Nutraceuticals for Peripheral Vestibular Pathology: Comparison
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Please note this is a comparison between Version 3 by Dean Liu and Version 2 by Dean Liu.

The term “nutraceuticals” is the object of continuous debate, and to date they are described as “a food or part of a food, such as a dietary supplement, that has a medical or health benefit, including the prevention and treatment of disease”.

  • nutraceuticals
  • vestibular

1. Introduction

Even if these compounds are commonly used in several clinical manifestations [1][2][3][4][5], e.g., when treating vestibular diseases, their role has not been well described. Vestibular disorders include different clinical manifestations related to an alteration of the balance of visual, auditory-vestibular, and somatosensory impulses [6] with connections to cognitive and psychological areas. Vertigo affects approximately 20–30% of the general population [7]. The most common causes of peripheral vertigo/dizziness are benign paroxysmal positional vertigo (BPPV), vestibular neuritis (or acute unilateral peripheral vestibulopathy), Ménière’s disease (MD), and bilateral vestibulopathy (BV) [6][8].
The most common drugs employed are diuretics, betahistine (a mild H1 agonist and strong H3 antagonist, that reduces both endolymphatic pressure and vestibular nuclei activity), and antiemetic or vestibular suppressants (benzodiazepines, anticholinergics, antihistamines, phenothiazines, and ondansetron) [6][7][8][9]. Surgery embraces different choices, depending on the gravity of the illness: intratympanic steroid perfusion, ablative techniques, endolymphatic sac decompression, intratympanic gentamycin perfusion, vestibular neurectomy, and labyrinthectomy [6][8][9][10][11][12][13]. Another potential treatment strategy is intravenous glycerol [14].
Vestibular neuritis (acute unilateral peripheral vestibulopathy) is characterized by nystagmus, posture alteration, or gait abnormalities (Table 1). Vestibular suppressants and antiemetics are very useful, whereas steroids, despite the absence of solid evidence, can have a certain effect [6][8][15].
Benign paroxysmal positional vertigo affects the inner ear and causes frequent and sudden attacks of positional vertigo (Table 1). Risk factors include advanced age, ear and dental surgery, vitamin D deficiency, menopause, and vascular disorders [16][17][18][19]. The main role is played by the otoconia, which may enter the semicircular canal and change position with head movements (canalithiasis theory) or adhere to the cupula of the canal and displace it (cupololithiasis theory) [8]. The main treatment is vestibular maneuvers, performed to reposition the otoconia outside of the semicircular canals. Vestibular suppressants should not be routinely used, even if some patients may benefit from it [6][8][20][21].
Bilateral vestibulopathy is characterized by postural imbalance and unsteadiness of gait, both of which worsen in darkness and on uneven ground. Head or body movement-induced oscillopsia is also present in some patients, in particular during walking, which engenders head movements with high frequency spectral content, particularly during each heel strike

2. Main Nutraceuticals

2.1. Ginkgo Biloba

Extracts from Ginkgo biloba (EGb 761 and LI 1370 [22]) have been shown to have several effects which explain its role in the treatment of vertigo [22][23]. Yabe et al. [24], in an experimental model, documented the effects of Ginkgo biloba on the vestibular system. In a multicenter clinical trial, Sokolova et al. [25], evaluating the effects of a 12-week treatment with EGb 761 (240 mg per day) or betahistine (32 mg per day) in 116 patients with vertigo, documented that both compounds are able to induce a clinical improvement of vertigo, but that EGb 761 induced lower adverse drug reactions (70% in EGb group vs. 79% in the betahistine group) [25].
The treatment with Ginkgo must be avoided in pregnancy and lactation, and with children below 12 years [26], while its use should be well evaluated in poly-treated patients.
In fact, EGb 761 inhibits cytochrome P450(CYP)1A2, CYP2C9, CYP2E1, CYP3A4, and P-glycoprotein (P-gp) [27], even if the clinical role of these interaction has not been well demonstrated [28].
In contrast, the presence of flavonoids in Ginkgo biloba potentiates the effects of anticoagulant and antiplatelet compounds (pharmacodynamic interaction), causing a prolongation of bleeding time [29].

2.2. Ginger

Ginger (Zingiber officinale) contains several active compounds: gingerols, shogaols (phenolic compounds), and terpenes (for example, zingiberene) [30][31], that are able to induce antioxidant and anti-inflammatory effects.
Even if some authors did not report an effect the on vestibular system [32], others described an effect in reducing vertigo/dizziness and motion sickness syndrome [32][33][34].
Ginger is also associated with dizziness [35], increasing doubts about the solidity of the evidences.
Possible adverse events mainly include gastrointestinal symptoms (reflux, bad taste, diarrhea, and abdominal discomfort) and sleepiness. Even if the development of drug interactions in patients using anti-coagulants were reported, these would not have a solid basis of evidence [32][30].
Ginger inhibits CYP 3A4, 2D6, 2C9, 2C19, and P-gp in vitro, but there are insufficient data to describe the development of drug interactions in clinical settings [32][36].

2.3. Citicoline

Citicoline is an intermediary in the phospholipids synthesis chain, with multiple properties, and which seems to have an effect on vertigo/dizziness [37][38], even if there is no strong evidence to support it [37][39]. Petrova et al. [38] documented a dose-dependent efficacy of citicoline (up to 2000 mg/day) in the management of central and ischemic vertigo. However, enrolled patients were treated with betahistine, so it is not easy to evaluate if clinical efficacy was related to citicoline, betahistine, or both. Martines et al. [37] used a combination of citicoline, ginger, B6 vitamin, lemon balm, and ViNitrox, and obtained a positive effect. In contrast, the development of dizziness was described in patients treated with citicoline at a high dosage [40].
Finally, in a previous sequential trial performed with 2298 patients with moderate-to-severe acute ischemic stroke, with patients randomly given citicoline (1000 mg every 12 h i.v. during the first 3 days and then orally, 500 mg bid, for a total of 6 weeks) or a placebo, Dávalos et al. [41] failed to report a difference in the development of adverse drug reactions or drug interactions between citicoline and the placebo (Table 3). However, the safety of citicoline must be evaluated carefully for its use in pregnancy, lactation, and childhood [42].

2.4. Magnesium

Magnesium is an enzymatic cofactor and its deficiency is associated with a lot of pathological issues, including enclosed vertigo [43][44]. Esposito et al. administered a combination of Griffonia simplicifolia/magnesium as a prophylaxis to treat childhood motion sickness, and demonstrated a better outcome vs. the control group. A possible application of magnesium is revealed by the demonstration of its effectiveness in the treatment of headaches and migraines, alongside vertigo/dizziness [8][43][45]. It may also be used to treat vestibular migraines, because these patients reported lower magnesium levels [46]. In patients with idiopathic sudden hearing loss, the treatment with magnesium reduced vertigo and vestibular damage [47]. Magnesium has also been used in post-stapedectomy vertigo, alongside vitamin B2 and conventional migraine medication [48].

2.5. Lemon Balm

There are little data concerning the use of lemon balm (Melissa officinalis) in the treatment of vertigo/dizziness [49]. The formulation Vertigoval® (Valeas, Italy), which contains ginger, lemon balm, ViNitrox, vitamin B6, and citicoline, showed an improvement of residual dizziness in VPPB compared with a placebo, and this effect is probably related to the action of lemon balm on the GABA system [50]. The action on the GABA system produces an anxiolytic effect, similar to benzodiazepines [51]. It is interesting to state that benzodiazepines are also used in the management of vertigo/dizziness [9], and this increases the importance of lemon balm. There are no data regarding the safety of this compound, but in an experimental study, the administration of oregano and lemon balm induced the prone position, decreased motor activity, created difficulty in breathing, and induced tremors in mice. Human studies showed rare adverse events (not significantly different from the placebo) [49], but it should be used carefully in pregnancy, lactation, or childhood [52].

2.6. Sage

Sage (Salvia spp., above all Salvia officinalis) is a plant with important medical properties due to its metabolites and components [53][54][55]. Salvia does not usually generate severe adverse events [53][55][56]. Some constituents in Salvia act on CYP450: for example, among phenolic acids, tanshinone IIA (TSIIA) inhibited CYP2C9/3A4, whereas salvianolic acid B (SAB) induced it; among the terpenoids, salvinorin A is a CYP2D6, 1A1, 2C18, and 2E1 substrate. CYP3A4, CYP1A2, CYP2E1, CYP2D6, CYP2C9, and CYP2C19 were inhibited by some molecules, while CYP3A4 and CYP1A2 were induced by others. Some compounds showed activity on P-gp and organic anion transporters (OATs), but all these data were ambiguous and not clear enough to determine the in vivo activity of the whole medicinal use of Salvia [57].

2.7. Omega-3 Fatty Acids

Omega-3 polyunsaturated fatty acids include stearidonic acid, docosapentaenoic acid, docosahexaenoic acid, eicosapentaenoic acid, and α-linolenic acid [58]. They perform multiple healthy actions on the human body: they are helpful in treating Alzheimer’s disease, cancer, cardiovascular disease, and the development of diabetes and neurological conditions [59]. Omega-3 fatty acids could represent a potential future option in the treatment of Meniere’s disease because they are able to induce hemodynamic changes.
Omega-3 fatty acids are well tolerated, even if their uses are related to the development of adverse drug reactions.

2.8. Specially Processed Cereals (SPC) Flakes

Antisecretory factor (AF) is a protein produced in the pituitary gland which fights infections and which performs an immunity role [60]. Moreover, it is able to regulate ions and water, interacting with aquaporins and modulating chloride homeostasis. Therefore, it can be used in patients with Meniere’s disease. Viola et al. documented an improvement in tinnitus and vertigo in patients treated with SPC vs. intravenous glycerol and dexamethasone [60]. In contrast, Scarpa et al. [61] failed to report a significant difference between glycerol, dexamethasone, and SPC, even if the time of the follow-up was lower (12 months, compared to 24 months in Viola’s study). Similarly, Ingvardsen and Klokker [62] showed no difference in the SPC flakes group compared with the placebo group, even if the follow up period was shorter.
These data support the idea that a long period of treatment is necessary to obtain clinical efficacy during the treatment with SPC flakes. However, no adverse drug reactions have been described.

2.9. Other Compounds/Supplements

Vertigoval® (Valeas, Italy) is a formulation composed of ginger, ViNitrox, citicoline, vitamin B6, and Melissa officinalis. ViNitrox is a combination of apple and grape polyphenols with vasodilator, which has an antioxidant effect. Vitamin B6 protects circulation and seems to facilitate the vestibular system [50]. The effects of vitamin B6 on vertigo have been known for decades [63][64]. Vertigoval® showed an improvement of symptoms and instability in patients [50].
Vestanol® (Erbozeta, Chiesanuova, Republic of San Marino) is a product which contains Ginkgoselect® plus Phytosome®, hawthorn, ginger, orthosiphon, polygonum, B vitamin complex, zinc, and copper. The most important active substances are terpenes, flavonoids, and oligomeric proanthocyanidins [65]. It can be used to treat gastrointestinal symptoms [66].
Zinc and copper have antioxidant effects, whereas vitamin B2, B3, and B6 aid the nervous system. B2 and B3 also maintain mucous membranes [67]. Vitamin B deficiency may lead to neurological symptoms, as well as dizziness and vertigo [68][69]. No correlation between vitamin B12, homocysteine, folic acid levels, and vertigo has been found [70], although were reported cases of patients affected by vestibular pathology of vascular origin, with homocysteine increases resulting in Meniere symptoms [71][72].
Vertiwin® (Pharmawin, Milan, Italy) is based on citicoline, ginger, Ginkgo select Phytosome, magnesium, vitamin C, and vitamin B complex [73]. Vitamin C and other radical scavengers led to an improvement in Meniere’s disease. A study evaluated this effect, but enrolled few patients, was not placebo controlled, and was biased by the fact that some patients would recover spontaneously, even without radical scavenger administration [74]. Vertase® (Polifarma S.p.A, Roma, Italy) contains Melissa, ginger, citicoline, and bioflavonoids from fruit.
Vertistop® L and D (Difass, Cerasolo, Rimini, Italy) are two different formulations. Vertistop® L is made by LICA® (alpha-lipoic acid, carnosine, and zinc) and curcumin [75]. Carnosine [76], alpha-lipoic acid [77], and curcumin have antioxidant effects [75].
Vertistop® D is formed by LICA®, vitamin D, and vitamin B complex. Vitamin D works on calcium metabolism but has been studied also in vertigo/dizziness. In a non-blinded, non-placebo-controlled study, vitamin D supplementation in BPVV showed a 24% reduction in the recurrence of symptoms [78][79]. Another study provided class III evidence for its administration in this group of patients [80]. Other authors suggest that vitamin D might play a role in treating Meniere’s disease, putting emphasis on the immunomodulatory activity of this compound [81].
Acuval® Vert (Sharper, Milan, Italy) is composed of coline, ginger, Ginkgoselect® Phytosome®, Qter® (coenzyme Q10), vitamin B complex, vitamin E, and lactium (hydrolyzed milk proteins) [82]. Vitamin E shows antioxidant properties [82][83], lactium has calming and sleep stimulating activity [84], and coenzyme Q10 (an antioxidant and important part of ATP production) acts in Meniere’s disease-like syndromes, preventing hypoxia and improving patients’ symptoms, especially if there is a deficiency [85].

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