PAGLUFERAL-3 N20 tab.

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Manufacturers: Moscow Pharmaceutical Factory (Russia)

Active ingredients

Calcium gluconate
Caffeine
Papaverine
Phenobarbital

Disease class

Pharmacodynamics

Combined antiepileptic drug.

Phenobarbital interacts with the barbiturate site of the benzodiazepine-GABA receptor complex, thereby increasing the sensitivity of GABA receptors to GABA, leading to the opening of neuronal channels for chlorine ions, which leads to an increase in their entry into the cell. Reduces the excitability of neurons in the epileptogenic focus and the propagation of nerve impulses. Shows antagonism towards a number of excitatory mediators (glutamate). Suppresses the sensory zones of the cerebral cortex, reduces motor activity, inhibits cerebral functions, incl. respiratory center. Reduces the tone of the smooth muscles of the gastrointestinal tract. It has anticonvulsant, sedative, hypnotic and antispasmodic effects.

Caffeine increases reflex excitability of the spinal cord, stimulates the respiratory and vasomotor centers, stimulates metabolic processes in organs and tissues, incl. in muscle tissue and the central nervous system.

Papaverine hydrochloride, an antispasmodic agent, has a hypotensive effect. Reduces tone and relaxes smooth muscles of internal organs and blood vessels.

Calcium gluconate compensates for the deficiency of calcium ions necessary for the process of transmitting nerve impulses.

Bromizoval has a sedative and moderate hypnotic effect.

Pagluferal in the treatment of epilepsy

Pharmacotherapy of epilepsy has a long history. Before the discovery of bromides as a treatment for epilepsy, there were no effective treatments for this disease. Bromine salts were described as AEPs in 1857, but the discovery was largely accidental. When E. Sieveking presented information on 52 cases of epilepsy at a meeting of the Royal Medical and Surgical Society in London (UK), one of the doctors, C. Locock, noted that he uses potassium bromide to treat “hysterical” epilepsy, which usually occurs during the menstrual period. He also noted that potassium bromide causes impotence in men, voicing the idea that this substance reduces sexual desire in women, thereby reducing epileptic activity [28].

A few decades later, the German chemist A. von Baeyer synthesized “malonylurea” by reacting urea with malonic acid, a substance found in apples. Subsequently, this compound was named “barbituric acid”. This discovery led to the emergence of various derivatives: for example, in 1903, Fischer and von Mering synthesized a medicinal barbiturate that had a hypnotic effect. Further research into barbiturates led to the creation of phenobarbital. A clinical study conducted by Hauptmann in 1912 demonstrated both the sedative and anticonvulsant effects of phenobarbital [28].

Further changes to the phenobarbital molecule led to the discovery of benzodiazepines [32]. The next drug after phenobarbital to enter widespread clinical practice was phenytoin. After this, other drugs began to be used: for example, primidone came into practice in 1952 [33]. It was synthesized by slightly altering the phenobarbital molecule. The effectiveness of primidone was proven using the maximal shock model developed by M. Putnam.

Ethosuximide was used to treat epilepsy in 1960, and carbamazepine in 1974. Valproic acid accidentally became an AED in 1960. Previously, it was used as a solvent for about 100 years, but in animal testing it was found to be more effective than experimental drug of initial interest.

In 1969, the National Institute of Neurological Disorders and Stroke (NINDS) initiated the AED development program under the leadership of J. Kiffen Penry. In 1975, given the shortage of drugs used to combat epilepsy, the NINDS Epilepsy Division, in collaboration with the University of Utah (USA), created the Anticonvulsant Screening Project [34, 35]. At this time, pharmaceutical companies were not developing new AEDs, and NINDS hoped to stimulate corporate interest by identifying promising compounds through a drug screening program.

Pagluferal as a drug based on the “mixture of Sereysky,” a leading Russian psychiatrist and biochemist, was introduced into medical practice on April 3, 1980. The mixture itself by M.Ya. Sereisky invented and began to use it in the mid-1940s. during and after the Great Patriotic War due to the huge number of wounded military personnel who had traumatic brain injuries. In Pagluferal, phenobarbital is not used as a single drug, but in combination with other active ingredients. The action of phenobarbital is supported by the sedative component bromizoval. Papaverine, which is part of the drug, improves cerebral blood flow, eliminating vasospasm, caffeine-sodium benzoate reduces excessive sedative effect, calcium gluconate has a general strengthening and desensitizing effect.

To date, the anticonvulsant screening project has identified more than 24 thousand compounds.

A long period of time passed between the introduction of valproate and carbamazepine and the FDA approval of a number of new AEDs. In the 1970s In France, the study of vigabatrin, which belonged to the second generation of AEDs, began. It was designed specifically to increase γ-aminobutyric acid (GABA) levels in the brain by blocking the enzyme GABA transaminase. This development was based on the basic hypothesis that by increasing the level of the main inhibitory neurotransmitter in the brain, seizure control can be achieved. Tiagabine, a GABA reuptake receptor inhibitor, has also been developed to increase GABA concentrations and is an effective treatment for partial-onset seizures.

The past 10 years have seen a rapid emergence of new AEDs, such as gabapentin, felbamate, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, topiramate, and zonisamide; these drugs entered the market between 1994 and the late 2010s. [10]. None of them were developed solely on the basis of a given hypothesis regarding the mechanism of action, although we subsequently learned a lot about the anticonvulsant effects of these drugs.

It is surprising that the rich arsenal of newer AEDs, many of which are associated with new mechanisms of action and better pharmacokinetics, have not demonstrated greater efficacy than classic drugs in comparative clinical studies in persons with newly diagnosed epilepsy. More often, these studies showed equivalent effectiveness of classic and new AEDs [20–22, 24–26,40, 43]. But new drugs more often had advantages related to safety, tolerability and pharmacokinetics. In patients with refractory epilepsy, new AEDs can reduce seizure frequency by up to 50% when added to existing therapy, but rarely eliminate seizures completely [31].

Tactics of drug therapy

The goal of treatment for patients with epilepsy is maximum effectiveness with a minimum of side effects. However, many patients experience side effects from AEDs, and some experience seizures that are refractory to drug therapy [15].

Monotherapy is preferred in treatment because it reduces the likelihood of side effects and avoids drug interactions [12].

People who suffer from epileptic seizures experience psychological problems after diagnosis; they may require social and/or vocational rehabilitation. According to the literature, the prevalence of anxiety disorders in people with epilepsy is 25%, which is twice as high as in the general population, but their actual prevalence needs further clarification [6]. High levels of anxiety are associated with young age and short duration of epilepsy [5]. Many doctors underestimate the impact that a diagnosis of epilepsy can have on patients. For example, patients with epilepsy may live in fear of another seizure, they may not be able to drive a car or work at heights. Only remission of seizures gives a person diagnosed with epilepsy the opportunity to live a full life, no different from the life of healthy people [13].

Some intractable cases require a neurologist or epileptologist to use additional diagnostic tools, including video-electroencephalographic monitoring, to identify the cause of these attacks. For example, in our study, epilepsy began with nocturnal attacks in 48% of those examined; in 30.5% of cases, attacks appeared exclusively during sleep [7]. If surgical treatment (for example, for Kozhevnikov–Rasmussen encephalitis) is possible for persons with epilepsy, consultation with a neurosurgeon is recommended [8, 9].

For patients who have had more than one unprovoked epileptic seizure, anticonvulsant therapy is recommended. However, the standard of care for a single unprovoked seizure is to avoid common seizure triggers (eg, alcohol, lack of sleep); It is not recommended to prescribe anticonvulsants in this case unless the patient has risk factors for relapse. According to various authors, the etiological factors of epilepsy in elderly patients are most often vascular diseases of the brain (48.3%), traumatic brain injury (12.1%), operated brain tumors (4.7%) and alcoholism ( 3.4%) [1]. The incidence of epileptic seizures in patients with multiple sclerosis is approximately 1%, which is 2.5 times higher than the population indicators for the adult population [2]. Disturbances in water-electrolyte homeostasis are considered in 2 aspects: as a possible factor in provoking acute symptomatic seizures in patients with decompensation of water-electrolyte hemostasis and as a factor in destabilizing the disease in patients with epilepsy [14]. Eating epilepsy is a type of reflex epilepsy [16].

The risk of relapse within 2 years after the first unprovoked attack is 15–70%. The main factors that increase the risk of relapse are brain abnormalities detected by magnetic resonance imaging (MRI), electroencephalography (EEG), and the partial nature of the attack.

MRI may reveal local abnormalities in the cortical or limbic region, indicating a possible epileptogenic substrate. Diffuse abnormalities such as hydrocephalus may increase the risk of cortical damage.

EEG abnormalities may include any of the following:

epileptiform discharges;
focal slowdown;
diffuse background slowdown;
periodic diffuse polymorphic slowing.

Epileptiform abnormalities and focal slowing on the EEG are associated with a high risk of seizure recurrence. However, even a normal EEG does not exclude the risk of relapse. The risk of relapse in a person with one generalized tonic-clonic seizure, normal EEG and MRI of the brain, and no evidence of partial seizure onset is about 15%; in such clinical cases, treatment is usually not prescribed. If the patient has all the risk factors, then the probability of relapse is approximately 80%, and this patient is prescribed treatment.

The main unresolved issue remains the treatment of patients with one of the risk factors, in which the probability of relapse is 30–50%. In such cases, the decision is made by discussing with the patient the risk of seizure recurrence, the risk of toxic effects from anticonvulsants, and the benefits of avoiding seizure recurrence. The doctor should also tell you in detail about precautions, including a ban on driving.

Treatment with anticonvulsants does not change the natural course of the disease, it only reduces the risk of seizures. Aggravation of attacks can occur when using various AEDs. An increase in the frequency of attacks when replacing with an analogue is most typical for topiramate. An increase in the frequency of attacks with an increase in the dose of the drug or from 2 or more AEDs is associated with an unfavorable prognosis [4, 11].

Of 397 patients with a single unprovoked tonic-clonic seizure who received either conventional anticonvulsants (carbamazepine, phenobarbital, phenytoin, valproate) or no treatment, about 18% of treated patients had a seizure recurrence within 1 year compared with 39% of untreated patients. patients. Thus, patients should be warned that anticonvulsants may reduce the risk of recurrent seizures, but not completely eliminate this risk [29].

The mainstay of treatment for seizures is anticonvulsant therapy. The choice of drug depends on the exact diagnosis, since the response to a specific anticonvulsant drug varies among different epileptic syndromes. The use of IV forms of AEDs is possible in various situations when the patient cannot use AEDs orally [3]. The difference in response likely reflects different pathophysiological mechanisms of different seizure types and specific epileptic syndromes.

Mechanism of action of benzodiazepines and barbiturates

Benzodiazepines and barbiturates increase GABAergic inhibition by interacting directly with GABA receptors [36]. GABA receptors are formed by combining several subtypes of subunits into a pentamer (α1–α6, β1–β3, γ1–γ3, δ, ε, π, θ and ρ1–ρ3), the most common combination of which is 2 α-, 2 β- and 1 γ-subunit [19]. The 5 subunits are located in a counterclockwise direction (from the point of view of the synaptic cleft) γβαβα [19]. Once assembled, GABA receptors form chloride (Cl) ion channels, and the ion current through these channels can be modulated by a number of AEDs, including barbiturates and benzodiazepines. GABA receptors have been shown to be involved in both phasic inhibition of synaptic transmission and tonic, perisynaptic inhibition [27, 37]. GABA regulates the opening and closing of the ion channel [36, 46, 48]. GABA binding increases the likelihood of a channel opening, and an open channel can close and quickly reopen, creating a sequence of openings.

Barbiturates (in particular phenobarbital, the main active ingredient of the drug Pagluferal) increase ion current through the GABA receptor by binding to an allosteric regulatory site on the receptor, but the specific residues that constitute the allosteric binding site are unknown [38]. Mutagenesis studies have demonstrated that a glycine residue in the first transmembrane domain and a tryptophan residue in the third transmembrane domain of the β subunit may be involved in the mechanism of action of barbiturate [18, 23]. All GABA receptor isoforms containing at least α and β subunits have been shown to be sensitive to barbiturates; Only small changes in sensitivity are known for different isoforms. However, GABA receptors containing a δ subunit instead of the more abundant γ2 subunit, which is thought to be perisynaptically localized and mediate tonic inhibition, are more sensitive to barbiturates than those containing a synaptically localized γ2 subunit [1]. Single-channel recordings of barbiturate-enhanced single GABA receptors demonstrate that barbiturates increase channel opening duration but do not alter receptor conductance or opening frequency [36, 45].

The sensitivity of GABA receptors to benzodiazepines requires the presence of a γ subunit coexpressed with the α1, α2, α3, or α5 subtypes of the GABA receptor [39]. Expression of the α4 or α6 subtypes with the β1 and γ2 subtypes results in the formation of receptors that are insensitive to benzodiazepines [49]. Thus, benzodiazepine sensitivity of the GABA receptor depends on both the γ subunit and the α subtype. There is 1 highly sensitive binding site for benzodiazepines at the α/γ-subunit boundary, while at least 2 binding sites for GABA are located at the α/β-subunit boundary. These 2 binding sites are allosterically linked [38]. Benzodiazepines increase GABA receptor current, and single-channel recordings have shown that they increase GABA receptor opening frequency without significantly changing opening time or conductance [41, 47].

Research conducted at the Department of MONICA

Our observational study included 116 patients (56 men and 60 women) taking the phenobarbital-containing drug Pagluferal. The average age of the subjects was 45.1±1.27 years, the average age at the onset of the disease was 19.7±1.38 years, the average duration of the disease was 25.5±1 year. In 32 of them, epiactivity was not detected on the EEG, in 31 nonspecific epileptiform changes were recorded in the form of slowing of electrical activity, in 27 - single or multiple island-wave activity, in 17 - regional or diffuse peak-wave activity or secondary bilateral synchronization syndrome. Neuroimaging data showed the following: in 32 patients there were no signs of structural brain damage, in 20 there were changes in the brain that were not associated with epilepsy (vascular encephalopathy, hydrocephalus), in 30 there were changes that were presumably the cause of epileptic seizures (consequences of trauma and surgical interventions in epileptogenic region), in 7 – changes characteristic of the clinical picture of epilepsy (space-occupying formations, hippocampal sclerosis). 16 patients were diagnosed with idiopathic epilepsy, 42 with symptomatic focal epilepsy, and 58 with cryptogenic epilepsy. Only 18 patients used Pagluferal monotherapy; 83 patients used combination antiepileptic therapy, of which Pagluferal was a component. At the time of inclusion in the study, 6 patients had attacks less than once a year, 15 had several attacks per year, 68 had several attacks per month, and 9 patients had attacks several times a day. At the time of completion of the study, 22.7% of those examined were free from attacks, a reduction in the frequency of attacks by 50% or more was achieved in 27.2%, and no effect was noted in 50.1% of patients. Obviously, the relatively low percentages of achieving remission or significant improvement are explained by the duration of the disease, the high frequency of attacks and unsuccessful previous attempts at therapy in the majority of those examined.

What are the main targets for the use of Pagluferal in the treatment of epilepsy? Firstly, the drug is indicated for patients who have been receiving other barbiturates for a long time, if it is impossible to continue taking them (for example, if the previously used barbiturate is not commercially available). Clinical practice shows that refusal of barbiturates in patients who have been receiving drugs of this group for a long time inevitably leads to relapse of attacks even after remission while taking barbiturates, which lasted several 10 years.

Secondly, Pagluferal may be the drug of choice in patients with ineffectiveness/intolerance to carbamazepine, valproate, topiramate and other antiepileptic agents.

Third, low doses of Pagluferal may be the optimal choice for seizure control in patients with relatively infrequent and/or mild seizures who are unwilling to take more expensive AEDs or have side effects from their use.

Fourthly, Pagluferal may be the optimal choice for inclusion in polytherapy in patients with frequent and severe epileptic seizures with ineffectiveness/intolerance/unavailability of “new generation” AEDs.

Conclusion

There are many unresolved issues regarding AEDs. Which drug is better? Is it possible that a drug that is qualitatively superior to others will soon appear? How to look for such a drug? Our understanding of the basic mechanisms of epilepsy and epileptogenesis is constantly improving. However, it is still unclear how these advances will lead to improved drug development and seizure control. Is selection for efficacy in animal models the optimal way to find new AEDs? Will the search for new mechanisms of methodology lead to the emergence of more effective and safe treatment? Will the solution to the problem of drug resistance be in individual selection of therapy or through a general drug? Perhaps the answer is not in the drug itself, but in the special mechanism of its delivery. There is great interest in the delivery of AEDs across the blood-brain barrier and in the direct delivery of the drug to the necessary parts of the central nervous system [30, 42]. In addition, targeted therapy allows for individual differences in response to therapy to be taken into account, and pharmacogenomics may become an important component of therapy [44]. While these possibilities have not yet been realized, optimal treatment requires a full understanding of the available drug therapies so that they can be used in the best way for the patient.

Pharmacokinetics

Phenobarbital. Absorbed slowly and completely. Cmax in blood plasma is determined after 1–2 hours, binding to plasma proteins is 50%. Metabolized in the liver, induces microsomal liver enzymes CYP3A4, CYP3A5, CYP3A7 (the rate of enzymatic reactions increases 10–12 times). Cumulates in the body. T1/2 is 2–4 days. It is excreted by the kidneys in the form of glucuronide, about 25% unchanged. Penetrates into breast milk and through the placental barrier.

Caffeine. Absorption is good and occurs throughout the intestine. Cmax in blood plasma is reached within 50–75 minutes. It is quickly distributed in all organs and tissues, penetrates the blood-brain barrier and the placenta. Communication with blood proteins (albumin) - 25–36%. More than 90% is metabolized in the liver, in children of the first years of life up to 10–15%. In adults, about 80% of a caffeine dose is metabolized to paraxanthine, about 10% to theobromine, and about 4% to theophylline. These compounds are subsequently demethylated into monomethylxanthines and then into methylated uric acids. T1/2 in adults is 3.9–5.3 hours (sometimes up to 10 hours). Caffeine and its metabolites are excreted by the kidneys.

Papaverine. Bioavailability on average is 54%. Communication with plasma proteins - 90%. It is well distributed and penetrates histohematic barriers. Metabolized in the liver. T1/2 - 0.5–2 hours (can be extended to 24 hours). Excreted by the kidneys in the form of metabolites.

Calcium gluconate. Approximately 1/5–1/3 is absorbed in the small intestine. About 20% is excreted by the kidneys, the rest is removed with the contents of the intestine (actively excreted by the wall of the terminal gastrointestinal tract).

Release form and composition

The dosage form of the drug Pagluferal-1 is tablets: white, in the middle with a chamfer and a score (in a cardboard pack there are 2 contour strip packs of 10 tablets each or 1 dark glass jar containing 40 tablets).

Active ingredients in 1 tablet:

brominated – 0.1 g;
phenobarbital – 0.025 g;
caffeine sodium benzoate – 0.007 5 g;
calcium gluconate – 0.25 g;
papaverine hydrochloride – 0.015 g.

Additional components: potato starch, calcium stearate.

Interaction

Phenytoin and valproate increase the content of phenobarbital in the blood serum. The effect of phenobarbital is reduced when taken simultaneously with reserpine, and increases when combined with amitriptyline, nialamide, diazepam, chlordiazepoxide. Reduces the effectiveness of oral contraceptives and salicylates. Reduces the blood levels of indirect anticoagulants, corticosteroids, griseofulvin, doxycycline, estrogens and other drugs metabolized in the liver via oxidation (accelerates their metabolism). Strengthens the effect of alcohol, neuroleptics, narcotic analgesics, muscle relaxants, sedatives and hypnotics. Acetazolamide, by alkalinizing the urine, reduces the reabsorption of phenobarbital in the kidneys and weakens its effect. Reduces the antibacterial activity of antibiotics and sulfonamides, the antifungal effect of griseofulvin.

Contraindications

broncho-obstructive diseases;
adrenal hypofunction;
porphyria;
severe anemia;
hyperthyroidism;
severe renal/liver failure;
depression;
drug dependence (including aggravated medical history);
myasthenia gravis;
active alcoholism;
diabetes;
hyperkinesis;
age up to 3 years;
pregnancy and lactation;
individual intolerance to the components included in the drug.

In weakened patients during treatment with Pagluferal-1, medical monitoring of the condition is required, since even with therapy in normal doses there is an increased risk of paradoxical agitation, depression and confusion.

special instructions

In patients with mild hypercalciuria, decreased glomerular filtration rate, or a history of nephrolithiasis, the drug should be prescribed under the control of calcium levels in the urine, which is due to the presence of calcium gluconate in the drug.

Alcohol consumption is not recommended during therapy.

Influence on the ability to drive a car and perform work that requires speed of psychomotor reactions. During treatment, you should refrain from performing work that requires speed of psychomotor reactions (including driving a car).

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