**1.3 Pharmacokinetics of glucocorticoids and studies on animal model**

Many factors have an impact on pharmacokinetics of drugs. Pharmacokinetics is described by acronym *LADME (liberation, absorption, distribution, metabolism, and elimination*). Firstly, the therapeutic (or its carrier) must be water-soluble, because of distribution in the blood. The protein binding of drugs is one of the key factors in initial parts in pharmacokinetic process. The greater the protein binding of drug is, the longer the activity of therapeutic due to its function as a stock of drug in the organism. Absorption depends on lipophilicity and solubility of drugs. According to the data and publications, only a few medical substances can effectively be used in otorhinolaryngological practice due to achieving sufficient concentration in the inner ear [9]. Two main groups of drugs are used in clinical practice: aminoglycoside (mainly gentamicin) in pharmacotherapy of Meniere's disease [10] and corticosteroids (dexamethasone, triamcinolone and dexamethasone) in pharmacotherapy of *idiopathic sudden sensorineural hearing loss* (ISSHL) and other cases of acute hearing loss [11]. The inner ear from a pharmacokinetic point of view is a multicompartment model [12, 13] with stable fluids and balance between them (due to the presence of *blood-labyrinth barrier* (BLB)). Distribution process depends on many different factors such as route of administration, model of administration (single or repeated administration), dose of medicine, ionic composition, and pH or osmolarity of solution. The same factors of drug chemical and physical properties influence the elimination of drug from the organism (clearance, rate of removal).

In a study published in 2017, authors in animal model (guinea pig) compared dexamethasone with saline. Both substances were administrated intravenously 60 min before implantation. As a final conclusion, authors stressed that

**161**

*Role of Glucocorticoids in Hearing Preservation in Partial Deafness Treatment*

dexamethasone could reduce scarring process as the electrode negotiated the hook region or near the electrode tip, but they did not observe the relation between dexamethasone and reduction of fibrosis relating to cochleostomy [13]. In vitro studies showed the correlation between reduction (loss) of auditory cells after exposure to *tumor necrosis factor* alpha (TNF-alpha) and dexamethasone-releasing polymer used

Research carried out on animal model proved that prolonged steroid therapy could significantly improve hearing preservation rate (including pharmacokinetic and morphological analysis) when the electrode of cochlear implants was covered with dexamethasone (special formulation with controlled drug release) [14]. However, Honeder et al. did not confirm that steroids could have a positive impact on residual hearing in a guinea pig model. One reason why both authors gain different results may lie in different types of steroid therapy. In the first study, dexamethasone was used on the contrary to the second study where triamcinolone was administrated [15]. Douchement et al. investigated the effects of steroids using a gerbil animal model. Animals were implanted with an electrode with controlled dexamethasone delivery (1 and 10% concentration of dexamethasone) on one side and a conventional electrode on the contralateral side. Hearing levels were established based on the tone bursts on auditory brain stem responses at 4–6-week postimplantation and at 1-year postimplantation period for older gerbils. A 1-year observation period showed significantly improved results obtained for the high auditory frequencies, but the results for the low frequencies were ambiguous [16]. Cho et al. analyzed the efficacy of preoperative and intraoperative schemes of administration of steroids for hearing preservation. Dexamethasone was administrated systematically at the dose of 5 mg/ml in the preoperative period and then topically (off-label) during cochlear implantation surgery. Pure tone audiometry (PTA) was measured in four frequencies: 250, 500, 1000, and 2000 Hz. Statistically significant differences were observed between the steroid group and the control group, supporting

the observation and beneficial impact of administration steroid treatment [17].

During treatment of otologic diseases, two routes of administration of glucocorticoids are possible: local and systemic. Local administration (e.g., transtympanic injection) allows to achieve high concentration of glucocorticoid in the middle ear, but due to presence of Eustachian tube, the medication may be partly evacuated. Local drug administration to the middle and inner ear avoids "the first pass effect."

Local drug administration may involve intracochlear administration (e.g., stem cell, gene therapy) or extracochlear administration (e.g., intratympanic injection). A combination of both routes of drug delivery to the ear is also possible [13]. According to publications, systemic administration in treatment of otorhinolaryngological

**1.4 Glucocorticoid administration: the possibilities**

The main advantages of local drug delivery are as follows:

1.Reduction dose of medicine

2.Achieving high concentration

4.Reducing possibility of adverse effects

5.Bypassing of the blood-labyrinth barrier (BLB)

3.Better effects of treatment

*DOI: http://dx.doi.org/10.5772/intechopen.88863*

to coat electrode of cochlear implant carries.

### *Role of Glucocorticoids in Hearing Preservation in Partial Deafness Treatment DOI: http://dx.doi.org/10.5772/intechopen.88863*

*The Human Auditory System - Basic Features and Updates on Audiological Diagnosis and Therapy*

amines; and reduction in production of histamine by basophils [7, 8].

1.Repression in responding on infections and injuries

6.Glaucoma (mostly in patients genetically predisposed)

2.Propensity to opportunistic infections

3.Propensity to hyperglycemia

corticoids slowly, not suddenly [5].

4.Muscular dystrophy

5.Cushing's syndrome

7.Osteoporosis

them are listed below:

Sometimes glucocorticoid treatment in the otorhinolaryngological diseases requires high doses or long time of therapy. It may cause adverse effects. Some of

Acute discontinuation of treatment may cause adrenocortical insufficiency, especially when therapy was long-term. It is important to reduce the dose of gluco-

Many factors have an impact on pharmacokinetics of drugs. Pharmacokinetics is described by acronym *LADME (liberation, absorption, distribution, metabolism, and elimination*). Firstly, the therapeutic (or its carrier) must be water-soluble, because of distribution in the blood. The protein binding of drugs is one of the key factors in initial parts in pharmacokinetic process. The greater the protein binding of drug is, the longer the activity of therapeutic due to its function as a stock of drug in the organism. Absorption depends on lipophilicity and solubility of drugs. According to the data and publications, only a few medical substances can effectively be used in otorhinolaryngological practice due to achieving sufficient concentration in the inner ear [9]. Two main groups of drugs are used in clinical practice: aminoglycoside (mainly gentamicin) in pharmacotherapy of Meniere's disease [10] and corticosteroids (dexamethasone, triamcinolone and dexamethasone) in pharmacotherapy of *idiopathic sudden sensorineural hearing loss* (ISSHL) and other cases of acute hearing loss [11]. The inner ear from a pharmacokinetic point of view is a multicompartment model [12, 13] with stable fluids and balance between them (due to the presence of *blood-labyrinth barrier* (BLB)). Distribution process depends on many different factors such as route of administration, model of administration (single or repeated administration), dose of medicine, ionic composition, and pH or osmolarity of solution. The same factors of drug chemical and physical properties influence

**1.3 Pharmacokinetics of glucocorticoids and studies on animal model**

the elimination of drug from the organism (clearance, rate of removal).

dexamethasone with saline. Both substances were administrated intravenously 60 min before implantation. As a final conclusion, authors stressed that

In a study published in 2017, authors in animal model (guinea pig) compared

reduction of activation of macrophages, neutrophils, mast cells and cytokines (interleukins 1, 2, 3, 4, 5, 6, 8), and tumor necrosis factor alpha (TNF-α); reduction in the expression of cyclooxygenase 2 (COX-2) resulting in dropping of production of a few prostanoids; intensification of activity of catechol

**160**

dexamethasone could reduce scarring process as the electrode negotiated the hook region or near the electrode tip, but they did not observe the relation between dexamethasone and reduction of fibrosis relating to cochleostomy [13]. In vitro studies showed the correlation between reduction (loss) of auditory cells after exposure to *tumor necrosis factor* alpha (TNF-alpha) and dexamethasone-releasing polymer used to coat electrode of cochlear implant carries.

Research carried out on animal model proved that prolonged steroid therapy could significantly improve hearing preservation rate (including pharmacokinetic and morphological analysis) when the electrode of cochlear implants was covered with dexamethasone (special formulation with controlled drug release) [14]. However, Honeder et al. did not confirm that steroids could have a positive impact on residual hearing in a guinea pig model. One reason why both authors gain different results may lie in different types of steroid therapy. In the first study, dexamethasone was used on the contrary to the second study where triamcinolone was administrated [15]. Douchement et al. investigated the effects of steroids using a gerbil animal model. Animals were implanted with an electrode with controlled dexamethasone delivery (1 and 10% concentration of dexamethasone) on one side and a conventional electrode on the contralateral side. Hearing levels were established based on the tone bursts on auditory brain stem responses at 4–6-week postimplantation and at 1-year postimplantation period for older gerbils. A 1-year observation period showed significantly improved results obtained for the high auditory frequencies, but the results for the low frequencies were ambiguous [16].

Cho et al. analyzed the efficacy of preoperative and intraoperative schemes of administration of steroids for hearing preservation. Dexamethasone was administrated systematically at the dose of 5 mg/ml in the preoperative period and then topically (off-label) during cochlear implantation surgery. Pure tone audiometry (PTA) was measured in four frequencies: 250, 500, 1000, and 2000 Hz. Statistically significant differences were observed between the steroid group and the control group, supporting the observation and beneficial impact of administration steroid treatment [17].

## **1.4 Glucocorticoid administration: the possibilities**

During treatment of otologic diseases, two routes of administration of glucocorticoids are possible: local and systemic. Local administration (e.g., transtympanic injection) allows to achieve high concentration of glucocorticoid in the middle ear, but due to presence of Eustachian tube, the medication may be partly evacuated. Local drug administration to the middle and inner ear avoids "the first pass effect." The main advantages of local drug delivery are as follows:


Local drug administration may involve intracochlear administration (e.g., stem cell, gene therapy) or extracochlear administration (e.g., intratympanic injection). A combination of both routes of drug delivery to the ear is also possible [13]. According to publications, systemic administration in treatment of otorhinolaryngological

diseases is known as noninvasive route of drug delivery, due to lack of damaging of tympanic membrane. Adverse effects of systemic delivery may be one of the purposes of discontinuation of the therapy. The presence of *blood-labyrinth barrier* (BLB) in the inner ear is one of the causes of problems with reaching high concentration of drug.
