Supplement for use in the treatment of side effects associated with Anti-epileptic drug therapy

Abstract

The present invention relates to a composition comprising a dry extract of Bacopa monnieri, a dry extract of Eleutherococcus senticosus and a dry extract of Griffonia simplicifolia for the treatment of side effects associated with taking anti-epileptic drugs, in particular a food supplement. A food supplement comprising the composition of the invention is also provided.

Description

“SUPPLEMENT FOR USE IN THE TREATMENT OF SIDE EFFECTS ASSOCIATED WITH ANTI-EPILEPTIC DRUG THERAPY” Cross-Reference to Related ApplicationsThis Patent Application claims priority from Italian Patent Application No. 102023000027672 filed on December 21, 2023, the entire disclosure of which is incorporated herein by reference.Technical FieldThe present invention relates to a composition comprising plant extracts and vitamins for the treatment of side effects associated with taking anti-epileptic drugs, in particular a food supplement.Background of the InventionThe epilepsy patient is invariably affected by a number of comorbidities, either intrinsically linked to the disease or to the use of drugs, where by drug-associated comorbidities we mean the side effects of the drugs themselves. These side effects, which affect the physical, mental and emotional spheres, are not always adequately treated, both because of the social and cultural difficulty of the patient in correctly reporting them to the specialist, and in order to avoid excessive polypharmacotherapy. As a consequence, especially when they do not assume a particularly serious character, the side effects can have a significant impact on the patient's quality of life, even risking compromising adherence to drug and behavioural therapy.The most frequently observed side effects in epileptic patients are sleep disturbances, memory deficits, loss or diminished sense of self-esteem, fatigue and tiredness, and reduced mood tone.Sleep alterations, which include both an insufficient amount of total sleep and, above all, an insufficient amount of REM sleep, are extremely common in epilepsy patients and in many cases form the organic basis from which other non-neurological alterations and dysfunctions in epilepsy patients originate. The vast majority of commonly prescribed anti-epileptic drugs produce frequent and significant sleep disturbances.Epilepsy inherently afflicts memory capacity, both as a result of the seizure and the altered electrical activity of the brain between seizure episodes, and due to secondary effects essentially linked to the alteration of the REM sleep cycle and the use of anti-epileptic drugs, which promote inhibitory stimuli in central nervous transmission. In addition, anti-epileptic drugs help to significantly attenuate the onset of convulsions and improve sleep quality. With proper pharmacological management of the disease, memory and concentration deficits should be of moderate severity. In this context, memory deficits may negatively impact professional or school performance, a condition that may not be fully compensated by drug therapy.Loss of self-esteem is common in chronic illnesses and reflects the patient's tendency to have recurring negative thoughts about himself / herself and his / her actions. In turn, this has a significant impact on social, relational and professional life, reducing its quality.Fatigue is a chronic feeling of tiredness, both mental and physical, that is excessive in relation to the undertaken activities. The epilepsy patient is generally more prone to experience fatigue and excessive tiredness, mainly due to alterations in the sleep cycle, induced by both the disease and the effect of anti-epileptic drugs. Fatigue can be controlled through diet and body weight control, through regular physical activity and through as regular a sleep cycle as possible.Epileptic patients are generally more likely to develop depression or altered mood tone. This may also frequently be due to side effects of anti-epileptic drugs, which, especially at high dosages, can produce generalised depression and recurring thoughts of self-harm.The side effects of anti-epileptic drugs can also affect the physical sphere, e.g. with gastrointestinal disorders (meteorism, nausea, vomiting, diarrhoea, etc.), weight gain and dermatological problems.The side effects associated with anti-epileptic therapy can greatly benefit from supplementary and integrative treatment which allows to alleviate non-neurological symptoms, promote a state of general well-being and improve adherence to drug therapy.The need is therefore felt in the art for supplementary compositions capable of reducing the symptomatology of associated side effects without interfering with the current drug therapy.Summary of the InventionThe purpose of the present invention is therefore to provide a new composition that is capable of reducing the symptomatology of the side effects associated with epilepsy without interfering with current drug therapy. In fact, the inventors discovered that three botanical extracts, known separately to have nootropic, adaptogenic, and mood-restoring effects, when used in certain combinations have a synergistic effect that can mitigate the side effects of epileptic treatment without interfering with drug therapy.This is achieved by a composition according to claim 1, its use according to claims 8-11 and a food supplement comprising the composition according to claim 12.Brief Description of the DrawingsFigure 1 depicts the percentage of subjects manifesting gastrointestinal symptoms at the time of recruitment (t0), after 3 months (t1) and after 6 months (t2) of treatment with the composition of the present invention as shown in Example 2.Description of EmbodimentsIn particular, according to a first aspect of the invention, a composition is provided comprising a dry extract of Bacopa monnieri, dry extract of Eleutherococcus senticosus and dry extract of Griffonia simplicifolia.In particular, Bacopa monnieri has a nootropic effect, which aids the management of memory deficits, and slower cognitive and memory performances. Particularly advantageous is the use of a dry extract of the tops and / or herb in titre from 40% to 55% in bacosides. Bacopa is generally safe. Gastrointestinal effects such as nausea and increased motility are reported sporadically. In animals, lethal doses are extremely high, 2400mg / kg body weight in acute and 500mg / kg body weight in subchronic. In humans, a phase I study with single doses (20 to 300 mg) of bacosides (equivalent to up to 600 mg of dry extract) showed no adverse effects (Singh et al, Indian J. Pharmacol. 1997;29:359–365).Eleutherococcus senticosus, on the other hand, acts as an adaptogen. In fact, the non-neurological symptomatology of epileptic patients is strongly based on a sense of inadequacy and loss of self-esteem due to the use of drugs, the sense of dependence on others, and the social unacceptability of the illness. Help in compensating for the state of inadequacy can come from the use of adaptogenic substances, i.e., substances that promote the improvement of physical and mental resistance to the state of stress, mainly through an activation of the neuroendocrine and adrenal functions.Eleutherococcus is able to increase tolerance to mental exhaustion, increase mental endurance and attention especially in patients with a mild to moderate state of fatigue and weakness, a state typical of epileptic patients. Although it is not directed at a specific organ or tissue, it has stimulating and adaptive properties in stressful situations. Eleutherococcus may be formulated as a dry extract from the root containing more than 1% eleutheroside. In particular, the combination of Bacopa and Eleutherococcus is able to mitigate the negative effect of the adaptogen, i.e. the lack of motivation towards new tasks in an overly relaxed subject.Griffonia simplicifolia acts as a mood enhancer and thus plays a positive role in re-establishing an adequate level of social relations and interest in daily activities, as well as being able to help in the prophylaxis of migraines, a frequent comorbidity in epileptic subjects and in children with hyperactivity syndrome. It is a source of hydroxytryptophan, the precursor of serotonin. Preferably, Griffonia simplicifolia is used as a dry extract of the seeds in titre from 20% to 95% in hydroxytryptophan. The composition of the invention comprises 20% to 30% of a dry extract of Bacopa monnieri, 30% to 40% of a dry extract of Eleutherococcus senticosus, and 20% to 30% of a dry extract of Griffonia simplicifolia. The percentage values are expressed as percentages by weight of the total weight of the active ingredients unless otherwise specified.In particular the composition may comprise 20% to 27% by weight of a dry extract of Bacopa monnieri, 30% to 35% of a dry extract of Eleutherococcus senticosus, and 20% to 25% of a dry extract of Griffonia simplicifolia. This composition is particularly suitable for use in paediatric age.In an embodiment, the composition comprises 27% to 30% of a dry extract of Bacopa monnieri, 35% to 40% of a dry extract of Eleutherococcus senticosus, and 25% to 30% of a dry extract of Griffonia simplicifolia. This composition is particularly suitable for use in adulthood.The composition may further comprise vitamin complexes such as vitamin B complex, vitamin C and vitamin E.Vitamin B complex is useful in counteracting the action of homocysteine, promotes the trophism of cell membranes and neurons, particularly stressed in epileptic subjects, and promotes energy metabolism. The vitamin B complex supports dietary intake and helps counteract the feeling of asthenia associated with fatigue. Vitamin B6 is particularly important. Vitamin C and Vitamin E are known antioxidants in circulation and cell membranes.In an embodiment, vitamin B complex is present in the composition in an amount comprised between 0.2 and 1% by weight, vitamin C is present in an amount comprised between 5 and 10% by weight, and vitamin E is present in an amount comprised between 2 and 10% by weight of the total weight of the active ingredients.The composition finds application in the treatment of side effects associated with taking anti-epileptic drugs, in particular selected from the group consisting of gastrointestinal disorders, disorders of the haematopoietic system, oral or dermatological disorders, weight changes due to increased / reduced appetite, muscle and joint pain, renal damage, liver damage and alkaline phosphatase levels, more in particular constipation, dyspepsia, nausea, and faecal incontinence.According to a further aspect of the invention, a food supplement comprising the composition of the invention is also provided.Further characteristics of the present invention will become apparent from the following description of some merely illustrative and non-limiting examples.ExamplesEXAMPLE 1The composition shown in table 1 was tested in a single-centre open-label study to assess its efficacy in counteracting the side effects (RA) of anti-epileptic drug (AE) therapy in paediatric epilepsy patients.  Table 1IngredientAmount (%w / w)dry extract of Bacopa monnieri26.14%dry extract of Eleutherococcus senticosus32.68%dry extract of Griffonia simplicifolia24.18%Vitamin B60.65%Vitamin C9.81%Vitamin E6.54%Patients and methods: 23 patients aged 1-17, on stable treatment (≥3 months) with ≥1 AE. The treatment period was six months. The RAs (by type, severity and frequency) were assessed by means of standardised questionnaires completed by the physician at the time of recruitment (t0) and then repeated after 3 and 6 months of treatment (t1 and t2). Statistical analysis was performed with the non-parametric Wilcoxon matched-pairs signed rank, two-tailed test. In particular, the RAs related to taking anti-epileptic drugs evaluated are shown in Table 2 divided into RAs related to systemic toxicity and neurotoxicity (J.A.Cramer et al., Neurology, 1983, 33(3 Suppl. 1):26-37). Table 2SYSTEMIC TOXICITYNEUROTOXICITYGastrointestinal disordersDiplopiaDisorders of the haematopoietic systemNystagmusOral or dermatological disordersDysarthriaWeight changes due to increased / reduced appetiteDeambulationMuscle and joint painFast, alternating movementsKidney damageIntentional tremorLiver damageSleepinessAlkaline phosphatase (ALP) levels Mood and behavioural disorders (depression, agitation, anxiety, hostility, aggression, fatigue, apathy, excitement, confusion) Cognitive disorders (attention and concentration deficit) Dizziness / Vertigo Headache The frequency of systemic RAs was significantly reduced from t0 to t1 (p < 0.05) and from t0 to t2 (p < 0.05), as the frequency of neuropsychiatric RAs was significantly reduced from t0 to t1 (p < 0.05) and from t0 to t2 (p < 0.05). The most commonly reported RAs were daytime sleepiness (reduced by 33% at t1), mood and behavioural disorders (reduced by 56% at t1), cognitive dysfunction (reduced by 56% at t1). Patients treated with the composition of the invention were significantly less likely to report any type of RA [Wilcoxon signed-rank test=1, p< 0.05] and, in particular, RAs of the neuropsychiatric type [Wilcoxon signed-rank test=0, p< 0.05]. Therefore, patients taking the composition reported fewer and / or reduced severity of RAs, already after 3 months of treatment. It has also been verified that the composition has no significant effect on the pathology; therefore, it has no direct action on the pathology, nor is it an adjuvant to drug therapy.EXAMPLE 2The composition shown in Table 1 was tested to assess its efficacy in counteracting the gastrointestinal side effects (RAG) of anti-epileptic drug (AE) therapy in paediatric epilepsy patients.Patients and methods: 25 patients aged 1-17 years on treatment (≥4 weeks) with ≥1 AE. The treatment period was six months. The RAs (by type, severity and frequency) were assessed by means of standardised questionnaires completed by the physician at the time of recruitment (t0) and then repeated after 3 and 6 months of treatment (t1 and t2). Statistical analysis was performed with the non-parametric Wilcoxon signed rank, two-tailed test. In particular, the RAGs related to the intake of anti-epileptic drugs evaluated are shown in Table 3 (using the validated ROMA IV test Zeevenhooven J, Koppen IJN, Benninga MA. The New Rome IV Criteria for Functional Gastrointestinal Disorders in Infants and Toddlers. Pediatr Gastroenterol Hepatol Nutr).Table 3GASTROINTESTINAL DISORDERSFunctional constipationFunctional dyspepsiaFunctional nauseaFaecal incontinenceThe percentage of patients with at least one gastrointestinal side effect was reduced by 30% at t1 and 66% at t2. The most commonly reported RAGs were: functional constipation (reduced by 25% at t1 and 50% at t2), functional dyspepsia (reduced by 50% at t1 and 100% at t2), functional nausea (reduced by 66% at t1) and faecal incontinence (reduced by 50% at t1 and 100% at t2). Patients treated with the composition of the invention were significantly less likely to report any type of RAG [Wilcoxon signed-rank test=1, p< 0.05].Therefore, patients taking the composition reported fewer and / or reduced severity of RAGs, already after 3 months of treatment. The study also confirmed the findings of a significant reduction in the frequency of systemic RAs from t0 to t1 (p < 0.05) and from t0 to t2 (p < 0.05), as well as in the frequency of neuropsychiatric RAs from t0 to t1 (p < 0.05) and from t0 to t2 (p < 0.05).It has also been verified that the composition has no significant effect on the pathology; therefore, it has no direct action on the pathology, nor is it an adjuvant to drug therapy.

Claims

1. - Composition comprising 20% to 30% by weight of a dry extract of Bacopa monnieri, 30% to 40% by weight of a dry extract of Eleutherococcus senticosus, and 20% to 30% by weight of a dry extract of Griffonia simplicifolia over the total weight of the active ingredients.2.- Composition according to claim 1 comprising 20% to 27% by weight of a dry extract of Bacopa monnieri, 30% to 35% by weight of a dry extract of Eleutherococcus senticosus, and 20% to 25% by weight of a dry extract of Griffonia simplicifolia over the total weight of the active ingredients.3.- Composition according to claim 1 comprising 27% to 30% by weight of a dry extract of Bacopa monnieri, 35% to 40% by weight of a dry extract of Eleutherococcus senticosus, and 25% to 30% by weight of a dry extract of Griffonia simplicifolia over the total weight of the active ingredients.4.- Composition according to claim 1, further comprising vitamin B complex, vitamin C and vitamin E.5.- Composition according to claim 2, characterised in that the vitamin B complex is present in an amount comprised between 0.2% and 1% by weight over the total weight of the active ingredients.6.- Composition according to claim 3, characterised in that the vitamin C is present in an amount comprised between 5 and 10% by weight over the total weight of the active ingredients.7.- Composition according to claim 4, characterised in that vitamin E is present in an amount comprised between 2 and 10% by weight over the total weight of the active ingredients.8.- Composition according to any one of claims 1-7 for the use in the treatment of side effects associated with the intake of anti-epileptic drugs.9.- Composition according to any one of claims 1-7 for the use in the treatment of systemic side effects associated with taking anti-epileptic drugs, selected from the group consisting of gastrointestinal disorders, disorders of the haematopoietic system, oral or dermatological disorders, weight changes due to increased / reduced appetite, muscle and joint pain, renal damage, liver damage and alkaline phosphatase levels.10.- Composition according to any one of claims 1-7 for the use in the treatment of gastrointestinal side effects associated with the intake of anti-epileptic drugs.

11. - Composition for use according to claim 10, characterised in that said gastrointestinal side effects are selected from the group consisting of constipation, dyspepsia, nausea, and faecal incontinence.12.- Food supplement comprising the composition according to any one of claims 1-7.

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