Crosstalk of hypothalamic chemerin, histamine, and AMPK in diet-and olanzapine-induced obesity in rats.

AIM: Contradiction overwhelms chemerin link to feeding behavior. Neither the chemerin central role on appetite regulation nor its relation to hypothalamic histamine and AMPK is verified. MAIN METHODS: Food intake, body weight and hypothalamic biochemical changes were assessed after a single intra-cerebroventricular or intraperitoneal injection (ip) (1 µg/kg or 16 µg/kg, respectively) or chronic ip administration (8 µg/kg/day) of chemerin for 14 or 28 days. Hypothalamic neurobiochemical changes in chemerin/histamine/AMPK induced by either 8-week high fat diet (HFD) or food restriction were also investigated. To confirm chemerin-histamine crosstalk, these neurobiochemical changes were assessed under settings of H1-receptor agonism and/or antagonism by betahistine and/or olanzapine, respectively for 3 weeks. KEY FINDINGS: Chemerin-injected rats exhibited anorexigenic behavior in both acute and chronic studies that was associated with a decreased AMPK activity in the arcuate nucleus (ARC). However, with long-term administration, chemerin anorexigenic effect gradually ceased. Contrarily to food restriction, 8-week HFD increased ARC expression of chemerin and its receptor CMKLR1, reducing food intake via an interplay of H1-receptors and AMPK activity. Blockage of H1-receptors by olanzapine disrupted chemerin signaling pathway with an increased AMPK activity, augmenting food intake. These changes were reversed to normal by betahistine coadministration. SIGNIFICANCE: Chemerin is an anorexigenic adipokine, whose dysregulation is implicated in diet, and olanzapine-induced obesity through a histamine/AMPK axis in the ARC. Hypothalamic chemerin/CMKLR1 expression is a dynamic time-dependent response to changes in body weight and/or food intake. Targeting chemerin as a novel therapeutic approach against antipsychotic- or diet-induced obesity is worth to be further delineated.

The effectiveness of transmeatal low-power laser stimulation in treating tinnitus.

The aim of this study is to examine the effectiveness of transmeatal low-power laser stimulation (TLLS) in treating tinnitus. This is a prospective, double-blinded, randomized, placebo-controlled trial. Patients with persistent subjective tinnitus as their main symptom were recruited into the study from the outpatient clinics. The recruited patients were randomized into the experimental group or TLLS+ group (patients in this group were prescribed to use TLLS at 5 mW at 650 nM wavelength for 20 min daily and oral betahistine 24 mg twice per day for a total of 10 weeks) and the control group or TLLS- group (patients in this group were prescribed with a placebo device to use and oral betahistine 24 mg twice per day for 10 weeks). All patients were required to answer two sets of questionnaires: the Tinnitus handicap inventory (THI) and visual analogue scales (VAS) symptoms rating scales, before starting the treatment and at the end of the 10-week treatment period. The total score of the THI questionnaire was further graded into five grades, grade 1 being mild and grade 5 being catastrophic. Wilcoxon-signed ranks test and Mann-Whitney test were used to compare and analyze the THI and VAS scores before and after treatment for each group. Changes with p value of <0.05 were considered as statistically significant. Chi square test was used to analyze the change of parameters in categorical forms (to compare between TLLS+ and TLLS-). Changes with p value of <0.05 were considered as statistically significant. Forty-three patients successfully and diligently completed their treatment. It was noted that using any condition of the device, TLLS+ or TLLS-, patient's tinnitus symptoms improved in terms of THI scores (TLLS+, p value = 0.038; TLLS-, p value = 0.001) or VAS scores with a change of at least one grade (TLLS+, p value = 0.007; TLLS-, p value = 0.002) at p value <0.05 significant level. In contrast when TLLS+ group was compared with TLLS- group, no statistically significant result was obtained. In term of VAS scores, there seems to be no statistically significant improvement in patients' annoyance, sleep disruption, depression, concentration and tinnitus loudness and pitch heard between the two groups. Transmeatal low-power laser stimulation did not demonstrate significant efficacy as a therapeutic measure in treating tinnitus.

Effect of a fixed combination of nimodipine and betahistine versus betahistine as monotherapy in the long-term treatment of Ménière's disease: a 10-year experience.

Despite an abundance of long-term pharmacological treatments for recurrent vertigo attacks due to Ménière's disease, there is no general agreement on the their efficacy. We present the results of a retrospective study based on a 10-year experience with two long-term medical protocols prescribed to patients affected by Ménière's disease (diagnosed according to the American Academy of Otolaryngology-Head and Neck Surgery Committee on Hearing and Equilibrium guidelines) who completed treatments in the period 1999-2009. A total of 113 medical records were analysed; 53 patients received betahistine-dihydrochloride at on-label dosage (32 mg die) for six months, and 60 patients were treated with the same regimen and nimodipine (40 mg die) as an add-therapy during the same period. Nimodipine, a 1,4-dihydropyridine that selectively blocks L-type voltage-sensitive calcium channels, has previously been tested as a monotherapy for recurrent vertigo of labyrinthine origin in a multinational, double-blind study with positive results. A moderate reduction of the impact of vertigo on quality of life (as assessed by the Dizziness Handicap Inventory) was obtained in patients after therapy with betahistine (p < 0.05), but a more significant effect was achieved in patients treated by combined therapy (p < 0.005). In the latter group, better control of vertigo was seen with a greater reduction of frequency of attacks (p < 0.005). Both protocols resulted in a significant improvement of static postural control, although a larger effect on body sway area in all tests was obtained by the fixed combination of drugs. In contrast, no beneficial effect on either tinnitus annoyance (as assessed by the Tinnitus Handicap Inventory) and hearing loss (pure-tone average at 0.5, 1, 2, 3 kHz frequencies of the affected ear) was recorded in patients treated with betahistine as monotherapy (p > 0.05), whereas the fixed combination of betahistine and nimodipine was associated with a significant reduction of tinnitus annoyance and improvement of hearing loss (p < 0.005). It was concluded that nimodipine represents not only a valid add-therapy for Ménière's disease, and that it may also exert a specific effect on inner ear disorders. Further studies to investigate this possibility are needed.

Topical application of betahistine improves eustachian tube function in an animal model.

CONCLUSION: Betahistine dihydrochloride, a drug used widely in the systemic treatment of balance disorders such as Ménière's disease, was found to improve eustachian tube function when applied topically in the nasopharynx of rats. OBJECTIVES: The study tested the effect of betahistine, a histamine receptor agonist, on eustachian tube function and tested the involvement of H1 and H3 histamine receptors. METHODS: Eustachian tube function was measured in anaesthetized rats while middle ear pressure was increased and then monitored during induced swallowing. Betahistine and other drugs were applied topically in the nasopharynx, bulla and epipharynx, and administered intraperitoneally. RESULTS: Systemic application of betahistine hardly changed eustachian tube function, but topical application significantly improved it. The action of topical betahistine was unaffected by the HI receptor antagonist mepyramine and was mimicked by the H3 agonist, ciproxifan.

Comparison of efficacy of different treatment methods in the treatment of idiopathic tinnitus.

OBJECTIVES: This study aims to detect whether any differences were present between betahistine dihydrochloride, transcutaneal electrical nerve stimulation and pure tone masking-tinnitus retraining therapy (TRT) methods in the effects on quality of life and treatment of the symptoms of the patients. PATIENTS AND METHODS: A total of 91 patients (42 females, 49 males; mean age 49.3±8.3 years; range 30 to 70 years) who admitted to the Otorhinolaryngology Clinic of the Ufuk University between June 2009 and June 2010 with a complaint of subjective tinnitus and who had no hearing loss were included in the study. In this study, the effects of these three treatment methods on healing and quality of life in patients suffering from bilateral subjective tinnitus were comparatively evaluated using Tinnitus Handicap Inventory Score (THIS), visual analog scale (VAS) and audiological parameters. The evaluations were made immediately before the treatment, immediately after the treatment and three weeks after the treatment. Kolmogorov-Smirnov analysis was used to test the normal distribution of the data and Wilcoxon signed rank test was used to show the differences between the different treatment methods before the treatment, immediately after the treatment and three weeks after the treatment. Mann-Whitney U and Kruskal-Wallis H tests were used to show the inter-group differences. RESULTS: In the inter-group analyzes, success rate of the pure tone masking-TRT was much higher when compared to the other treatment methods. In the evaluations performed at the end of the three-month period, it was seen that the efficacy of the treatment was continuing. CONCLUSION: According to these results, pure tone masking-TRT was found to be the best treatment method when compared to other methods and it was concluded that this treatment may be considered as the first choice in patients with idiopathic tinnitus.

[A clinical study on the effect of Yinxing Damo combined with betahistine hydrochloride injection on vertebral basilar artery ischemic vertigo].

OBJECTIVE: To evaluate the therapeutic efficacy of Yinxing Damo (YXDM) combined with Betahistine Hydrochloride Injection (BHI) on vertebra basilar artery ischemic vertigo (VBIV). METHODS: Ninety patients with VBIV were randomly divided into two groups; 45 patients (the treated group) were treated with YXDM and BHI intravenous dripping, once a day for 14 days. Another 45 patients (control group) were treated with Xueshuantong and BHI intravenous dripping, once daily for 14 days. The clinical syndromes and the index of the transcranial Doppler (TCD) and hemorheology were observed. RESULTS: The total effective rate was 100% in the treated group, which was better than that in the control group 90.5%, (P < 0.05). The indexes of TCD and hemorheology in the treated group were obviously improved after treatment, (P < 0.01). CONCLUSION: YXDM combined with BHT injection had better effect in treating patients with VBIV is an ideal drug for VBIV.

Mechanism for enhancement effect of lipid disperse system on percutaneous absorption.

To clarify the mechanism involved in the enhancement effect of lipid disperse systems (LDS) on percutaneous absorption, the effect of the LDSs of betahistine (BH), prepared using egg phosphatidylcholine (EPC, phase transition temperature, tau m, -15 to -17 degrees C) or hydrogenated soybean phosphatidylcholine (HSPC, tau m, 50 to 60 degrees C), cholesterol, and dicetylphosphate, on the percutaneous absorption of BH, the amount of skin lipids (ceramides, triglycerides, and phospholipids), the fluidity of skin lipids, and the partitioning of LDS-BH into the skin layers were investigated using Wistar and hairless rats. Also examined was whether the LDS penetrated through the stratum corneum (SC) or follicles, using a fluorescent probe (Nile Red). The plasma concentrations of BH were much higher and more sustained after application of a gel formulation containing EPC-LDS and D-limonene (prep. 2) than those after the non-LDS formulation containing D-limonene (prep. 1), whereas the plasma levels after application of a formulation containing HSPC-LDS (prep. 5) were not largely increased compared with those after prep. 1. The content of ceramides (intercellular lipids) and triglycerides (sebaceous gland lipides) in the SC were dramatically decreased by the treatment with prep. 1 and prep. 2, with the more decreased levels of these lipids by the treatment with prep. 2. The phospholipid content of the SC was enhanced by 2-fold following the prep. 2 treatment, indicating the extensive incorporation of LDS lipids into the SC. The histochemical examination of the skin, following application of EPC-LDS with a fluorescent probe, indicated that the LDS lipids penetrated rapidly through the SC and follicles into the viable skins. The fluidity of the SC lipids was dramatically increased following the treatment with the fluid EPC-LDS, whereas the fluidity was significantly decreased by the solid HSPC-LDS. The BH in each skin layer was also significantly increased by the treatment with prep. 2. These results surely demonstrated that the fluid LDS permeated rapidly into the SC and the viable epidermis through the intercellular domains and the follicles in intact vesicles or lipid mixtures, thus ensuring the facilitated transport of LDS-drug through the skin.