RU2468799C1 - Method of relieving alcohol abstinence syndrome by blockade of benzodiazepine receptors - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely addictology, and deals with relief of alcohol abstinence syndrome by blockade of benzodiazepine receptors. For this purpose anexate is introduced intravenously. Introduction is performed twice in strict succession through fixed 3 hours in dose 0.5 mg, reaching complete reduction of main clinical manifestations of alcohol abstinence syndrome. Duration of each introduction is 3-5 minutes.

EFFECT: method ensures increase of treatment efficiency and reduction of terms of relieving psychoneurologic and somato-vegetative manifestations of alcohol abstinence.

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Description

The invention relates to medicine, namely to the clinical and pharmacological section of narcology, in particular, can be used to stop the neuropsychiatric and somatovegetative manifestations of alcohol withdrawal.

The relief of alcohol withdrawal syndrome (AAS) continues to be a serious problem even when this event is carried out in specialized institutions, as the slightest underestimation of the general and individual features of this symptom complex, untimely or insufficiently balanced therapy of its main, key manifestations can lead to aggravation of AAS, be the starting point for the recovery of comorbid pathology, and cause disability or death of the patient.

In the treatment of AAS, a wide range of drugs (PMs) are used that have a clinically significant anxiopaedic effect as the main action in one of them or present as part of other effects in other drugs that have a greater breadth of pharmacological action (barbiturates, sedative antipsychotics, antidepressants , antihistamines and anticonvulsants, GABA (A) receptor agonists and GABA (B) subtypes, µ-opioid receptor antagonists, etc.).

Despite belonging to different pharmaceutical groups, pharmacodynamic and pharmacokinetic differences, many AAS-stopping drugs most often have a common final property - blockade of adreno-, dopamine- and noradrenergic structures, activation of GABA-positive effect. Their affinity for dopamine, opioid receptors, receptors for GABA (A) and GABA (B) subtypes, barbituric site, etc. should be higher than that of anxiogens, the overproduction of which during the AAS period is the neurochemical basis of this condition (acetaldehyde and condensation products, corticotropin-releasing hormone, β-phenylethylamine, stimulating neurokinurenins, free radical forms of oxygen, a wide group of β-carbolines and tribulin components " etc.). Having lost their place to drugs in receptor complexes, anxiogens undergo metabolic degradation, and drugs occupying receptors shield them from the effects of unmetabolized anxiogens.

It was confirmed that during emotional stress (and AAS includes this component), the neuronal receptors of the GABA (A) subtype lose their sensitivity to endogenous reception regulators. One of the primary links in this case was a decrease in the availability of the benzodiazepine site (α-subunit) to the ligand, which leads to a weakening of GABA transmission and the predominance of the action of anxiogens, including due to the inverse agonism of α-subunits, as well as through an agonistic effect in against picrotoxin receptors.

A presumptive circumstance that determines the functional tolerance of the GABA (A) subtype receptors is the conformational changes that occurred in them, in particular in the α-subunits. For this reason, the action of benzodiazepine anxiolytics (BDA), recognized as reference drugs in the treatment of AAS, can be not only weakened, but also cause a paradoxical (anxiogenic) effect, similar to the action of inverse agonists of BDR, and the additional introduction of these drugs can aggravate the course of AAS .

It should be emphasized that along with brain-specific BJD, localized only in the central nervous system (CNS), and in the central nervous system and outside it there is a mass of peripheral-type BJD. Little is known about them so far: the affinity of these receptors for BDR is extremely low, and the place of their localization is receptor complexes of various types. The assumption of their high affinity with various anxiogens is allowed. If confirmed, the role of a gigantic number of all BJDs (brain-specific and peripheral) may turn out to be more than large-scale in the genesis of various stressful, distressing states, including AAS. Significant changes in the point of view on the pharmacotherapy of this symptom complex are possible in a strategic and tactical relationship.

A known method of stopping alcohol withdrawal symptoms, selected as a prototype, including intravenous administration of flumazenil (anexate) (patent for the invention of the Russian Federation No. 2300378). Flumazenil (anexate) is administered sequentially in doses of 0.1 to 0.3 mg at time intervals of 1 to 15 minutes (international non-proprietary name flumazenil, trade name anexate)

The objective of the present invention is to optimize an individual approach to the relief of alcohol withdrawal syndrome anexat, increasing efficiency and reducing treatment time depending on the severity of alcohol withdrawal.

The problem is solved due to the fact that in the method of stopping alcohol withdrawal syndrome through blockade of benzodiazepine receptors, including intravenous administration of anexate, according to the invention, administration is carried out twice in a strict sequence after a fixed 3 hours at a dose of 0.5 mg, achieving complete reduction of the main clinical manifestations of alcohol withdrawal syndrome, with each administration being carried out within 3-5 minutes.

The technical result from the use of the invention is the relief of alcohol withdrawal symptoms by introducing in a strict sequence and in a certain dose of anexate.

Flumazenil (anexate) is an antagonist of benzodiazepine, which selectively blocks the effects on the central nervous system through benzodiazepine receptors.

The dosage of intravenously administered anxate (0.5 mg) is selected in accordance with the recommendations of all radars (Russian Drug Register). In this case, the introduction of anexate must be carried out slowly, within 3-5 minutes, which depends on the patient's current state of health, as well as on the state of his venous system. A more frequent administration of this drug helps to distract the patient in achieving relaxation processes, which are so necessary for AAS pharmacotherapy, which affects not only the normalization of the somatovegetative, but also the neuropsychiatric components of this condition. It must be emphasized that after 15-20 minutes after such an anxate administration, and often even during this procedure, a number of patients noted an improvement in overall well-being and mitigation of individual manifestations of AAS. Often this is accompanied by mild somnolence, and in some cases, the onset of drug sleep. Patients who woke up after anxate injection were distinguished by sufficient vigor, a tendency to compliance, significantly diminished manifestations of AAS and of all this symptom complex. It should be emphasized that a number of AAS symptoms in this group of patients were relatively easily qualified during their sleep (redness of the sclera, hyperreflexia, tachycardia, systolic hypertension, sweating). Other manifestations were evaluated immediately after awakening. Since the alleviation of individual symptoms of AAS and the improvement of overall well-being occurs in the absence of undesirable side effects, and often sleep, it was possible to interview awake patients for almost a 3-hour period.

The three-hour interval is explained by the fact that the drug actually leaves the body in an average of 160 minutes, i.e. only 20 minutes less than administration intervals (3 hours). The daily dose should not exceed 1 mg / day, therefore, division into two injections is necessary. Management is carried out depending on the individual characteristics of the patient for 3-5 minutes.

The relief of the main clinical manifestations of alcohol withdrawal syndrome, as practice has shown, occurs in two injections.

From the pharmacological properties of anexate (flumazenil), it was found that, along with blockade of the α-subunit of the GABA (A) subtype receptors, it at the 159 position of the amino acid sequence of the protein (anchor amino acid - tyrosine) has an internal agonistic activity to this site. In addition, anexate is also active against the non-benzodiazepine locus of the GABA (A) subtype receptors - its γ subunit: at position 77 (anchor amino acid - phenylalanine) and at position 130 (anchor acid - methionine) of the amino acid sequence of this subunit. Possessing such specific activity, anexate reduces the central psychomotor effects of anxiogens, whose production during the AAS period increases very much, and also eliminates convulsive activity. The drug is rapidly absorbed by parenteral administration. Its working concentration corresponds to 50%, and the volume of distribution in the equilibrium state is quite high and ranges from 0.9 to 1.1 l / kg. The action of anexate occurs within 1-2 minutes after its administration. Elimination is almost completely completed in 72 hours. The elimination half-life is within 40-80 minutes. The rate of administration is selected individually: from instant to 0.1-0.4 mg per hour. Symptoms of an overdose are not observed. The drug does not have addictive potential.

Data on the use of anexate were obtained experimentally after a series of experiments. Positive results of the experiments made it possible to determine the initial parameters, modes, and determine the sequence of actions. All this made it possible to conduct, in the established manner, clinical testing of the proposed method. This method reduces the treatment time and increases the effectiveness of treatment.

Patent studies have not identified methods characterized by the claimed combination of features, therefore, we can assume that this method meets the criterion of "novelty."

The use of a combination of distinctive features is also unknown, which indicates compliance with the criterion of "inventive step".

The inventive method can be carried out in any specialized medical institution, because this requires a well-known drug produced by domestic and foreign industry, therefore, it meets the criterion of "industrial applicability".

The essence of the method is illustrated by scheme 1 and tables: scheme 1 - research design; table 1 - groups of patients according to the most important clinical and anamnestic characteristics; table 2 - rating scale standardized registration of clinical symptoms of AAS; table 3 - indicators of the severity of clinical symptoms of AAS before the study; table 4 - a comparative analysis of the effect of the studied drugs on the duration of the relief of the clinical appearance of AAS (in hours).

To solve the problem on the basis of the drug treatment department of the Chelyabinsk Regional Drug Treatment Hospital from 2003 to 2005. a prospective (longitudinal), single-blind, randomized, placebo-controlled study was conducted. Its design was approved by the Hospital Committee on Biological Ethics (protocol No. 2 of 04/20/03). A comparative analysis of the AAS-stopping activity of flumazenil, BDA-relanium and placebo, a 0.9% sodium chloride solution, was performed.

Organization of the study. Patients were selected for the study with clinical inclusion and exclusion criteria.

Criteria for the selection of patients.

I. Criteria for inclusion in a clinical trial.

- Alcoholism stage II.

- Symptoms of AAS.

II. Exclusion criteria from a clinical trial.

- Untimely registration of indicators of clinical severity of AAS.

- Severity of symptoms ≥ 22 points.

- Any somatoneurological pathology requiring a special medication correction.

- Psychotic manifestations of any genesis.

- Convulsive seizure.

- The clinical picture of intoxication without manifestations of AAS.

- Pharmacological addiction of non-ethanol genesis.

- Female patients.

The distribution of patients in the studied groups. To comply with the principle of random selection, dynamic randomization was carried out (see Scheme 1 - study design). This randomization scheme ensures the random nature of patients entering the study groups and ensures equality of choice in groups throughout the study.

Since AAS is one of the urgent conditions requiring immediate treatment, the randomization procedure was ahead of the exclusion of patients from the study. If exclusion criteria were found at any time during the treatment of AAS, the patient dropped out of the study. So, for example, in 2 patients (Anexat group), 7 patients (Relanium group) and 27 people from the placebo control group, symptomatic relief of AAS did not occur (and in the placebo control group it even got a tendency to increase in 4 patients). In addition, failures were made in the timely registration of the dynamics of the clinical condition in the Anexat group (2 patients), the Relanium group (3 patients) and the placebo control group (3 patients). This led to the fact that the sample size exceeded the final values for these study groups who completed the procedure for stopping AAS.

Research Methods. The condition of patients included in the study was evaluated clinically. Immediately after hospitalization and clinical verification of AAS, a quantified assessment of the severity of the clinical manifestations of this condition was carried out in patients. In this case, a modified version of the scale used in the practice of narcological St. Petersburg was used. Research institute them. V.M. Bekhterev (see table 2).

Methods and routes of administration of drugs for the relief of AAS were as follows.

Anexate (0.5 mg of an aqueous solution of flumazenil in a 5 mg ampoule) was used in a single dose of 0.5 mg intravenously by slow titration of the dose for 3-5 minutes. With a visible alleviation of the clinical symptoms of AAS, the second administration was performed 3 hours before the clinical reduction of this condition was complete (in the case of the occurrence of drug sleep lasting more than 3 hours, quantification of the symptoms of AAS and the decision to administer 0.5 mg of anxate were taken intravenously after the patient woke up) . The absence of the desired effect after the first injection or the aggravation of the symptoms of AAS meant the transfer of the patient to "conventional stopping treatment."

Relanium (0.5% solution in an ampoule of 20 mg) was used in a single dose of 20 mg intravenously by slow, for 3-5 minutes, titration of the dose and a thorough assessment of the current condition of the patient with AAS. With a visible alleviation of the clinical symptoms of AAS, each subsequent administration of relanium was carried out 3 hours before the clinical manifestations of this condition were completely reduced (in the case of the occurrence of drug sleep lasting more than 3 hours, quantification of the symptoms of AAS and the decision to administer the next dose of the drug intravenously were made after the patient woke up ) In the absence of a stopping effect or aggravation of the symptoms of AAS, the patient was transferred to the "usual stopping treatment."

Sodium chloride (0.9% solution in an ampoule of 10.0 ml) was used in a single dose of 10.0 ml intravenously by slowly titrating this placebo with an exposure time between doses of 3 hours for 3-5 minutes. In the absence of an AAS-stopping effect or aggravation of the manifestations of AAS, the patient was transferred to "conventional stopping treatment."

Such an approach to the AAS relief procedure allows one to determine with sufficient accuracy the timing of the relief of symptoms of this condition and the entire AAS symptom complex. The duration of the relief of manifestations of AAS and all this condition is considered as an indicator of the effectiveness of the studied pharmacological agents. The results of dynamic observation of the clinical picture of AAS were recorded in a specially developed map.

Statistical processing of the results was carried out using the SPSS-10.0 application software package in the Windows-98 environment on a Pentium III PC. To process the obtained data, descriptive statistics methods and criteria for assessing the reliability of intergroup differences were used.

The results were expressed as the arithmetic mean and its standard error (M ± m). Intergroup comparisons of the studied parameters before the start of treatment were carried out using the Kolmogorov-Smirnov bilateral criterion recommended for this purpose. One-way Wilcoxon-Mann-Whitney test was used to compare independent samples after completion of treatment. In all cases, the differences were considered significant at p <0.05.

A comparative analysis of the clinical efficacy of AAS suppressants showed the following: AAS is a common manifestation of ethanol withdrawal syndrome in patients with alcoholism. The frequency of occurrence of AAS significantly exceeds alcoholic psychoses and convulsive states, which usually develop in alcoholic illness. Despite the evidence of the possibility of spontaneous relief of AAS, this syndrome can be fatal.

The above circumstances determine interest in the optimization of AAS relief methods. A comparative analysis of the effectiveness of AAS - stopping drugs (anexate, relanium, placebo) was carried out according to the criterion for the timing of the reduction of the condition in question. The studied drugs were used in monotherapy mode.

As a result of a quantified assessment of the clinical severity of the condition of patients with AAS before treatment, there was no intergroup differences in the clinical and anamnestic characteristics of patients with AAS included in the study (see table 1), as well as in the integrated indicator of the severity of the AAS symptom complex. This fact indicates the adequacy of the randomization procedure, which meets the requirements for controlled clinical trials.

A comparative assessment of the initial main (key) clinical manifestations of AAS (general weakness, tremor, hyperreflexia, tachycardia, sweating, systolic hypertension, redness of the sclera, addiction to alcohol, attraction to drinking liquids, language obstruction, anxiety, depression, agripnia, asthenia) is also not revealed significant differences between the studied groups. The same applies to its other symptoms (see table 3).

The most important criterion for the validity of clinical and pharmacological studies is placebo control. The indicators of the clinical effectiveness of placebo therapy were chosen as a control analysis of the effectiveness of the pharmacological means of stopping AAS - anexate and relanium. As a result of the comparisons, it was found that the most rapid relief of the AAS symptom complex as a whole and most of its clinical manifestations was observed with the use of anexate compared with not only placebo, but also relanium (see table 4).

As a result of comparisons, it was found that accelerated relief of the AAS symptom complex was generally observed with the use of anexate. The use of this drug significantly reduced the time to stop AAS, not only in comparison with placebo, but even with Relanium - the "gold standard" in the treatment of AAS. The prescription of anexate was clearly superior to the effects of relanium and in such important AAS symptoms as tremor, asthenia, depression, loss of appetite, a desire to drink fluids, anxiety, general weakness, redness of the sclera, tachycardia and systolic hypertension. Only 5 of the symptoms of this complex stopped without significant differences among themselves, but at a time much shorter than when using a placebo. These are agripnia, sweating, tongue overlay, alcohol craving and hyperreflexia (see table 4). Of the manifestations of AAS, the rate of regression of the most persistent and most sensitive to therapy symptoms should be noted. Sweating and tremors last the longest, and the craving for alcohol and poor appetite regress most quickly. In our study, agripnia, asthenia, and tremor, and sweating were effectively removed by anexate compared with placebo and relanium, and the rate of their reduction, even if it did not always reach significant differences among themselves, was quite high, although the initial severity of these symptoms exceeded the severity the rest. The craving for alcohol and poor appetite were among the most rapidly disappearing symptoms. However, if anexat exceeded relanium in the rate of regression of loss of appetite, then no significant difference between them was found to reduce the symptoms of craving for alcohol, although each drug in its effect on these manifestations of AAS was significantly superior to placebo control. Tongue obstruction and hyperreflection behaved in a similar way.

Based on the above, we can conclude that the screening of GABA (A) -type receptors during the AAS period is an effective way to accelerate overcoming this condition. The effective dosage of anexate found to be more directly related to the severity of AAS than to the weight of the patient. Both the initial and other dosages of anxate were administered intravenously, slowly, within 3-5 minutes, and the condition of the patient with AAS qualified both immediately (against the background of the introduction of drugs), and for the next 3 hours. In all the cases we examined, the alleviation of the symptoms of AAS and its clinical manifestations left no doubt about the advantage of anexate (flumazenil). It should be emphasized that the rapid reduction of tremor and the duration of drug sleep occurred within up to 3 hours after the first injection. After awakening, in such patients, a sharp abatement of the symptoms of AAS, as well as of this whole condition, was qualified. After the 2nd administration of anexate, within 3 hours of observation, signs of AAS in patients were not detected. None of them presented complaints of an agri-type nature, etc., that is, symptoms that not only resemble AAS, but also post-withdrawal manifestations. Undesirable side effects were not observed in any case. The drug had a noticeable anti-anxiety effect and, in our opinion, the antidepressant effect of anexate was supposedly indirect in nature. However, it should be noted that the significant effects of anexate in the reduction of symptomatic hypertension, redness of the sclera and tachycardia were due to the effective effect of this drug on the anxiety-depressive component of AAS, tremor and asthenia.

An example of treatment.

Patient I., born in 1964 hospitalized at 10:00 after a 1.5-week binge, followed by a 2-day abstinence from drinking alcohol. The clinical picture was determined by the presence of AAS (severity = 21 points) with the presence of such particular symptoms as: tremor - 2 points, agripnia - 1 point, asthenia - 1 point, depression - 1 point, loss of appetite - 1 point, sweating - 2 points , attraction to drink liquids - 1 point, anxiety - 2 points, language overlay - 1 point, craving for alcohol - 1 point, general weakness - 2 points, redness of the sclera - 1 point, hyperreflexia - 1 point, tachycardia - 2 points, systolic hypertension - 2 points. Already 15 minutes after the slow administration of anexate intravenously (administered within 5 minutes), there was a significant decrease in the feeling of internal tension, tremor from generalized was transformed into localized, weak severity (eyelids, tip of the tongue), the external manifestations of anxiety-depressive disorders faded, blood pressure from 160 / 90 was reduced to 145/90 mm Hg, and heart rate from 112 beats. in 1 min to 82 beats. in 1 min. As these changes, yawning intensified, which gradually, 30 minutes after the administration of anexate, developed into a medical sleep lasting 2 hours and 35 minutes. Upon awakening, a re-quantification of the manifestations of AAS and of this whole state was made, the severity of which corresponded to 8 points (local tremor - 1 point, asthenia - 1 point, sweating - 1 point, tongue overlay - 1 point, total weakness - 1 point, tachycardia - 1 point, systolic hypertension - 1 point, redness of the sclera - 1 point). Other signs of AAS were not detected. Repeated administration of anxate led to a final regression of the remaining symptoms for the period of sleep, which lasted 2 hours 15 minutes.

Thus, a 2-fold slow (over 5 minutes) intravenous administration of anexate to a patient with AAS (the interval between drug administration was 3 hours) led to accelerated reduction of the symptom complex of AAS itself and all of its listed manifestations. It should be emphasized that the amount of anexate (flumazenil) used was only 2 ampoules of 5 ml of an aqueous solution of drugs.

The whole process of stopping alcohol withdrawal in the Anexat group was significantly ahead of the time for stopping AAS in 2 other groups and amounted to 4 hours 50 minutes. The subsequent use of any means of AAS correction did not occur due to the exhaustive reduction of this state by anexat.

The result obtained in the implementation of this invention are the following points.

- The relief of AAS with anexate (flumazenil) was significantly more effective than the use of BDA and placebo.

- A single optimal dosage (0.5 mg) of anexate (flumazenil), the appropriate route and speed of its intravenous administration, as well as the time interval (3 hours) between these procedures during the AAS were determined.

- An accelerated reduction of the leading symptoms of AAS has been achieved, noted in all patients after the 1st intravenous injection of 0.5 mg of anexate (flumazenil) and is already final after the 2nd.

- No unwanted side effects.

- Lack of addictive potential.

- Ease of performing the cupping procedure.

Claims (1)

A method of stopping alcohol withdrawal syndrome through blockade of benzodiazepine receptors, including intravenous administration of anexate, characterized in that the administration is carried out twice in a strict sequence after a fixed 3 hours at a dose of 0.5 mg, achieving complete reduction of the main clinical manifestations of alcohol withdrawal syndrome, with each introduction carried out within 3-5 minutes

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