondria of hepatocytes (beta-oxidation) or with the participation of microsomal enzymes. The half-life of valproic acid ranges from 6 to 16 hours (depending on the activity of microsomal liver enzymes). Conjugates and metabolites of valproic acid are excreted by the kidneys. Valproic acid is excreted in breast milk.

Indications

Various forms of generalized seizures: large (convulsive), small (absences), polymorphic; childhood tics, focal seizures.

Method of administration of valproic acid and dose

Valproic acid is taken orally, immediately after or during meals. For adults, the daily dose at the beginning of therapy is 0.3 - 0.6 g, over 7 - 14 days it is gradually increased to 0.9 - 1.5 g, a single dose for adults is 0.3 - 0.45 g. For children, the daily dose is 15–50 mg/kg (at the beginning of therapy - 15 mg/kg, then gradual increase by 5 – 10 mg/kg per week).

When treating with valproic acid, it is advisable to monitor the level of bilirubin, the activity of liver transaminases, the activity of amylase, blood platelets, the picture of peripheral blood, the state of the blood coagulation system (every 3 months, especially with joint use with other antiepileptic drugs). For patients receiving other antiepileptic drugs, the transition to the use of valproic acid should be carried out gradually, after 2 weeks reaching a clinically effective dose, only then is it possible to gradually withdraw other antiepileptic drugs. In patients who have not received therapy with other antiepileptic drugs, a clinically effective dose should be achieved after 1 week. Development risk adverse reactions from the liver is higher when using combined anticonvulsant treatment, as well as in patients under 18 years of age. During therapy, it is necessary to refrain from potentially dangerous species activities (including driving), which require speed of psychomotor reactions and increased concentration attention. Drinks that contain ethanol are not allowed. Before surgical intervention must be carried out general analysis blood, determine coagulogram parameters, bleeding time. If symptoms develop during therapy with valproic acid acute abdomen, before surgical intervention it is necessary to determine the level of amylase in the blood to exclude acute pancreatitis. If any acute serious adverse reactions occur, you must immediately inform your doctor and decide whether to stop or continue therapy. To reduce the likelihood of developing dyspepsia, it is possible to take enveloping agents and antispasmodics. Abrupt withdrawal of valproic acid may lead to an increase in epileptic seizures.

Contraindications for use

Hypersensitivity, including familial (death of close relatives when using valproic acid), hemorrhagic diathesis, diseases of the pancreas and liver (in some patients there may be a marked decrease in the metabolism of valproic acid in the liver).

Restrictions on use

Aplasia bone marrow, childhood.

Use during pregnancy and breastfeeding

The use of valproic acid is contraindicated in the 1st trimester of pregnancy. In the 2nd and 3rd trimester of pregnancy, use is possible if the expected effects of treatment for the mother are higher possible risk for the fetus. While taking valproic acid, you must stop breastfeeding.

Side effects of valproic acid

Nausea, diarrhea, vomiting, stomach pain, increased appetite or anorexia, liver dysfunction, confusion, tremor, drowsiness, paresthesia, peripheral edema, leukopenia, bleeding, thrombocytopenia; with prolonged use - temporary hair loss.

Interaction of valproic acid with other substances

The effects of valproic acid are enhanced by other anticonvulsants, hypnotics and sedatives. When taking enveloping agents and antispasmodics, dyspeptic disorders caused by taking valproic acid are less likely to develop. Hepatotoxic drugs (including alcohol) increase the risk of liver damage, acetylsalicylic acid or anticoagulants increase the possibility of bleeding.

N03AG01 (Valproic acid)

Before using VALPROIC ACID you should consult your doctor. These instructions for use are for informational purposes only. For more complete information, please refer to the manufacturer's instructions.

Clinical and pharmacological group

02.011 (Anticonvulsant)

pharmachologic effect

Antiepileptic drug. It is believed that the mechanism of action is associated with an increase in the content of GABA in the central nervous system, which is due to inhibition of GABA transaminase, as well as a decrease in the reuptake of GABA in brain tissue. This apparently leads to a decrease in excitability and convulsive readiness of the motor areas of the brain. Helps improve the mental state and mood of patients.

Pharmacokinetics

Valproic acid is quickly and almost completely absorbed from the gastrointestinal tract, bioavailability when taken orally is about 93%. Food intake does not affect the degree of absorption. Cmax in blood plasma is achieved after 1-3 hours. The therapeutic concentration of valproic acid in blood plasma is 50-100 mg/l.

Css is achieved on days 2-4 of treatment, depending on the intervals between doses. Plasma protein binding is 80-95%. Concentration levels in the cerebrospinal fluid correlate with the size of the non-protein-bound fraction. Valproic acid penetrates the placental barrier and is excreted in breast milk.

Metabolized by glucuronidation and oxidation in the liver.

Valproic acid (1-3%) and its metabolites are excreted by the kidneys. T1/2 with monotherapy and in healthy volunteers is 8-20 hours.

When combined with other drugs, T1/2 can be 6-8 hours due to the induction of metabolic enzymes.

VALPROIC ACID: DOSAGE

Individual. For oral administration in adults and children weighing more than 25 kg, the initial dose is 10-15 mg/kg/day. Then the dose is gradually increased by 200 mg/day at intervals of 3-4 days until a clinical effect is achieved. The average daily dose is 20-30 mg/kg. For children weighing less than 25 kg and newborns, the average daily dose is 20-30 mg/kg.

Frequency of administration: 2-3 times/day with meals.

Maximum doses: when taken orally for adults and children weighing more than 25 kg - 50 mg/kg/day. Use at a dose of more than 50 mg/kg/day is possible subject to monitoring the concentration of valproate in the blood plasma. If the plasma concentration is more than 200 mg/l, the dose of valproic acid should be reduced.

Drug interactions

With the simultaneous use of neuroleptics, antidepressants, MAO inhibitors, benzodiazepine derivatives, ethanol, the inhibitory effect on the central nervous system increases.

With the simultaneous use of drugs that have a hepatotoxic effect, the hepatotoxic effect may be enhanced.

With simultaneous use, the effects of antiplatelet agents (including acetylsalicylic acid) and anticoagulants are enhanced.

With simultaneous use, the concentration of zidovudine in the blood plasma increases, which leads to increased toxicity.

When used simultaneously with carbamazepine, the concentration of valproic acid in the blood plasma decreases due to an increase in the rate of its metabolism due to the induction of microsomal liver enzymes under the influence of carbamazepine. Valproic acid potentiates the toxic effect of carbamazepine.

With simultaneous use, the metabolism of lamotrigine slows down and its T1/2 increases.

When used simultaneously with mefloquine, the metabolism of valproic acid in the blood plasma increases and the risk of developing seizures increases.

With simultaneous use, valproic acid displaces phenobarbital from binding to plasma proteins, resulting in an increase in its concentration in the blood plasma. Phenobarbital increases the rate of metabolism of valproic acid, which leads to a decrease in its concentration in the blood plasma.

There are reports of increased effects of fluvoxamine and fluoxetine when used simultaneously with valproic acid. When used concomitantly with fluoxetine, some patients experienced an increase or decrease in the concentration of valproic acid in the blood plasma.

With the simultaneous use of cimetidine and erythromycin, it is possible to increase the concentration of valproic acid in plasma due to a decrease in its metabolism in the liver.

Pregnancy and lactation

Valproic acid is excreted in breast milk. Concentrations of valproate in breast milk have been reported to be 1-10% of maternal plasma concentrations. During lactation, use is possible in cases of extreme necessity.

Women of childbearing age are advised to use reliable methods of contraception during treatment.

VALPROIC ACID: SIDE EFFECTS

From the side of the central nervous system: possible trembling of the hands or arms; rarely - changes in behavior, mood or mental state, diplopia, nystagmus, spots before the eyes, incoordination, dizziness, drowsiness, headache, unusual agitation, restlessness or irritability.

From the digestive system: possible mild cramps in the abdomen or in the stomach area, loss of appetite, diarrhea, digestive disorders, nausea, vomiting; rarely - constipation, pancreatitis.

From the blood coagulation system: thrombocytopenia, prolongation of bleeding time.

Metabolic: unusual decrease or increase in body weight.

From the gynecological status: menstrual irregularities.

Dermatological reactions: alopecia.

Allergic reactions: skin rash.

Indications

Epileptic seizures: generalized, focal (focal, partial) with simple and complex symptoms, minor. Convulsive syndrome in organic brain diseases. Behavioral disorders associated with epilepsy. Manic-depressive psychosis with a bipolar course that cannot be treated with lithium or other medications. Febrile convulsions in children, childhood tics.

Contraindications

Liver and pancreatic dysfunction, hemorrhagic diathesis, acute and chronic hepatitis, porphyria; hypersensitivity to valproic acid.

special instructions

Use with caution in patients with pathological changes in the blood, organic brain diseases, a history of liver disease, hypoproteinemia, and renal dysfunction.

In patients receiving other anticonvulsants, treatment with valproic acid should be initiated gradually, reaching a clinically effective dose after 2 weeks. Then the gradual withdrawal of other anticonvulsants is carried out. In patients not treated with other anticonvulsants, a clinically effective dose should be achieved after 1 week.

It should be borne in mind that the risk of side effects from the liver is increased during combination anticonvulsant therapy.

During the treatment period, it is necessary to regularly monitor liver function, peripheral blood patterns, and the state of the blood coagulation system (especially during the first 6 months of treatment).

Impact on the ability to drive vehicles and operate machinery

During the treatment period, care should be taken when driving vehicles and other activities that require high concentration and rapid psychomotor reactions.

Valproic acid is active substance, which has an antiepileptic effect and is part of a significant number of drugs used to treat convulsive syndrome. Active ingredient presented in the form of a sodium salt with a white crystalline structure, it is soluble in water and other organic compounds.

What is the effect of Valproic Acid?

Valproic acid has anticonvulsant, mild sedative and muscle relaxant effects. The direct mechanism of action is associated with inhibition of the enzyme GABA transferase, which leads to an increase in the content of gamma-aminobutyric acid directly in the structures of the central nervous system, and as a consequence, to a decrease in the level seizure activity most motor areas of the brain.

The use of valproic acid drugs entails a decrease in the incidence and severity of seizures, facilitates the course of epilepsy, reduces the likelihood of developing extremely severe complications.

Secondly, valproic acid can act on postsynaptic membranes, inhibiting transmission processes nerve impulse. This circumstance underlies the muscle relaxant effect of drugs containing this medicinal substance.

When the drug enters the intestinal lumen, it is quickly absorbed into the bloodstream, and the use of the drug with food reduces the effectiveness of drugs containing valproic acid.

The therapeutic concentration of the substance, which is about 50 - 100 micrograms per milliliter, is created 1 - 4 hours after taking the medicine. The connection with blood albumin is high, reaching 90 percent.

Penetrates well through most tissue barriers. Traces of this substance are detected not only in the cerebrospinal fluid, but also in the vast majority of other internal environments body, including amniotic fluid.

Metabolization processes are carried out by liver cells. Microsomal enzymes of hepatocyte mitochondria are involved in these reactions. The half-life ranges from 6 to 16 hours and depends on the functional state of the liver. End products of metabolism are eliminated by organs excretory system.

Some of the medicine is excreted in breast milk. Due to this circumstance, you should stop taking medications while breastfeeding.

What are the indications for use of the drug "Valproic acid"?

The instructions for use of drugs containing “Valproic acid” allow their use for the following diseases:

Treatment and prevention epileptic seizures, both focal and generalized;
Convulsive states with various diseases CNS;
Prevention of complications of epilepsy;
Manic-depressive psychosis, resistant to lithium drugs;
Availability nervous tic;
Convulsive conditions in childhood.

I remind you that the uncontrolled use of valproic acid drugs is inadmissible. Only a specialist who has the results of all necessary research, can select an effective and safe dosage medicines.

What are the contraindications for use of the drug “Valproic acid”?

The use of drugs is unacceptable in the presence of the following conditions:

Liver diseases;
Pathology of the pancreas;
Hemorrhagic diathesis;
Individual intolerance;
Porphyria.

Use of medication during pregnancy and lactation period absolutely unacceptable. During therapy, women should use reliable contraceptive methods.

What is the use and dosage of Valproic Acid?

The dosage should be selected individually. Typically, adult patients and children whose body weight exceeds 25 kilograms should be prescribed 10–15 mg per kilogram of body weight per day.

After several days of therapy, the amount of the drug should be increased by 200 mg per day. This technique must be practiced every 4 days until a significant effect is achieved. Maximum daily dosage should not exceed 50 mg per kilogram per day.

Intravenous administration involves the administration of 400–800 milligrams of sodium valproate during the day. During treatment, the level of valproate in the patient's blood should be constantly assessed, making adjustments to treatment if necessary.

What are the side effects of Valproic Acid?

From the outside nervous system: tremor of the limbs, changes in mental state, double vision, nystagmus, visual disturbances, headache, drowsiness, dizziness, psychomotor agitation, severe drowsiness, apathy, depressive states.

From the digestive system: pain in the stomach, loss of appetite, stool disorders, nausea, occasionally vomiting, liver damage.

Other consequences: increase or decrease in body weight, occur allergic reactions, menstrual irregularities, hair loss, changes in the hemogram.

What are the analogues of the drug “Valproic acid”?

The drugs are as follows: Konvulex, Dipromal, Depakine-chrono, Depakine 300 enteric, Depakine chrono 500, Valparin XP, Acediprol, Encorat chrono, Apilepsin, Encorat, Everiden, Orfiril, Convulsofin.

Conclusion

We talked about what and how to treat convulsive syndrome- treatment with Valproic acid. Treatment of central nervous system diseases is impossible without integrated approach, which includes means drug therapy, as well as general measures: a special medical and protective regime, correct balanced diet, preventing psycho-emotional overload and so on.

depakine

Depakine/Konvulex (Valproic acid)

Pharmacological group: anticonvulsants
Systematic (IUPAC) name: 2-propylpentanoic acid
Legal status: Prescription only (UK, US)
Application: orally, intravenously
Bioavailability: rapid absorption
Protein binding: depending on concentration, from 90% at 40 μg/ml to 81.5% at 130 μg/ml
Metabolism: hepatic-glucuronide coupling 30-50%, mitochondrial β-oxidation more than 40%
Half-life: 9-16 hours
Excretion: Less than 3% is excreted unchanged in urine
Formula: C8H16O2
Mol. mass: 144.211 g/mol

Valproic acid (VPA, valproate), acidic chemical compound, found clinical application as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and less commonly depression. It is also used to treat migraine headaches. VPA is liquid at room temperature, but it can react with a base such as sodium hydroxide to form the sodium salt valproate, which is a solid. This acid, salt or mixture of the two (valproate semisodium) is sold under various brands: Depakote, Depakote ER, Depakene, Depakene Crono (extended release in Spain), Depacon, Depakine, Valparin and Stavzor.
Approved uses various compositions vary by country, for example Valproate Semisodium is used as a mood stabilizer and in the US also as an anticonvulsant.
VPA is a histone deacetylase inhibitor and is being investigated as a treatment for HIV infection and various types cancer.

Indications for use of Depakine

As an anticonvulsant, valproic acid is used to control absence seizures, tonic-clonic seizures (grand mal seizures), complex partial seizures, and juvenile myoclonic epilepsy associated with Lennox-Gastaut syndrome. The drug is also used to treat myoclonus. In some countries, preparations containing valproate for parenteral use are also used as a second-line treatment for status epilepticus, as an alternative to phenytoin. Depakine is one of the most common drugs used to treat post-traumatic epilepsy. IN Lately the drug is used for the treatment of neuropathic pain, as a second-line drug, in particular for shooting pain from delta fibers.
In the United States, valproic acid is approved by the FDA for the treatment of manic episodes associated with bipolar disorder, How additional therapy for multiple seizures (including epilepsy), and for the prevention of migraines.
Depakine is also used not for direct purpose for control behavioral disorders in patients with dementia.
Randomized controlled trials have repeatedly shown that sodium valproate and valproic acid, when borderline disorder personality and antisocial disorder individuals may exhibit some (low to moderate) mood stabilizing effects that are noticeable compared to no treatment or placebo. This is because the drug is supposed to help reduce impulsive aggressive behavioral episodes and improve interpersonal understanding. These improvements are likely to be somewhat greater when used alongside a standard psychotherapeutic regimen for the treatment of these disorders, which often includes, among other things, individual intensive one-on-one cognitive behavioral therapy, possibly in a secure setting. However, these two personality disorders are known to be lifelong and quite resistant to treatment, with significant relapse rates.

Depakine's research

Depakine and HIV

The enzyme histone deacetylase 1 (HDAC1) is required for the HIV virus to remain latent, or dormant, in infected cells. When the virus is hidden, it cannot be killed by anti-HIV drugs. A study published in August 2005 showed that three out of four patients taking valproic acid in addition to highly active antiretroviral therapy (HAART) showed an average 75% reduction in latent HIV infection. The idea was that valproic acid, by inhibiting HDAC1, could bring HIV out of latency (reactivate it) and place it into the replicative cycle. Highly active antiretroviral drugs can stop the virus while the immune system can destroy infected cells. This flushing out of all latent viruses could thus potentially cure HIV-infected patients. Subsequent trials, however, did not find long-term effectiveness of valproic acid in HIV infections.

Use of Depakine for other diseases

IN clinical studies for the treatment of colorectal polyps in patients with familial adenomatous polyposis; treatment of hyperproliferative skin diseases (for example, basal cell carcinoma), as well as for the treatment inflammatory diseases skin (eg, acne) TopoTarget studied three different formulas of valproic acid. Current titles of these therapeutic agents– Savicol, Baceca and Avugane respectively.

Valproic acid and the creation of stem cells

Valproic acid's function as an HDAC inhibitor also leads to its use in direct reprogramming in the creation of induced pluripotent stem (pluripotent) cells, where the addition of VPA has been shown to reprogram human fibroblasts to pluripotent cells without the addition of the Klf4 and c-myc genetic factors. This function has also been explored in epigenetic therapy for the treatment of lupus.

History of the creation of valproic acid

Valproic acid was first synthesized in 1882 by Dr. B.S. Burton as an analogue of valeric acid, naturally found in valerian. It consists of two groups of cuts, hence the name “val.pro~ic”. Valproic acid at room temperature is a carboxylic acid. clear liquid. For many decades it was used only in laboratories as a “metabolically inert” solvent. organic compounds. In 1962, French researcher Pierre Eymard serendipitously discovered the anticonvulsant properties of valproic acid while using it as a vehicle for a number of other compounds that were being studied for anticonvulsant activity. He found that in laboratory rats the substance prevented the development of seizures induced by pentylenetetrazole. The substance was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide. Valproic acid is also used to prevent migraines and bipolar disorder.

Mechanism of action of Depakine

Valproate is believed to affect neurotransmitter function in the human brain, making it an alternative to lithium salts in the treatment of bipolar disorder. Its mechanism of action involves enhanced neurotransmission (by inhibiting transaminase, which breaks down). However, in last years Several other mechanisms of action of valproic acid on neuropsychiatric disorders have been proposed.
Valproic acid also blocks tension sodium channels and T-type calcium channels. These mechanisms make valproic acid anticonvulsant wide range actions.
Valproic acid is an inhibitor of the enzyme histone deacetylase 1 (HDAC 1), hence a histone deacetylase inhibitor.

Instructions for use of Depakine

The dosage depends on the disease and whether the treatment is preventative or emergency. For preventive treatment For bipolar disorder type 1, the dosage range can be tested using serum testing or mg per kilogram body weight testing: from a minimum of 250 mg of Depakine per day to 3000 mg per day. At emergency treatment For bipolar disorder type 1, the minimum dose would be 1000 mg per day.

Combination therapy

Valproic acid, or valproate, acts simultaneously with lithium, while combination therapy appears to be more effective than monotherapy with valproic acid or valproate. That's right, by at least, in relation to glutamate toxicity, amyotrophic lateral sclerosis, Huntington's disease and bipolar disorder.

Contraindications for taking Depakine

Pregnancy

Valproate causes birth defects; its use during pregnancy is associated with an approximately threefold increase in major anomalies, mainly spina bifida, and less commonly with the development of some other defects, including “valproate syndrome.” Characteristics of this syndrome include changes in facial features that typically develop with age and include trigonocephaly, forehead enlargement with bifrontal narrowing, palpebral folds, medial brow deficiency, flat nasal bridge, broad root nose, forward-turned nostrils, small septum, long upper lip and thin red borders of the lips, thick lower lip and a slight drooping of the corners of the lips.
Women who are planning to become pregnant should switch to another drug if possible. Women who become pregnant while taking valproate should be aware that it causes birth defects and cognitive impairment in newborns, especially when taken in high doses (although sometimes valproate is the only drug that can control seizures and seizures during pregnancy, which may still have more harmful consequences). Women in this case should take high doses and undergo prenatal screening (alpha-fetoprotein and ultrasound scanning in the second trimester), although screening and scanning do not detect all birth defects.
Valproate is an antagonist that can cause neural tube defects. Thus, folic acid may alleviate teratogenic problems. A recent study found that children of mothers taking valproate during pregnancy are at risk of having a significantly reduced IQ.

Autism risk

Human fetal exposure to valproic acid is associated with a risk of autism, and may duplicate features associated with autism associated with rat fetal exposure to valproic acid during neural tube closure.
One study found that embryonic exposure to valproate at day 11.5 resulted in significant local periodic connectivity in the cerebral cortex of young rats, consistent with a related theory of autism.

Risk of Low IQ

A 2009 study found that 3-year-old children of pregnant women taking valproate had a nine-point lower IQ than a well-matched control group. However, further research is needed in older children and adults.

Side effects of Depakine

Side effects are dose-dependent.
The main risk faced by individuals taking valproic acid is the possibility of sudden and severe, possibly fatal, immediate liver failure and disruption of pancreatic hematopoietic function, especially in individuals just starting treatment. This warning is the first listed side effect of the drug.
Anecdotal evidence suggests that long-term users of valproic acid (long-term users) suffer from kidney failure, usually as a result of having been injured or ill, or being on medication that has left their immune system suppressed.
Valproate is not recommended for many patients because it can cause weight gain.
Absolute contraindications are pre-existing severe hepatic or renal failure And certain types metastatic cancer, severe hepatitis or pancreatitis, terminal stage HIV infections AIDS, severe bone marrow suppression, urea cycle disorders and hematological coagulation disorders that cause lesions. Some patients with symptomatic but manageable AIDS, cancer, and liver or kidney disease continue to take the medication (usually at a reduced dose for more frequent analyzes blood) to avoid the need to manipulate drug treatment as long as possible.
Common side effects include dyspepsia or weight gain. Less common are fatigue, peripheral edema, acne, feelings of cold or chills, blurred vision, burning eyes, dizziness, drowsiness, hair loss, headaches, nausea, sedative effect and tremor. Valproic acid also causes hyperammonemia, an increase in ammonia levels in the blood that can lead to vomiting and lethargy, and ultimately cause mental changes and brain damage. Valproate levels within the normal range can cause hyperammonemia and subsequent encephalopathy. Lactulose does not reduce hyperammonemia caused by valproic acid. L-carnitine is used for hyperammonemia caused by valproic acid toxicity. There have been reports of cerebral encephalopathy without hyperammonemia or elevated levels valproate.
IN in rare cases valproic acid may cause pathological change blood, liver dysfunction, jaundice, thrombocytopenia and increased coagulation (clotting) due to lack of blood cells. In approximately 5% of pregnant users, valproic acid crosses the placenta and causes congenital anomalies that remind alcohol syndrome fetus, with the possibility of cognitive impairment. Because of these side effects, most doctors try to continue treatment, but insist on blood tests, first once a week and then every two months (those who have been taking it for long period, may be retested after six months; If a pregnant woman and her doctor decide to continue using the drug and continue the pregnancy, then frequent blood testing is mandatory, and possibly more high frequency diagnostic ultrasound of the fetus to identify the problem). In 20% of cases, a temporary increase in liver enzyme activity was reported during the first few months of taking the drug. In rare cases, inflammation of the liver (hepatitis) occurs, the first symptom of which is jaundice.
Valproic acid may also cause acute hematologic toxicity, especially in children, including rare reports of myelodysplasia and acute leukemia.
Use of valproate in women with epilepsy or bipolar disorder is associated with an increased prevalence of polycystic ovary syndrome.
Cognitive dysfunction, symptoms of Parkinson's disease, and even reversible pseudoatrophic brain changes have been reported with long-term treatment with valproic acid.
According to information provided with the prescription information for this drug, some people have become depressed or have suicidal thoughts while taking the drug, so those taking it should monitor for this side effect.

Overdose and toxicity of Depakine

Excessive amounts of valproic acid can lead to tremors, stupor, respiratory depression, coma, metabolic acidosis and death. Overdose in children is usually accidental, while in adults it is more likely to be a deliberate act. In general, serum or plasma concentrations of valproic acid are in the range of 20-100 mg/L at controlled treatment, but can reach 150-1500 mg/l in case acute poisoning. Monitoring serum levels is often done using commercial immunoassay methods, although some laboratories use gas or liquid chromatography.
In case of severe intoxication, hemoperfusion or hemofiltration can be used to accelerate the elimination of the drug from the body. Supplements are indicated for patients with acute overdose, as well as prophylactically for patients high risk. Acetyl-L-carnitine reduces hyperammonemia less noticeably than.

Drug interactions

Valproic acid may interact with carbamazepine because valproate inhibits microsomal epoxide hydrolase (mEN), the enzyme responsible for the breakdown of carbamazepine-10,11 epoxide (the main active metabolite of carbamazepine) into inactive metabolites. When inhibiting Meh, valproic acid causes accumulation of the active metabolite, prolonging the effect of carbamazepine and delaying its elimination.
Valproic acid also reduces the clearance of amitriptyline and nortriptyline.
may decrease the clearance of valproic acid, resulting in higher than expected serum levels of the anticonvulsant. In addition, combining valproic acid with the benzodiazepine clonazepam may result in profound sedation and increases the risk of absence seizures in patients predisposed to them.
Valproic acid and sodium valproate reduce the clearance of lamotrigine (Lamictal). In most patients, the dose of lamotrigine for coadministration with valproate should be reduced to half the monotherapy dose.
Valproic acid is contraindicated during pregnancy as it reduces intestinal reabsorption folic acid, which leads to the development of neural tube defects. Due to a decrease in the amount of folic acid, megaloblastic anemia can also develop. Phenytoin also reduces the absorption of folic acid, which may lead to the same side effects as well as valproic acid.

Valproic acid preparations

Branded products include:
Convulex (Pfizer in the UK and Byk Madaus in South Africa)
Depakene (Abbott Laboratories in the US and Canada)
Depakine ( Sanofi Aventis, France)
Depakine (Sanofi Synthelabo, Romania)
Deprakine (Sanofi Aventis, Finland)
Encorate (Sun Pharmaceuticals, India)
Epival (Abbott Laboratories, USA and Canada)
Epilim (Sanofi Synthelabo, Australia)
Stavzor (Noven Pharmaceuticals Inc)
Valcote (Abbott Laboratories, Argentina)

Chemistry

Valproic acid, 2-propylvaleric acid, is synthesized by alkylation of cyanoacetic ester with two moles of propyl bromide to produce dipropylcyanoacetyl ester. Hydrolysis and decarboxylation of the carboethoxy group produces dipropylacetonitrile, which hydrolyzes to valproic acid.

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depakin.txt · Last changes: 2016/03/17 19:59 - nataly