Food-induced stimulation of the antisecretory factor to improve symptoms in Meniere's disease: our results.

PURPOSE: Specially processed cereals (SPC) that increase endogenous antisecretory factor (AF) synthesis have been proposed to improve symptoms of Meniere's disease (MD) with controversial results. The aim of this study was to evaluate the effects of SPC in patients with definite unilateral MD and compare the results to a treatment protocol with intravenous glycerol and dexamethasone. METHODS: Thirteen patients with unilateral MD were treated with SPC and 13 patients were treated with intravenous glycerol and dexamethasone for 12 months. Audio-vestibular evaluation was performed before (T0) and at the end of the treatments (T12). The number of vertigo spells were evaluated before and after therapy and the Efficacy Index (EI) was calculated. Questionnaires for hearing loss (HHIA), tinnitus (THI) and quality of life (TFL) were administered. RESULTS: EI decreased in the SPC group in the second semester compared to the first although not significantly (p = 0.6323). There was a significant reduction for THI score in the SPC group at T12 (p = 0.0325). No significant differences were found between the two groups at T0 (p = 0.4723), while a significant difference was found at T12 (p = 0.0041). Quality of life showed an improvement in daily activities in the SPC group compared to infusion therapy group. CONCLUSION: Our study shows a reduced number of vertigo attacks and a positive effect on the discomfort generated by tinnitus and quality of life in patients with unilateral MD treated with SPC and when compared to patients treated with intravenous glycerol and dexamethasone. No effects on hearing thresholds were noted in both groups.

Modeling drug exposure in rodents using e-cigarettes and other electronic nicotine delivery systems.

Smoking tobacco products is the leading cause of preventable death worldwide. Coordinated efforts have successfully reduced tobacco cigarette smoking in the United States; however, electronic cigarettes (e-cigarette) and other electronic nicotine delivery systems (ENDS) recently have replaced traditional cigarettes for many users. While the clinical risks associated with long-term ENDS use remain unclear, advancements in preclinical rodent models will enhance our understanding of their overall health effects. This review examines the peripheral and central effects of ENDS-mediated exposure to nicotine and other drugs of abuse in rodents and evaluates current techniques for implementing ENDS in preclinical research.

miR-221-3p Inhibits Schwann Cell Myelination.

Following peripheral nerve injury, Schwann Cells (SCs) undergo dedifferentiation, proliferation, migration, and remyelination. Recent works demonstrated the importance of the short non-coding RNA (miRNAs) in SC dedifferentiation and remyelination after nerve injury. Previously, we found some miRNAs like miR-9, miR-221, miR-222 and miR-182 could regulate the proliferation and migration of SCs. Therefore, it is imperative to ask whether these miRNAs could regulate the myelination of SCs. Here we demonstrated that miR-221-3p could inhibit the myelination of SCs when co-cultured with dorsal root ganglion cells in vitro. In addition, NGF1-A binding protein 1 (Nab1) which was essential for SCs myelination could be downregulated by miR-221-3p. Suppressing the expression of Nab1 could reverse the promotion of miR-221-3p antagomir on SC myelination. The effects of miR-221-3p on SC myelination might be used to improve peripheral nerve regeneration, thus offering a new approach to peripheral nerve repair.

Growth hormone promotes neurite growth of spiral ganglion neurons.

Intact spiral ganglion neurons are a specific requirement for hearing rehabilitation in deaf patients by cochlear implantation. Neurotrophic growth factors have been proposed as effective tools to protect and regenerate spiral ganglion neurons that are degenerated in the majority of patients suffering from hearing loss. Here, we show that growth hormone (GH), a pleiotropic growth factor whose neurotrophic role in the inner ear is still unclear, significantly increases neurite extension, as well as neuronal branching, in spiral ganglion cell cultures derived from early postnatal rats. Our data suggest that GH can act as a potent neurotrophic factor for inner ear neurons, which specifically promotes neurite growth. These effects might be elicited in a direct way or, alternatively, by induction of other growth factors that account for the observed neurotrophic effects. Thus, we conlude that GH might represent a novel candidate for the treatment of neurodegeneration in the hearing-impaired inner ear that has the potential to ultimately improve the performance and outcome of modern auditory implants.

The use of botulinum toxin in the treatment of sialorrhea in parkinsonian disorders.

Drooling is a common symptom in parkinsonian disorders. Our aim was to assess the safety and effect of botulinum toxin when applied to parotid glands without ultrasound guidance for sialorrhea in parkinsonian disorders in a retrospective study with a long-term follow-up. We evaluated 53 patients (64.2% male and 35.8% female) with a mean age of 70.18 ± 9.25 years who were treated in our centre between 2007 and 2013. We analysed the mean dose, latency, effect duration, response and adverse effects of treating sialorrhea by injecting botulinum toxin type A (Botox) into the parotid glands without ultrasound guidance. A total of 41 patients with Parkinson's disease, 6 with progressive supranuclear palsy, 4 with multiple system atrophy and 2 with corticobasal degeneration were included. The mean duration of the disease at onset was 10.51 ± 6.81 years and the mean sialorrhea duration was 1.99 ± 1.55 years. The initial dose used for each parotid gland was 14.53 ± 3.95 units of Botox, with a mean dose of 22.17 ± 8.76 units. There was an improvement after treatment in 65.22% of patients with an average score of 6.85 ± 1.58 points on a scale from 0 to 10. The duration of the treatment effect was 4.38 ± 2.11 months, with a latency period of 10.06 ± 9.63 days. Adverse effects were mild and infrequent. Botulinum toxin is a safe and effective therapy for the treatment of sialorrhea in parkinsonian disorders and there is no requirement for ultrasound guidance. It has a rapid onset and lasting effect without requiring a high dosage.

Outcomes of greater occipital nerve injections in pediatric patients with chronic primary headache disorders.

BACKGROUND: Chronic migraine is common in pediatrics and generally disabling. In adults, infiltration of the area around the greater occipital nerve can provide short- to medium-term benefit in some patients. This study reports the efficacy of greater occipital nerve infiltrations in pediatric patients with chronic primary headache disorders. METHODS: Retrospective chart review of patients <18 years with a chronic primary headache disorder undergoing a first-time injection. Infiltrations were unilateral and consisted of a mixture of methylprednisolone acetate, adjusted for weight, and lidocaine 2%. RESULTS: Forty-six patients were treated. Thirty-five (76%) had chronic migraine, 9 (20%) new daily persistent headache (NDPH), and 2 (4%) a chronic trigeminal autonomic cephalalgia. Medication overuse was present in 26%. Ages ranged from 7 to 17 years. Follow-up data were available for 40 (87%). Overall, 53% (21/40) benefitted, and 52% (11/21) benefitted significantly. Benefit onset ranged from 0 to 14 days, mean 4.7 (SD 4.3), with mean benefit duration of 5.4 (SD 4.9) weeks. In chronic migraine, 62% (18/29) benefitted, and 56% (10/18) significantly benefitted. In NDPH, 33% (3/9) benefitted; 33% (n = 1) significantly. Neither child with a chronic trigeminal autonomic cephalalgia benefitted. In logistic regression modeling, medication overuse, age, sex, and sensory change in the distribution of the infiltrated nerve did not predict outcome. There were no serious side effects. CONCLUSIONS: Greater occipital nerve injections benefitted 53% of pediatric patients with chronic primary headache disorders. Efficacy appeared greater in chronic migraine than NDPH. Given the benign side effect profile, a greater occipital nerve infiltration seems appropriate before more aggressive approaches.

Chromenopyrazoles: non-psychoactive and selective CB1 cannabinoid agonists with peripheral antinociceptive properties.

The unwanted psychoactive effects of cannabinoid receptor agonists have limited their development as medicines. These CB1-mediated side effects are due to the fact that CB1 receptors are largely expressed in the central nervous system (CNS). As it is known that CB1 receptors are also located peripherally, there is growing interest in targeting cannabinoid receptors located outside the brain. A library of chromenopyrazoles designed analogously to the classical cannabinoid cannabinol were synthesized, characterized, and tested for cannabinoid activity. Radioligand binding assays were used to determine their affinities at CB1 and CB2 receptors. Structural features required for CB1/CB2 affinity and selectivity were explored by molecular modeling. Some compounds in the chromenopyrazole series were observed to be selective CB1 ligands. These modeling studies suggest that full CB1 selectivity over CB2 can be explained by the presence of a pyrazole ring in the structure. The functional activities of selected chromenopyrazoles were evaluated in isolated tissues. In vivo behavioral tests were then carried out on the most effective CB1 cannabinoid agonist, 13 a. Chromenopyrazole 13 a did not induce modifications in any of the tested parameters on the mouse cannabinoid tetrad, thus discounting CNS-mediated effects. This lack of agonistic activity in the CNS suggests that this compound does not readily cross the blood-brain barrier. Moreover, 13 a can induce antinociception in a rat peripheral model of orofacial pain. Taking into account the negative results obtained with the hot-plate test, the antinociception induced by 13 a in the orofacial test could be mediated through peripheral mechanisms.

Subcutaneous injection of endokinin C/D attenuates carrageenan-induced inflammation.

Endokinins, encoded by the human preprotachykinin C (PPT-C)/TAC4 gene, are peptides that consist of endokinin A (EKA), B (EKB), C (EKC) and D (EKD) and belong to the tachykinin family. Intrathecal injection of EKC/D (using the common carboxyl-terminal duodecapeptide in EKC and EKD) markedly attenuated the induction of thermal hyperalgesia and scratching behavior by intrathecal administration of substance P (SP), indicating that EKC/D has an antagonistic effect on the neurokinin 1 receptor (NK1R), SP-preferring receptor, at the spinal level; however, the pharmacological function of EKC/D at the periphery is not yet understood. Therefore, to clarify the effect of EKC/D on the peripheral tissue, the effect of subcutaneous injection of EKC/D on carrageenan-induced inflammation was examined. Subcutaneous injection of EKC/D attenuated an increase in paw volume following carrageenan-induced inflammation in a dose-dependent manner. Indeed, the increased paw volume was significantly decreased 40 min after treatment with 10(-4) M (10 nmol) and 10(-3) M (100 nmol) EKC/D (100 microl/rat). Similarly, injection of NK1R antagonists such as L-703,606 and Spantide I (10(-3) M) attenuated the increased paw volume following inflammation. Furthermore, the reduced withdrawal latency evoked by inflammation following subcutaneous injection of carrageenan was also dose-dependently attenuated by EKC/D administration. These results indicate that subcutaneous injection of EKC/D elicits an anti-inflammatory effect on carrageenan-induced inflammation.

Glucagon-like peptide-1 protects NSC-34 motor neurons against glucosamine through Epac-mediated glucose uptake enhancement.

Bioenergetic deficits are considered a common cause of neurodegenerative diseases. Although creatine supplementation has been shown to be effective in certain neurodegenerative disorders, it is less effective in amyotrophic lateral sclerosis, a disease that primarily affects motor neurons. These neurons are particularly vulnerable to a cellular energy deficit. Using the ATP-depleting drug glucosamine, we evaluated whether the incretin hormone glucagon-like peptide (GLP)-1 protects motor neurons against glucosamine-induced cytotoxicity. Undifferentiated NSC-34 cells were differentiated into glutamate-sensitive motor neurons by a modified serum deprivation technique. Glucosamine inhibited the viability of differentiated NSC-34 cells in a time- and dose-dependent manner. Glucosamine also acutely reduced cellular glucose uptake, glucokinase activity and intracellular ATP levels. As a result, the activity of AMP-activated protein kinase as well as endoplasmic reticulum stress increased. Pretreatment with GLP-1 significantly alleviated glucosamine-mediated neurotoxicity by restoring cellular glucose uptake, glucokinase activity and intracellular ATP levels. The protective effect of GLP-1 was replicated by Exendin-4 but not Exendin-9, and not blocked by inhibitors of phosphoinositide-3 kinase, protein kinase A, cSrc, or epidermal growth factor receptor, but it was blocked by an adenylate cyclase inhibitor. A selective activator for exchange proteins directly activated by cAMP (Epac), but not a selective activator for protein kinase A, mimicked the GLP-1 effect. Therefore GLP-1 may exert its effect mainly through cAMP-dependent, Epac-mediated restoration of glucose uptake that is typically impaired by glucosamine. These findings indicate that GLP-1 could be employed therapeutically to protect motor neurons that are susceptible to bioenergetic deficits.

[Pharmacological treatment of diabetic neuropathy in the elderly]. / Tratamiento farmacológico de la neuropatía diabética dolorosa en el anciano.

Diabetic neuropathy is the third most common complication of diabetes mellitus. When this neuropathy is accompanied by pain, it requires a specific treatment. In the elderly patient, the pain has an enormous impact on quality of life, as it is associated with anxiety, depression and sleep disorders, leading to a direct impact on the functionality of the patient. Likewise, there are a number of changes at the central and peripheral nervous system, which contribute to the chronicity of painful processes, and eventually also affect and impact on the quality of life of elderly patients. It is fundamental before initiating treatment, to know of all aspects related to drug pharmacokinetics and pharmacodynamics, especially those related to aging, because this will allow you to select the best drug for each patient. This article aims to review the pathophysiological concepts related to diabetic neuropathy in the elderly and the best treatment options.

Recurrent vasovagal syncope: comparison between clomipramine and nitroglycerin as drug challenges during head-up tilt testing.

AIMS: To compare the responses between clomipramine, a centrally acting substance, and nitroglycerin, with mainly peripheral action, when each drug is used during tilt test for the induction of vasovagal syncope (VVS). METHODS AND RESULTS: Hundred patients with recurrent episodes of classical VVS underwent two tilt tests in a randomized sequence. One test included 20 min of tilt at 60 degrees with intravenous administration of 5 mg clomipramine (clomipramine tilt), whereas the other test included an initial 30 min period of passive 60 degrees tilt, followed by sublingual spray administration of 400 microg nitroglycerin (nitroglycerin tilt). Fifty asymptomatic subjects served as controls. Following clomipramine tilt, a positive response occurred in 73 patients (73%), a negative response in 23 (23%), and drug intolerance in 4 (4%). With nitroglycerin tilt, these percentages were 52, 48, and 0%, respectively. Significant differences were observed regarding positive responses (clomipramine vs. nitroglycerin: 73/100 vs. 52/100, P < 0.05), as well as negative responses (23/100 vs. 48/100, respectively, P < 0.05). A high concordance rate was observed in positive responses. CONCLUSION: In the evaluation of patients with recurrent classical VVS, clomipramine tilt is associated with an increased positive yield relative to nitroglycerin tilt. This suggests that central mechanisms may be more important than peripheral ones in VVS pathogenesis.

Pharmacological analysis of components of the change in transmural potential difference evoked by distension of rat proximal small intestine in vivo.

The reflex response to distension of the small intestine in vivo is complex and not well understood. The aim of this study was to characterize the neural mechanisms contributing to the complex time course of the intestinal secretory response to distension. Transmucosal potential difference (PD) was used as a marker for mucosal chloride secretion, which reflects the activity of the secretomotor neurons. Graded distensions (5, 10, and 20 mmHg) of distal rat duodenum with saline for 5 min induced a biphasic PD response with an initial peak (rapid response) followed by a plateau (sustained response). The rapid response was significantly reduced by the neural blockers tetrodotoxin and lidocaine (given serosally) and by intravenous (iv) administration of the ganglionic blocker hexamethonium and the NK(1) receptor antagonist SR-140333. Serosal TTX and iv SR-140333 significantly reduced the sustained response, which was also reduced by the NK(3) receptor antagonist talnetant and by the vasoactive intestinal polypeptide (VPAC) receptor antagonist [4Cl-d-Phe(6), Leu(17)]-VIP. Serosal lidocaine and iv hexamethonium had no significant effect on this component. Inhibition of nitric oxide synthase had no effect on any of the components of the PD response to distension. The PD response to distension thus seems to consist of two components, a rapidly activating and adapting component operating via nicotinic transmission and NK(1) receptors, and a slow component operating via VIP-ergic transmission and involving both NK(1) and NK(3) receptors.

Comparison of the analgesic effects of intra-articular injections administered preoperatively and postoperatively in knee arthroscopy.

Perioperative injection of analgesic agents is widely used for postoperative pain control following knee arthroscopy. This prospective, randomized, double-blind study explored whether a preoperative analgesic injection offered better pain control than a postoperative injection. Patients undergoing knee arthroscopy under general anesthesia were randomized to receive a standardized combination of intra-articular bupivacaine, morphine, and epinephrine administered either 20 minutes prior to incision or at the end of the procedure. Outcome measures included visual analog pain scores at 0, 30, 60, 90, and 120 minutes after the procedure, total recovery room fentanyl consumption, total oral narcotics consumption for the first 24 hours after surgery, and a validated pain and satisfaction instrument. Of the 22 patients enrolled in the study, 21 successfully completed the study protocol. Pain scores, narcotics consumption, and overall patient satisfaction were not significantly different between the two groups. These findings indicate the timing of intra-articular analgesic injections during outpatient knee arthroscopy, either preoperatively or postoperatively, may be at the discretion of the surgeon.

Dose-independent pharmacokinetics of a candidate for diabetic neuropathy, SR-4668, after intravenous and oral administration to rats: Intestinal first-pass effect.

Dose-independent pharmacokinetic parameters of SR-4668 were observed after intravenous (i.v.) administrations at doses of 25, 50, and 75 mg/kg and oral administrations at doses of 50, 100, and 150 mg/kg to rats. The hepatic, gastric, and intestinal first-pass effects of SR-4668 were also measured after i.v., intraportal (i.p.), intraduodenal (i.d.), and intragastric (i.g.) administrations at a dose of 50 mg/kg to rats. Although a considerable amount of orally administered SR-4668 was absorbed, the F was low--only 33%. This indicates considerable first-pass (gastric, intestinal, and/or hepatic) effects of SR-4668 in rats. After i.v. administrations, the total body clearances of SR-4668 were considerably slower than the reported cardiac output in rats, suggesting that the first-pass effects of SR-4668 in the lung and heart could be negligible, if any, in rats. The AUCs of SR-4668 were comparable between i.v. and i.p. administrations, suggesting that the hepatic first-pass effect of SR-4668 was not considerable in rats. The AUCs were also comparable between i.d. and i.g. administrations, suggesting that gastric first-pass effect was almost negligible in rats. However, the AUC after an i.d. administration was significantly smaller (approximately 55% decrease) than that after an i.p. administration, suggesting that the intestinal first-pass effect was approximately 55% of oral dose. The rests of the orally administered dose could be mainly due to degradation of SR-4668 in gastric juices; 77.3-95.6% of the spiked amount of SR-4668 were recovered after 4-h incubation in five human gastric juices. The above data suggested that the low F of SR-4668 could be mainly due to considerable intestinal first-pass effect in rats.