Expression of histamine receptors in the human endolymphatic sac: the molecular rationale for betahistine use in Menieres disease.

The human endolymphatic sac (ES) is situated in a duplicature of the dura in the posterior cranial fossa and constitutes a part of the inner ear. The sac possesses immunological capacities and is responsible for a major part of the trans-epithelial ion transport occurring within the inner ear, via molecular mechanisms similar to that of the kidney collecting duct epithelia. Dysfunction of the trans-epithelial ion transport has been hypothesized as the reason for the endolymphatic hydrops occurring in Menieres diseases. Thus, candidate drug selection for medical treatment of Menieres disease has been based on a potential capability of improving trans-epithelial ion transport. However, recent human studies seems to rule out diuretic therapy and The Committee for Medicinal Products for Human Use redrew the recommendation for trimetazidine (Vastarel) treatment in the management of Meniere disease in 2012. This leaves betahistine (Betaserc) as the only drug for potential prevention of the incapacitating attacks of dizziness, tinnitus and hearing loss. However, the histamine receptors targeted by betahistine have never been demonstrated in the human ES. Accordingly, this study aims to investigate the expression of histamine receptors of the human ES epithelium and sub-epithelial stroma. Following sampling of human endolymphatic sac tissue during translabyrinthine surgery, the expression of histamine receptor genes was determined by cDNA microarray analysis. Results were subsequently verified by immuno-histochemistry. The combined results of microarrays and immuno-histochemistry showed expression of the histamine receptor HRH1 in the epithelial lining of the ES, whereas HRH3 was expressed exclusively in the sub-epithelial capillary network. Receptors HRH2 and -4 were not expressed. The present data provide the first direct evidence of a molecular rationale for betahistine treatment in Menieres disease. A potential betahistine effect in Menieres disease may primarily be through the H3-receptor antagonism, leading to inhibition of vestibular neuro-transmission and central vaso-dilation. The H1-receptor localization in the ES epithelium suggests an immuno-regulatory effect.

Phase transitions of rat stratum corneum lipids by an electron paramagnetic resonance study and relationship of phase states to drug penetration.

In order to relate barrier function to stratum corneum structure and the thermal transitions of corneum lipids, samples from hairless rat skin were investigated by using ESR and drug penetration techniques. The phase transition of stratum corneum lipids was estimated using a deeper probe (16-doxyl-stearic acid) inserted in the lipid bilayers and measuring the rotational correlation time, tau(c). Results of ESR study showed that stratum corneum lipids underwent thermal transitions at 39.3 +/- 1.6 degrees C and 63.6 +/- 2.6 degrees C roughly similar to the data obtained by differential scanning calorimetry measurements. Cholesterol oxidase treatment decreased the fluidity of the lipids at lower temperatures. The treatment of stratum corneum with laurocapram (1%) and isopropyl myristate (IPM, 2%) little changed both phase transition temperatures, although the treatment highly increased the molecular motion of the lipids. The flux (J(s)) of lipophilic drugs (beta-estradiol, indomethacin and betahistine) through the skin was enhanced with increasing temperatures, with an increase in the diffusion constant within skin and a decrease in the lag time. There was a good relationship between log J(s) or log permeability coefficient (K(p)) and 1/tau(c) in the temperature range of 45 to 64 degrees C. The calculated activation energy (delta E) for diffusion of these drugs across skin was 17-40 kcal/mol. Judging from our data, stratum corneum lipids of rat probably exist as the gel, crystalline state below 39 degrees C, the mesomorphic state between 39 and 64 degrees C and the fluid, liquid-crystalline state at temperatures of 64 degrees C or above. These results are in line with the permeability of these lipophilic drugs through the intercellular lipids disordered is highly increased.