Alimemazin-Advance

Introduction

In modern psychopharmacotherapy, the main attention is paid to the use of second-generation antipsychotics (SGAs), which allow, with the least risk of complications, to reduce the severity of psychotic symptoms, prevent exacerbations and contain the progression of the disease, creating conditions for social rehabilitation measures [1-3].
At the same time, insufficient attention is paid to the treatment of the most acute manifestations of psychotic disorders, in particular psychomotor agitation, in the world scientific literature. In this regard, the exception is some domestic clinical guidelines [2-4], where the algorithm for prescribing antipsychotic drugs is presented in sufficient detail. Elimination of psychomotor agitation is the first and most important step in achieving the goals of the relief stage of treatment for psychosis. The speed of elimination of acute symptoms determines the length of the patient’s stay in the hospital, the resolution of legal issues, and the amount of medical care resources that are used to treat a particular patient. Moreover, agitation is the most risky manifestation of a mental disorder, not only due to the threat of dangerous actions, but also due to the high frequency of various medical complications - decompensation of existing diseases and the development of complications of psychopharmacotherapy. To prevent the latter, it is increasingly recommended to prescribe monotherapy with SGAs, which have a better safety profile, and only if they are ineffective, a transition to first-generation antipsychotics (FGAs), including injectable forms, is proposed, and in monotherapy with any of the high-potency drugs [3] . Unfortunately, a significant proportion of patients with exacerbation of schizophrenia are admitted to the hospital involuntarily, many patients tend to violate the treatment regimen, and the agitation is sometimes so pronounced that oral medication does not quickly produce the desired effect [5-7]. The situation is complicated by the fact that only a small number of antipsychotics have injectable dosage forms, and among SGAs there is only one such drug, which will be discussed below.

An option to overcome these difficulties was the transfer of patients at the relief stage of treatment or at the stage of follow-up treatment with traditional antipsychotics, FGAs, to atypical SGAs [8, 9]. But replacing an antipsychotic during the period of active reduction of psychosis is associated with the risk of deterioration of the patient’s mental state and the appearance of adverse events (AEs), which generally creates additional difficulties during the transition from inpatient to out-of-hospital treatment. For this reason, augmentation with tranquilizers is usually recommended to relieve agitation. However, there are also difficulties here: firstly, these are difficulties of an administrative and legal nature, secondly, tranquilizers have their own side effects and complications, and in addition, in a state of psychosis they act only as a palliative, putting the patient to sleep, without affecting the pathogenetic basis of psychosis. The point is that their positive effect is limited to the period of somnolence and tranquilization.

The topic of agitation, hostility and aggression is discussed in most detail in his work by S. Stahl [8] in the aspect of augmentation of the action of neuroleptics. By stipulating various conditions, the author acknowledges the possibility, validity, and sometimes the need for neuroleptic polypharmacy. In the manual G.Ya. Avrutsky and A.A. Neduva [10], the clinical rationale for the combined use of drugs (polyneurothymoanalepsy) was considered in the light of the general principles of stimulating the positive and correcting the negative aspects of pharmacotherapy.

A possible drug of choice for adjuvant treatment of agitation during manifest attacks and exacerbation of schizophrenia, for which SGAs are the main treatment, can be Alimemazine, which has an injectable form - a solution for intramuscular administration. Alimemazine is an aliphatic phenothiazine derivative, a “small, low-potency antipsychotic”, which, in its pharmacological properties, occupies an intermediate position between FGAs from a number of aliphatic phenothiazine derivatives and sedative antihistamines. Introduced into clinical practice in 1956, Alimemazine began to be used in psychiatry as a sedative and antipsychotic in the treatment of anxiety, insomnia, depression, senesto-hypochondriacal disorders and dermatozoal delirium [11, 12]. The uniqueness of Alimemazine's clinical activity vectors is determined by its receptor binding profile. It has weak D2-blocking activity, therefore it very rarely causes extrapyramidal symptoms, and this is associated with its antipsychotic activity, which, however, may be quite sufficient to relieve moderately severe psychotic manifestations, when the use of more powerful and less tolerated antipsychotic drugs may be unjustified [ eleven]. Alimemazine is effective in schizotypal disorder or low-progressive, senesto-hypochondriacal schizophrenia [13]. By moderately blocking α-adrenergic receptors (α1-adrenergic blocking effect) of the locus coeruleus and reducing ascending noradrenergic activation of the amygdala, Alimemazine has a pronounced anti-anxiety and sedative effect, which helps reduce symptoms of anxiety, fear, restlessness, and internal tension. Alimemazine blocks central H1-histamine receptors, which helps reduce agitation, irritability, anxiety, insomnia, algic manifestations and senestopathies. Additionally, it has a strong antiserotonin effect - it blocks 5-HT2A and 5-HT2C receptors. Alimemazine, like some other tricyclic phenothiazine antipsychotics, has an effect on monoamine reuptake and antidepressant activity and 5-HT1A partial agonist properties [11]. Blockade of presynaptic α2-adrenergic receptors to a greater extent than of postsynaptic α1-adrenergic receptors enhances the release of monoamines (norepinephrine and serotonin) into the synaptic cleft and brings Alimemazine closer to such well-known antidepressants as mirtazapine and mianserin. The presence of 5-HT6 and 5-HT7 blocking activity in Alimemazine can contribute to both its antidepressant, anxiolytic and analgesic properties, normalization of circadian rhythms and sleep architecture, and procognitive properties [14]. The wide spectrum of receptor activity of Alimemazine and its significantly stronger affinity for nondopamine receptors makes it similar to SGAs, and in clinical practice ensures its safety, especially with regard to the development of neurological side effects. For these reasons, the use of Alimemazine as an additional treatment for agitation, anxiety and sleep disturbances in patients with exacerbations of schizophrenia may be an alternative to the use of tranquilizers and sedative antipsychotics [11].

The purpose of this study was to analyze the effectiveness and safety of additional therapy of the injectable form of Alimemazine in exacerbation of the mental state of patients with schizophrenia with psychomotor agitation (agitation), impulsivity (sudden unmotivated, including dangerous behavior), irritability, conflict, hostility and aggressiveness, anxiety, and disorders sleep (insomnia),

The objectives of the observation program included:

— assess the general dynamics of psychosis and changes in mental status (reduction of positive symptoms) using the PANSS scale;

— assess the dynamics (reduction) of psychomotor agitation using the PANSS scale of positive and negative syndromes and the agitation scale (Agitated behavior scale, ABS);

— assess the dynamics (reduction) of anxiety using the Hamilton Anxiety Rating Scale (HARS);

— assess the dynamics (reduction) of sleep disorders based on clinical data, as well as on the basis of a visual analogue scale (VAS) for sleep quality filled out by the doctor and the patient;

— determine the nature and frequency of adverse events/reactions (AEs/ARs) when using Alimemazine.

The main parameter of effectiveness was a decrease in indicators of psychomotor agitation (agitation) by 20%. It was planned to obtain relevant data from the analysis of clinical manifestations, as well as the PANSS and ABS scales filled out by the doctor.

The following additional indicators were taken: a) reduction in the severity of exacerbation of schizophrenia according to clinical data, as well as the positive syndrome scale filled out by the doctor according to PANSS); b) reduction of anxiety by 30% according to clinical dynamics, as well as the HARS anxiety scale filled out by the doctor and, if possible, together with the patient; c) reducing the severity of sleep disturbances and improving its quality according to clinical data and indicators of the VAS scale filled out by the doctor and, if possible, together with the patient.

Material and methods

The study was conducted in the form of an observational program at the Moscow Psychiatric Clinical Hospital No. 1 named after. ON THE. Alekseeva. We observed 30 patients aged 18 to 65 years with a diagnosis of paranoid schizophrenia, established in accordance with ICD-10 criteria.

Clinical and demographic characteristics of patients are presented in Table. 1 .

Table 1. Clinical and demographic characteristics of patients

Table 1. Clinical and demographic characteristics of the studied group of patients

The criteria for inclusion of patients in the study were paranoid schizophrenia diagnosed according to ICD-10 (F20.0); the presence of an exacerbation of the disease, which was the reason for treatment in a psychiatric hospital with the prescription of an AVP; written informed consent of the patient for the collection of socio-demographic and medical data.

Non-inclusion criteria were patients’ refusal to be examined and participate in the study; the presence of contraindications to the prescription of Alimemazine solution for intramuscular administration.

All patients during the study period were hospitalized due to an exacerbation of the disease, accompanied by agitation, which arose or persisted at the start of observation during SGA therapy. In these cases, the psychopharmacotherapy chosen by the attending physician included various antipsychotics of this group, mainly those that have the ability to reduce the severity of positive and negative symptoms, but have a lesser inhibitory effect and influence on the extrapyramidal system.

Before Alimemazine was prescribed, 3 patients were treated with aripiprazole (at a dose of up to 20 mg/day), olanzapine (15-20 mg/day) - 6, paliperidone (6-9 mg/day) - 4 and risperidone (4-8 mg/day). ) - 17.

Alimemazine solution was used for 8-9 days. It was allowed to take concomitant therapy (correctors, antidepressants, mood stabilizers, etc.), which was prescribed by the attending physician according to indications: in connection with existing affective disorders or side effects of psychopharmacotherapy.

Observation of patients during the period of adjuvant use of Alimemazine to eliminate agitation was carried out for no more than 9 days at a daily individually selected daily dose - from 25 mg to 200 mg permitted by the instructions for the drug. Alimemazine solution was prescribed intramuscularly in addition to the main therapy of SGAs, which were used to treat exacerbation of paranoid schizophrenia. The treatment regimen assumed the possibility of repeated (1 to 4 times a day) intramuscular administration.

The dosage of basic antipsychotics/neuroleptics that have a reducing effect on the positive and negative symptoms of schizophrenia, as well as correctors of extrapyramidal symptoms, was determined by the doctor in accordance with the indications for the use of these drugs and the doses recommended in the instructions.

During the study period, the assessment of the patients' condition on the above scales was carried out 4 times: initially (before treatment, on the 1st day) and then on the 3rd, 5th or 6th day and on the 8th or 9th day of treatment with Alimemazine.

Patient observation was terminated if, in the opinion of the attending physician, there was a need to change antipsychotic therapy, for example, prescribing any additional sedative therapy, replacing the main SGA with an FGA, or prescribing combination therapy with two antipsychotics with a strong general or selective effect or more.

Statistical processing of the obtained data was carried out using the SPSS Statistics 23 program. The indicators were checked using non-parametric statistical methods (Wilcoxon test).

Teraligen tablet p/o 5 mg N 25

Trade name: Teraligen® Valenta

International nonproprietary name: alimemazine

Dosage form: film-coated tablets

Compound

One tablet contains:

active substance:

alimemazine tartrate - 5.0 mg or 10.0 mg;

Excipients:

lactose monohydrate, microcrystalline cellulose, pregelatinized starch, colloidal silicon dioxide (Aerosil), croscarmellose sodium, magnesium stearate.

shell composition:

for 5 mg dosage:

Opadry II 85F34655: partially hydrolyzed polyvinyl alcohol, macrogol-3350, talc, titanium dioxide E 171, carmine red dye E 120, aluminum varnish based on sunset yellow dye E 110, aluminum varnish based on indigo carmine E 132;

for 10 mg dosage:

Opadry II 85F34750: partially hydrolyzed polyvinyl alcohol, macrogol-3350, talc, titanium dioxide E 171, aluminum varnish based on charming red dye E 129, yellow iron oxide dye E 172, black iron oxide dye E 172.

Description: Round biconvex tablets, coated pink (for a dosage of 10 mg) or dark pink with a score (for a dosage of 5 mg); on the cross section, two layers are visible: the shell is pink (for a dosage of 10 mg) or dark pink (for a dosage of 5 mg) and the core is white.

Pharmacotherapeutic group: Anxiolytic agent. Sedative.

ATX code: [R06AD01].

Pharmacological properties

Pharmacodynamics

It is a phenothiazine derivative. Alimemazine acts as a mild sedative and anti-anxiety agent, has a positive effect on senesthopathy, obsession and phobia. It is used for psychosomatic manifestations that develop as a result of neurovegetative disorders, vascular, traumatic and infectious disorders of the central nervous system. The sedative effect helps normalize sleep in patients in this category. Has antiemetic and antitussive activity. The sedative and anxiolytic effect is due to the blockade of adrenergic receptors in the reticular formation of the brain stem. The antiemetic and vegetative stabilizing effect is due to the blockade of dopamine D2 receptors in the trigger zone of the vomiting center. Due to its antihistamine activity, alimemazine is used for allergic diseases, especially the respiratory tract, and for itchy skin. Alimemazine is more active in antihistamine and sedative action than diprazine. The antipruritic effect is due to the effect on type 1 histamine receptors.

Pharmacokinetics

Quickly and completely absorbed by any route of administration. The effect of alimemazine begins 15-20 minutes after administration and lasts 6-8 hours. The binding to plasma proteins is 20-30%. Metabolized in the liver. Excreted by the kidneys - 70-80% in the form of a metabolite (sulfoxide).

Indications for use

In adults and children over 7 years of age:

As a sedative (calming), anxiolytic (anti-anxiety) and sleep aid:

- dementia (including dementia due to epilepsy), occurring with manifestations of psychomotor agitation, anxiety affect (as part of combination therapy);

- organic anxiety disorder (as monotherapy or as part of combination therapy);

- schizophrenia (with a predominance of neurosis-like disorders, as part of combination therapy);

- mood disorders (affective disorders) - as part of combination therapy;

- generalized anxiety disorder (as part of combination therapy);

— obsessive-compulsive disorder (as part of combination therapy);

- reaction to severe stress and adaptation disorders (acute reaction to stress, post-traumatic stress disorder, unspecified reaction to severe stress, other reactions to severe stress) - as part of combination therapy;

— dissociative (conversion) disorders (as part of combination therapy);

- somatoform disorders (somatization disorder, undifferentiated somatoform disorder, hypochondriacal disorder, somatoform dysfunction of the autonomic nervous system, persistent somatoform pain disorder, unspecified somatoform disorder, other somatoform disorders) - as part of combination therapy for severe anxiety or when standard therapy is ineffective;

- unspecified disorder of the autonomic nervous system, other disorders of the autonomic nervous system (as part of combination therapy);

- anorexia nervosa (as part of combination therapy);

- emotionally unstable personality disorder (impulsive and borderline types) - as part of combination therapy;

- hysterical personality disorder, anxious (avoidant, avoidant) personality disorder (as part of combination therapy);

— persistent personality change after experiencing a disaster (as part of combination therapy);

- hyperkinetic behavior disorder (as part of combination therapy);

- behavioral disorder limited to the family ( as part of combination therapy when standard therapy is ineffective);

- unsocialized behavior disorder (in the form of monotherapy or as part of combination therapy);

- anxiety, agitation and other symptoms and signs related to the emotional state (as part of combination therapy);

- other neurotic disorders ( neurasthenia, unspecified neurotic disorder) - as part of combination therapy;

— insomnia of non-organic etiology (as part of combination therapy when standard therapy is ineffective);

- emotional disorders whose onset is specific to childhood (phobic anxiety disorder in childhood, social anxiety disorder in childhood, sibling rivalry disorder, unspecified emotional disorder in childhood, other emotional disorders in childhood ) - as part of combination therapy.

As an antiallergic agent:

- itching regardless of location and etiology (anal itching, vulvar itching, unspecified anogenital itching, itching with photocontact dermatitis and solar urticaria, dermatitis, eczema, urticaria, bites or stings from non-venomous insects or other non-venomous arthropods, chickenpox, measles, Hodgkin's disease , diabetes mellitus, herpes zoster) as monotherapy or as part of combination therapy;

- asthma, hay fever, whooping cough (as part of complex therapy as an antiallergic agent to relieve cough, shortness of breath and asthma attacks);

- unspecified allergy (as monotherapy or as part of combination therapy).

In children from 3 years of age:

As an antiallergic agent:

- itching regardless of location and etiology (itching with photocontact dermatitis and solar urticaria, dermatitis, eczema, urticaria, bites or stings from non-venomous insects or other non-venomous arthropods, chickenpox, measles, Hodgkin's disease, diabetes mellitus, herpes zoster, itching of the anus, vulvar itching, unspecified anogenital itching) as monotherapy or as part of combination therapy.

As a sedative (calming agent):

- during medicinal preparation for surgery (for the purpose of sedation before surgery).

Contraindications

- hypersensitivity to the components of the drug;

- lactose intolerance, lactase deficiency, glucose-galactose malabsorption;

- angle-closure glaucoma;

- prostatic hyperplasia;

- severe liver and/or kidney failure;

- parkinsonism;

- myasthenia;

- Reye's syndrome;

- simultaneous use of monoamine oxidase inhibitors (MAO);

- pregnancy;

- lactation period;

- children up to 3 years of age when used as an antiallergic agent and for sedation before surgery, up to 7 years for other indications.

Precautions for use

The drug should be used with caution in case of alcoholism if there is a history of complications when using phenothiazine drugs; with obstruction of the bladder neck; predisposition to urinary retention; for epilepsy; open-angle glaucoma; jaundice; suppression of bone marrow function; arterial hypotension.

Use during pregnancy and breastfeeding

Contraindicated for use during pregnancy and lactation (breastfeeding). If pregnancy occurs during treatment, the drug should be discontinued. If it is necessary to use the drug during lactation, breastfeeding should be stopped.

Directions for use and doses

Inside. Without chewing. The effect of the drug is dose-dependent; doses are selected depending on the goals of therapy.

For adults

To achieve a vegetative stabilizing effect, 15-60 mg/day.

To achieve an anxiolytic effect, 20-80 mg/day.

To achieve a sedative and/or hypnotic effect, 5-10 mg once (20-30 minutes before bedtime).

For the symptomatic treatment of allergic reactions, 10-40 mg/day.

The course of treatment should begin with 2.5-5 mg in the evening with a gradual increase in the daily dose until the desired effect. The daily dose can be divided into 3-4 doses.

The duration of the course of treatment can be from 2 to 6 or more months and is determined by the doctor.

The highest dose for adults is 500 mg/day, for elderly people (over 60 years old) – 200 mg/day.

Children from 7 years of age are prescribed according to the following scheme (depending on age and body weight).

To achieve an anxiolytic effect, 20-40 mg/day.

The course of treatment should begin with 2.5-5 mg with a gradual increase in the daily dose until the desired effect. The daily dose can be divided into 3-4 doses.

To achieve a sedative and/or hypnotic effect, 2.5-5 mg once (20-30 minutes before bedtime).

To achieve a sedative effect in behavioral disorders in psychotic conditions, it is possible to increase the daily dose to 60 mg/day.

For the symptomatic treatment of allergic reactions, 5-20 mg/day.

The duration of the course of treatment can be from 2 to 6 or more months and is determined by the doctor.

Children from 3 years old

For the symptomatic treatment of allergic reactions, 2.5-5 mg 3-4 times a day.

The duration of the course of treatment can be from 2 to 6 or more months and is determined by the doctor.

For the purpose of sedation before surgery, children from 3 to 7 years old are prescribed at the rate of 2 mg/kg 1-2 hours before surgery. The maximum daily dose is 2 mg/kg.

Side effect

Side effects are extremely rare and mild.

From the nervous system: drowsiness, lethargy, fatigue (occurs mainly in the first days of use and rarely requires discontinuation of the drug), paradoxical reaction (anxiety, agitation, nightmares, irritability); confusion, extrapyramidal disorders (hypokinesia, akathisia, tremor).

From the senses: blurred visual perception (accommodation paresis), noise or ringing in the ears.

From the cardiovascular system: dizziness, decreased blood pressure (BP), tachycardia.

From the digestive system: dryness of the oral mucosa, atony of the gastrointestinal tract, constipation, loss of appetite.

From the respiratory system: dry nose, throat, increased viscosity of bronchial secretions.

From the urinary system: bladder atony, urinary retention.

Other: allergic reactions, inhibition of bone marrow hematopoiesis, increased sweating, muscle relaxation, photosensitivity.

Overdose

Symptoms: increased manifestations of the described side effects, with the exception of allergic reactions.

Treatment: drug withdrawal, symptomatic therapy.

Interaction with other drugs

Alimemazine enhances the effects of narcotic analgesics, hypnotics, anxiolytic (tranquilizers) and antipsychotic (neuroleptic) drugs (drugs), as well as drugs for general anesthesia, m-anticholinergic drugs and antihypertensive drugs (dose adjustment required). Tricyclic antidepressants and anticholinergic drugs enhance the m-anticholinergic activity of alimemazine. With the simultaneous use of alimemazine with ethanol, increased depression of the central nervous system is possible.

Alimemazine weakens the effect of phenamine derivatives, m-cholinomimetics, ephedrine, guanethidine, levodopa, dopamine.

When alimemazine is used together with antiepileptic drugs and barbiturates, the threshold for convulsive activity is reduced (dose adjustment required).

When alimemazine is used together with beta-blockers, a pronounced decrease in blood pressure and arrhythmias are possible.

Alimemazine weakens the effect of bromocriptine. With simultaneous use in nursing mothers, an increase in the concentration of prolactin in the blood serum is possible.

With the simultaneous use of alimemazine and MAO inhibitors (simultaneous use is not recommended) and alimemazine and phenothiazine derivatives, the risk of arterial hypotension and extrapyramidal disorders increases.

With the simultaneous use of alimemazine with drugs that inhibit bone marrow hematopoiesis, the risk of myelosuppression increases.

The combined use of phenothiazine derivatives (which includes alimemazine) with hepatotoxic drugs may enhance the manifestations of hepatotoxicity of the latter.

special instructions

Alimemazine may mask the ototoxic effect (tinnitus, dizziness) of co-administered drugs.

Alimemazine increases the body's need for riboflavin.

To prevent distortion of the results of skin prick tests for allergens, the drug should be discontinued 72 hours before allergy testing.

During treatment, false positive results for pregnancy are possible.

During treatment you should not drink alcohol.

Impact on the ability to drive vehicles and operate machinery:

During treatment with the drug, you should not engage in activities that require increased concentration of attention and speed of psychomotor reactions (driving a car and other vehicles, working with moving mechanisms, working as a dispatcher and operator).

Release form

Film-coated tablets, 5 mg and 10 mg.

25 tablets in a blister pack or in a blister pack with perforation made of polyvinyl chloride film and printed varnished aluminum foil.

1, 2 or 4 contour packages along with instructions for use are placed in a pack.

Storage conditions

In a place protected from light at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Best before date

3 years.

Do not use after the expiration date stated on the packaging.

Vacation conditions

Available with prescription