Selective H1 Receptor Antagonist Research Articles

The Efficacy and Safety of High Dose (10 mg) of Desloratadine (Dazit® 10) in the Treatment of Chronic Spontaneous Urticaria in India: A Phase III, Multicentric, Open-Label, Single-Arm Study.

Chronic spontaneous urticaria (CSU) is a debilitating affliction that affects diverse quality of life (QoL) parameters such as sleep, self-esteem, and daily activities. Second-generation antihistamines, such as desloratadine, are more effective and safer in managing CSU. Desloratadine is a nonsedating, potent, and highly selective H1 receptor antagonist. At its daily dose of 5 mg, almost half of CSU patients do not show symptomatic improvement. European Academy of Allergy and Clinical Immunology (EAACI)/Global Allergy and Asthma European Network (GA2LEN)/European Dermatology Forum (EDF) (EuroGuiDerm)/Asia Pacific Association of Allergy, Asthma and Clinical Immunology (APAAACI) guidelines recommend increasing the dosage to up to four times in such nonresponsive patients. However, there is insufficient clinical evidence in Indian settings. We evaluated the efficacy and safety of 10 mg desloratadine (OD) in 256 nonresponsive patients with moderate to severe CSU. The primary outcome was the change in Urticaria Activity Score (UAS7) from baseline to four weeks. Additionally, change in Chronic Urticaria Quality of Life (CU-Q2oL) scores during the course of treatment was also evaluated. The mean UAS7 scores showed a significant reduction from 31.9 ± 4.8 at baseline to 18.2 ± 8.1 at the end of the study (p < 0.0001). The use of a higher dose of desloratadine also decreased the CU-Q2oL scores significantly from 59.8 ± 14.7 at baseline to 35.4 ± 10 at four weeks (p < 0.0001). The incidence of adverse events (AEs) possibly linked to the drug was low (1.6%), and no serious adverse events were reported. Results indicated improvements in the disease severity as well as its positive impact on participants' QoL. This study confirms the efficacy and safety of daily use of a twofold dose of desloratadine in nonresponsive moderate to severe CSU patients.

Molecular modeling and solubility of olopatadine hydrochloride polymorphs

Olopatadine hydrochloride is a selective H1 receptor antagonist used in ophthalmic solutions to treat the signs and symptoms of allergic conjunctivitis. This compound presents a phenomenon known as polymorphism, which can cause changes on physicochemical characteristics. Considering the worldwide regulatory requirements for drug registration and the complexity of the pharmacotechnical development of ophthalmic preparations, both supramolecular arrangements (carried out by the Hirshfeld surface) and theoretical calculations (through the quantum theory of atoms in molecules) led to understand the physicochemical properties of polymorphs I and II and possible differences in solubility. The supramolecular arrangement for both polymorphs consists of the chloride anion participating in strong NH ⋯ Cl and OH ⋯ Cl intermolecular interactions as well as two weak CH ⋯ Cl intermolecular interactions, which generate an ionic tetramer. The shape index HS shows the hydrophobic space, which is around the ionic tetramer formed by CH ⋯ π intermolecular interaction for form I as well as π ⋯ π stacking for form II. The supramolecular crystal arrangement provides an essential aspect of its solubility in drug polymorphs.

Comparative study on the efficacy and safety of bepotastine besilate versus levocetirizine in chronic spontaneous urticaria: A randomised, open-label, parallel study.

Background Urticaria is a common skin disease which often causes impairment in the quality of life. The ideal drug for chronic urticaria would have antihistaminic and anti-inflammatory actions. Bepotastine besilate is a recently approved novel anti-allergic agent with multiple mechanisms of action; levocetirizine is a potent and selective second-generation H1 receptor antagonist used in the treatment of urticaria. Aim To compare the efficacy and safety of bepotastine besilate versus levocetirizine in patients with chronic spontaneous urticaria. Methods The study design is a randomised, open-label, parallel-group, prospective interventional study. The study subjects were randomly assigned to either of the two groups a and b, each group had 50 patients with chronic urticaria. Statistical analyses were performed using (SPSS, version 18) for all the variables. Chi-square test was used for comparison between categorical variables. An unpaired student's t-test was done for quantitative variables. Results There was a significant decrease in mean urticaria activity score (P < 0.001), chronic urticaria quality of life (P < 0.001) and clinical global improvement (P < 0.001) in both the treatment groups but this improvement was higher in the bepotastine than in the levocetirizine group. There was no significant difference in the mean of absolute eosinophil count, C-reactive protein, aspartate transaminase, alanine transaminase from baseline to 4th week between the two study groups. Visual analogue scale showed statistically significant improvement from baseline to 4th week (P < 0.001) of follow-up but this increase was higher in levocetirizine group (0.64-4.24) than in bepotastine group (0.56-2.56) Limitations Blinding was not done. To assess the efficacy and safety of bepotastine, a larger study can be planned. Conclusion This study found that bepotastine is superior to levocetirizine and showed a statistically significant reduction in mean urticaria activity score 7, improved quality of life and clinical global improvement in patients with urticaria.

Improving the Quality of Life in the Management of Allergic Rhinitis: New Perspective on Cetirizine.

Allergic rhinitis (AR) is associated with disturbed sleep and subsequent functioning, and an impaired quality of life (QoL). The symptoms of AR exhibit prominent circadian variations, with symptoms being more common at the night-time or early morning. Addressing these allergy-related sleep issues, impaired QoL, and circadian variation in symptoms is important from the patient perspective and should be considered in the management of AR. To review the efficacy of cetirizine, a second-generation antihistamine and selective H1-receptor antagonist, in relation to improvement in the QoL of the patients, addressing the sleep disturbances and circadian variations in the symptoms of AR in clinical practice, and establishing its role as a contemporary antihistamine for the management of AR compared to newer antihistamines. Systematic literature review of the databases such as PubMed/MEDLINE, Google Scholar, and the Cochrane Central Register of Controlled Trials from 1990 to 2020. The symptoms of AR exhibited a circadian variation, with symptoms being worse during the night and early morning. The patients with AR encountered several sleep-related symptoms, including poor sleep quality, daytime somnolence, fatigue, and impaired productivity and QoL. Impaired QoL in AR was related to the disease severity. Administration of cetirizine at bedtime provides effective control of sleep impairment and symptoms of AR, besides improving the QoL. The efficacy of cetirizine has been demonstrated to be superior or comparable to the newer second-generation antihistamines. Cetirizine exhibits a tolerability profile comparable to the newer antihistamines. With long years of clinical experience and a good tolerability profile, cetirizine represents a valuable therapeutic option for the management of AR, even 30 years after its introduction. Cetirizine is included in the National List of Essential Medicines of India for the management of allergic disorders in view of its established efficacy and safety profile as well as being a cost-effective option.

An Innovative Spectrophotometric Method for the Estimation of H1 Receptor Antagonists in Pharmaceutical Formulations

An innovative, sensitive, simple and rapid method has been developed for estimation of selective H1 receptor antagonist. The method is based on bromination of drug. The proposed spectrophotometric method was developed using potassium bromate-potassium bromide mixture in acidic condition followed by the reaction of surplus bromine with methyl orange dye and measure the absorbance at 506 nm. Beer’s law was obeyed in the concentration range of 0.2-1.2 μg/ml, 0.3-1.7 μg/ml and 0.03-0.18 μg/ml for olopatadine hydrochloride, fexofenadine hydrochloride and azelastine hydrochloride respectively. The method was optimized for concentration of hydrochloride, ml of hydrochloride, ml of potassium bromate-potassium bromide mixture, ml of dye and reaction time. Developed method has been validated in accordance to International Council on Harmonisation guideline Q2R1. Statistical analysis proved that the method is accurate, sensitive, selective, precise and reproducible. The simple procedure with high accuracy, wide linearity range and sensitivity imply that the demonstrated method to be appropriate for routine estimation and quality control assay of pharmaceutical formulations.

Effect of the Fexofenadine on the expression of HRH-1 and HRH-4 receptor in Peripheral Blood Mononuclear Cell isolated from children with diagnosed allergy - in vitro study Short communication.

Fexofenadine (FXF) is the active metabolite of terfenadine with selective peripheral H1receptor antagonist activity. FXF is a third-generation antihistamine, non-sedating, rapid and very long acting used in symptoms associated with allergic diseases such as allergic rhinitis, asthma and dermatitis. The pleiotropic effects of histamine are mediated by four types of receptors that belong to the G-protein-coupled receptor family: histamine H1 receptor (HRH-1), histamine H2 receptor, histamine H3 receptor, and histamine H4 receptor. Our hypothesis is that HRH-4 opens new possibility in treatment in allergy diseases and FXF could be the antagonist of both HRH-1 and HRH-4. We isolated a peripheral blood mononuclear cell (PBMC) from children with diagnosed allergies and healthy - control group and measured the HRH-1 and HRH-4 mRNA gene expression using Quantitive Real-Time PCR. We obtained the results from basal gene expression and after FXF and histamine stimulation. HRH-1 mRNA basal gene expression shows significantly higher, and HRH-4 shows significantly lower expression in allergy group compared to control. In both groups HRH-1 mRNA gene expression was observed as statistically significant increased after histamine stimulation compared to cells not treated, while in HRH-4 only in allergy group we observed statistical increase. FXF successively blocked histamine affinity in HRH-1 mRNA gene expression but not in HRH-4, where we not observed any reaction. Results clearly overturned our hypothesis about the possibility of using FXF to block over-expression HRH-4 and open new way of treatment in allergy diseases.

Formulation and characterization of oral rapid disintegrating tablets of levocetirizine.

Levocetirizine, active R (-) enantiomer of cetirizine, is an orally active and selective H1 receptor antagonist used medically as an anti-allergic. Allergic rhinitis is a symptomatic disorder of the nose induced by inflammation mediated by immunoglobulin E (IgE) in the membrane lining the nose after allergen exposure. The purpose of the present study was to prepare rapidly disintegrating tablets of levocetirizine after its complexation with β-cyclodextrin (β-CD). Levocetirizine-β-CD complex tablets were prepared by direct compression technique using 3 synthetic superdisintegrants in different proportions. Development of the formulation in the present study was mainly based on the concentration of superdisintegrants and the properties of the drug. Nine batches of tablets were formulated and evaluated for various parameters: drug content, weight variation, water absorption ratio, wetting time, in vitro disintegration, hardness, friability, thickness uniformity, and in vitro dissolution. A Fourier-transform infrared spectroscopy (FTIR) study showed that there were no significant interactions between the drug and the excipients. The prepared tablets were good in appearance and showed acceptable results for hardness and friability. The in vitro disintegrating time of the formulated tablet batches was found to be 15-35 s percentage and the drug content of tablets in all formulations was found to be between 90-102%, which complied with the limits established in the United States Pharmacopeia. Complexation of levocetirizine with β-CD significantly improves the solubility of the drug. The disintegration time of the tablets was decreased with an increase in superdisintegrant amount. The tablets (batch CPX5) had a minimum disintegration time of 20 s and 99.99% of the drug was released within 10 min.

H3 antagonists and postoperative cognitive dysfunction.

Since histamine (HA) was first synthesized in 1907 and isolated as a bacterial contaminant of an extract of ergot in 1910, its role in health and disease and its molecular mechanism of action have been unraveled, leading to the formulation of an array of drugs with immense therapeutic value. HA is produced by decarboxylation of histidine, and its biological actions are mediated through four HA receptors, namely, H1, H2, H3, and H4 based on their sequence, their link to differential intracellular signaling mechanisms, and their unique pharmacological properties. H1 and H2 receptors have been targeted for treating allergic conditions and peptic ulcers, respectively. The discovery of a third HA receptor subtype (H3R) by molecular biologists in 1983, structurally a member of the G-protein-coupled receptor family, has led to the development of many potent and selective H3 receptor antagonists having the potential to treat a wide spectrum of neurological diseases including postoperative cognitive dysfunction.

Histamine H3 Inverse Agonist BF 2649 or Antagonist with Partial H4 Agonist Activity Clobenpropit Reduces Amyloid Beta Peptide-Induced Brain Pathology in Alzheimer's Disease.

Alzheimer's disease (AD) is one of the leading causes for disability and death affecting millions of people worldwide. Thus, novel therapeutic strategies are needed to reduce brain pathology associated with AD. In view of increasing awareness regarding involvement of histaminergic pathways in AD, we explored the role of one H3 receptor inverse agonist BF 2649 and one selective H3 receptor antagonist with partial H4 agonist activity in amyloid beta peptide (AβP) infusion-induced brain pathology in a rat model. AD-like pathology was produced by administering AβP (1-40) intracerebroventricular (i.c.v.) in the left lateral ventricle (250ng/10μl, once daily) for 4weeks. Control rats received saline. In separate group of rats, either BF 2649 (1mg/kg, i.p.) or clobenpropit (1mg/kg, i.p.) was administered once daily for 1week after 3weeks of AβP administration. After 30days, blood-brain barrier (BBB) breakdown, edema formation, neuronal, glial injuries, and AβP deposits were examined in the brain. A significant reduction in AβP deposits along with marked reduction in neuronal or glial reactions was seen in the drug-treated group. The BBB breakdown to Evans blue albumin and radioiodine in the cortex, hippocampus, hypothalamus, and cerebellum was also significantly reduced in these drug-treated groups. Clobenpropit showed superior effects than the BF2649 in reducing brain pathology in AD. Taken together, our observations are the first to show that blockade of H3 and stimulation of H4 receptors are beneficial for the treatment of AD pathology, not reported earlier.

A prospective study of efficacy and safety of olopatadine versus azelastine in allergic conjunctivitis at a tertiary care hospital

Background: Allergic conjunctivitis, an ocular surface inflammatory disease with significant social and economic impact affects approximately 25% of the general population. H1 receptor blockers, mast cell stabilizers and drugs that block cytokine and prostaglandin formation form the treatment armamentarium. Olopatadine hydrochloride and Azelastine hydrochloride are dual-acting selective H1 receptor antagonist with mast-cell stabilizing property. This study was undertaken to assess the efficacy and safety of olopatadine hydrochloride 0.1% and Azelastine hydrochloride 0.05% in allergic conjunctivitis amongst Indians.Methods: After obtaining Institutional Ethics Committee approval and written informed consent, 120 patients diagnosed with allergic conjunctivitis fulfilling the inclusion/exclusion criteria were enrolled in the study. Study was done from April 2014 to June 2015 at Minto eye hospital. Study subjects were treated with olopatadine hydrochloride 0.1% and Azelastine hydrochloride 0.05% eye drops BD for 15 days. Ocular symptoms, instead of and signs and adverse events, if any were recorded on the day 8 and day 15 follow up visits.Results: At the end of the study period, the reduction in the ocular itching score from baseline was higher in the olopatadine group compared to the azelastine group (p&lt;0.002). Similarly, the scores of ocular congestion (p&lt;0.008), foreign body sensation (p&lt;0.009), tearing (p&lt;0.001), erythema (p&lt;0.002) and chemosis (p&lt;0.015) also showed larger reduction in the olopatadine treated patients. The common adverse events encountered in both the groups were stinging after instillation, burning, bitter taste and headache.Conclusions: In allergic conjunctivitis, both olopatadine and azelastine were found to be effective in relieving ocular signs and symptoms, but olopatadine was found to be superior in terms of efficacy, safety and tolerability with minimal side effects.

Brain Activation by H1 Antihistamines Challenges Conventional View of Their Mechanism of Action in Motion Sickness: A Behavioral, c-Fos and Physiological Study in Suncus murinus (House Musk Shrew).

Motion sickness occurs under a variety of circumstances and is common in the general population. It is usually associated with changes in gastric motility, and hypothermia, which are argued to be surrogate markers for nausea; there are also reports that respiratory function is affected. As laboratory rodents are incapable of vomiting, Suncus murinus was used to model motion sickness and to investigate changes in gastric myoelectric activity (GMA) and temperature homeostasis using radiotelemetry, whilst also simultaneously investigating changes in respiratory function using whole body plethysmography. The anti-emetic potential of the highly selective histamine H1 receptor antagonists, mepyramine (brain penetrant), and cetirizine (non-brain penetrant), along with the muscarinic receptor antagonist, scopolamine, were investigated in the present study. On isolated ileal segments from Suncus murinus, both mepyramine and cetirizine non-competitively antagonized the contractile action of histamine with pKb values of 7.5 and 8.4, respectively; scopolamine competitively antagonized the contractile action of acetylcholine with pA2 of 9.5. In responding animals, motion (1 Hz, 4 cm horizontal displacement, 10 min) increased the percentage of the power of bradygastria, and decreased the percentage power of normogastria whilst also causing hypothermia. Animals also exhibited an increase in respiratory rate and a reduction in tidal volume. Mepyramine (50 mg/kg, i.p.) and scopolamine (10 mg/kg, i.p.), but not cetirizine (10 mg/kg, i.p.), significantly antagonized motion-induced emesis but did not reverse the motion-induced disruptions of GMA, or hypothermia, or effects on respiration. Burst analysis of plethysmographic-derived waveforms showed mepyramine also had increased the inter-retch+vomit frequency, and emetic episode duration. Immunohistochemistry demonstrated that motion alone did not induce c-fos expression in the brain. Paradoxically, mepyramine increased c-fos in brain areas regulating emesis control, and caused hypothermia; it also appeared to cause sedation and reduced the dominant frequency of slow waves. In conclusion, motion-induced emesis was associated with a disruption of GMA, respiration, and hypothermia. Mepyramine was a more efficacious anti-emetic than cetirizine, suggesting an important role of centrally-located H1 receptors. The ability of mepyramine to elevate c-fos provides a new perspective on how H1 receptors are involved in mechanisms of emesis control.

Histamine Increases Neuronal Excitability and Sensitivity of the Lateral Vestibular Nucleus and Promotes Motor Behaviors via HCN Channel Coupled to H2 Receptor

Histamine and histamine receptors in the central nervous system actively participate in the modulation of motor control. In clinic, histamine-related agents have traditionally been used to treat vestibular disorders. Immunohistochemical studies have revealed a distribution of histaminergic afferents in the brainstem vestibular nuclei, including the lateral vestibular nucleus (LVN), which is critical for adjustment of muscle tone and vestibular reflexes. However, the mechanisms underlying the effect of histamine on LVN neurons and the role of histamine and histaminergic afferents in the LVN in motor control are still largely unknown. Here, we show that histamine, in cellular and molecular levels, elicits the LVN neurons of rats an excitatory response, which is co-mediated by the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and K+ channels linked to H2 receptors. Blockage of HCN channels coupled to H2 receptors decreases LVN neuronal sensitivity and changes their dynamic properties. Furthermore, in behavioral level, microinjection of histamine into bilateral LVNs significantly promotes motor performances of rats on both accelerating rota-rod and balance beam. This promotion is mimicked by selective H2 receptor agonist dimaprit, and blocked by selective H2 receptor antagonist ranitidine. More importantly, blockage of HCN channels to suppress endogenous histaminergic inputs in the LVN considerably attenuates motor balance and coordination, indicating a promotion role of hypothalamo-vestibular histaminergic circuit in motor control. All these results demonstrate that histamine H2 receptors and their coupled HCN channels mediate the histamine-induced increase in excitability and sensitivity of LVN neurons and contribute to the histaminergic improvement of the LVN-related motor behaviors. The findings suggest that histamine and the histaminergic afferents may directly modulate LVN neurons and play a critical role in the central vestibular-mediated motor reflexes and behaviors.

Efficacy of transdermal rivastigmine for treatment hypersexuality in Alzheimer disease

Objective: Hypersexuality in Alzheimer's disease (AD) has been rarely investigated. No randomized clinical trials regarding the treatment of hypersexuality in demented people have been conducted, but available data from isolated case reports suggest the efficacy of selective serotonin reuptake inhibitors (SSRIs), antipsychotics, antiandrogens, and H2-receptor antagonists. Method: The patient was a 72-year-old man, who presented for a neuropsychological evaluation performed at the Elbistan State Hospital with a Mini-Mental State Examination (MMSE) value of 18/30. The presenting symptom was persistent sexual desire. Transdermal rivastigmine was started at a dose of 5 (9mg) once daily and the sexual desires terminated on the second week of the treatment. Unfortunately, hypersexuality occurred 1 month later. Rivastigmine patch 10 (18 mg) was prescribed again to reduce the hypersexuality, and this proved to be effective. Result: We present a case of a 72-year-old male patient with Alzheimer's disease with hypersexual behaviour as reported by his wife. Our patient exhibited significant improvement with rivastigmine. Conclusion: Hypersexuality, also referred to in the literature as sexually inappropriate behavior and sexual disinhibition, involves persistent, uninhibited sexual behaviors directed at oneself or at others. In this case we would like to emphasize that cholinesterase inhibitors can be effective in treatment of hypersexuality in Alzheimer's disease.

TREATMENT OF HYPERSEXUALITY IN ALZHEIMER'S DISEASE

Hypersexuality in Alzheimer's disease (AD) has been rarely investigated. No randomized clinical trials regarding the treatment of hypersexuality in demented people have been conducted, but available data from isolated case reports suggest the efficacy of selective serotonin reuptake inhibitors (SSRIs), antipsychotics, antiandrogens, and H2-receptor antagonists. Although theere are no evidence-based treatment guidelines for hypersexuality in AD. The patient was a 72-year-old man, who presented for a neuropsychological evaluation performed at the Elbistan State Hospital with a Mini-Mental State Examination (MMSE) value of 18/30. The presenting symptom was persistent sexual desire. Rivastigmine was started at a dose of 5 mg once daily and the sexual desires terminated on the second week of the treatment. Unfortunately, hypersexuality occurred 1 month later. Rivastigmine patch (10mg) was prescribed again to reduce the hypersexuality, and this proved to be effective. We present a case of a 72-year-old male patient with Alzheimer's disease with hypersexual behaviour as reported by his wife. Our patient exhibited significant improvement with rivastigmine. Hypersexuality, also referred to in the literature as sexually inappropriate behavior and sexual disinhibition, involves persistent, uninhibited sexual behaviors directed at oneself or at others. Hypersexuality is a significant symptom because of logistical and ethical problems for caregivers. In this case we would like to emphasize that cholinesterase inhibitors can be effective in treatment of hypersexuality in Alzheimer's disease.

Histamine H3 receptor antagonism by ABT-239 attenuates kainic acid induced excitotoxicity in mice

The multifaceted pathogenesis of temporal lobe epilepsy (TLE) offers a number of adjunctive therapeutic prospects. One such therapeutic strategy could be targeting H3 receptor (H3R) by selective H3R antagonists which are perceived to have antiepileptic and neuroprotective potential. Kainic acid (KA) induced seizure, a reliable model of TLE, triggers epileptogenic events resulting from initial neuronal death and ensuing recurring seizures. The present study aimed to determine whether pre-treatment with ABT-239, a novel H3R antagonist, and its combinations with sodium valproate (SVP) and TDZD-8 (glycogen synthase kinase-3β (GSK3β) inhibitor) can prevent the excitotoxic events in mice exposed to KA (10mg/kg i.p.). ABT-239 (1 and 3mg/kg i.p.) significantly attenuated KA-mediated behavioural and excitotoxic anomalies and restored altered expression of Bax, cleaved caspase-3, phospho-Akt (Ser473) and cAMP response element binding protein (CREB). Surprisingly, restoration of Bcl2 and phospho-GSK3β (Ser9) by ABT-239 did not reach the level of statistical significance. Co-administration of ABT-239 (1 and 3mg/kg) with a sub-effective dose of SVP (150mg/kg i.p.) yielded improved efficacy than when given alone. Similarly, low and high dose combinations of ABT-239 (1 and 3mg/kg) with TDZD-8 (5 and 10mg/kg i.p.) produced greater neuroprotection than any other treatment group. Our findings suggests a neuroprotective potential of ABT-239 and its combinations with SVP and TDZD-8 against KA-induced neurotoxicity, possibly mediated through in part each by modulating Akt/GSK3β and CREB pathways. The use of H3R antagonists as adjuvant in the treatment of human TLE might find potential utility, and can be pursued further.

The H3antagonist ABT-288 is tolerated at significantly higher exposures in subjects with schizophrenia than in healthy volunteers

ABT-288 is a potent and selective H3 receptor antagonist with procognitive effects in several preclinical models. In previous studies, 3 mg once daily was the maximal tolerated dose in healthy volunteers. This study characterized the safety, tolerability and pharmacokinetics of ABT-288 in stable subjects with schizophrenia. This was a randomized, double-blind, placebo-controlled, dose-escalating study of ABT-288 (10 dose levels, from 1 to 60 mg once daily for 14 days) in stable subjects with schizophrenia treated with an atypical antipsychotic. In each dose group, five to seven and two to three participants were assigned to ABT-288 and placebo, respectively. Of the 67 participants enrolled, nine participants (on ABT-288) were prematurely discontinued, in seven of these due to adverse events. ABT-288 was generally safe and tolerated at doses up to 45 mg once daily. The most common adverse events, in decreasing frequency (from 31 to 5%), were abnormal dreams, headache, insomnia, dizziness, somnolence, dysgeusia, dry mouth, psychotic disorder, parosmia and tachycardia. Adverse events causing early termination were psychotic events (four) and increased creatine phosphokinase, pyrexia and insomnia (one each). The half-life of ABT-288 ranged from 28 to 51 h, and steady state was achieved by day 12 of dosing. At comparable multiple doses, ABT-288 exposure in subjects with schizophrenia was 45% lower than that previously observed in healthy subjects. At trough, ABT-288 cerebrospinal fluid concentrations were 40% of the total plasma concentrations. ABT-288 was tolerated at a 15-fold higher dose and 12-fold higher exposures in subjects with schizophrenia than previously observed in healthy volunteers. The greater ABT-288 tolerability was not due to limited brain uptake.

From the Guest Editor

Back to table of contents Next article From the Guest EditorFull AccessFrom the Guest EditorKarl Doghramji, M.D.Karl DoghramjiSearch for more papers by this author, M.D.Published Online:1 Jan 2014https://doi.org/10.1176/appi.focus.12.1.1AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail This issue of Focus is dedicated to the update and review of major developments in our understanding and management of sleep disorders, with an emphasis on those disorders that are commonly confronted by psychiatrists and other mental health practitioners. A staggering one-third of all humans are affected by sleep disorders. Sleep-related complaints are also disproportionately high in prevalence in psychiatric practice, and are actively expressed by patients suffering from almost all major psychiatric conditions. Proper identification, clinical evaluation, and effective management of sleep disorders are, therefore, of significant importance for psychiatrists.In the first paper, “Recent Advances in the Understanding of Insomnia,” I explore key developments in clarifying the pathophysiology of insomnia, and explain how these have led to an evolution of our view of the relationship between co-occurring insomnia and medical/psychiatric disorders from a model of unidirectional causality to one of autonomous disorders interacting in a bidirectional fashion. I also clarify how these constructs are reflected in the newly introduced DSM-5 diagnostic nosology. Pharmacological agents have played a crucial role in the management of insomnia for many decades; in his paper, “Novel Developments in the Pharmacological Management of Insomnia,” Dr. David Neubauer explores the many available agents and provides an evidence-based approach in their selection and use. Whereas GABA receptor agonists have dominated the therapeutic armementarium, Dr. Neubauer reviews novel and investigational agents with mechanisms traversing the receptor systems that are involved in the control of sleep and arousal, such as selective histamine H1 receptor antagonists, selective melatonin receptor agonists, and dual orexin receptor antagonists. “Natural” compounds enjoy a significant allure by virtue of their widespread availability, and the perception that they are safer than prescription medications for insomnia. In his “Ask the Expert” column, Dr. Milton Erman explores the array of products most commonly utilized for sleep-related complaints and provides empirical data to guide practitioners through the morass of widespread claims regarding the benefits of these agents. Although less widely utilized than pharmacological agents, cognitive and behavioral therapies are of clear benefit in insomnia. In her paper entitled, “Psychological and Behavioral Treatments for Insomnia,” Dr. Brenda Byrne explores the principles underlying these techniques and guidelines in their implementation. She also reviews exciting new evidence demonstrating the lasting benefit of these therapies for extended periods of time following termination of treatment. Dr. John Khoury and myself, in our paper entitled, “Circadian Rhythms in Health and Disease,” review our current understanding of the neurophysiology of the circadian regulation system, which encompasses a complex array of physiological and psychological variables including core body temperature, hormone secretion, hunger, mood, and sleep, among others. We then explain how misalignments in the timing of these variables can lead to circadian rhythm disorders, and explore many of the treatment modalities that can be utilized in the context of psychiatric practice for these disorders. Finally, in their paper, entitled “Parasomnias, A Review for Psychiatrists,” Drs. Thomas Hurwitz, Michael Howell, and Imran Khawaja review a fascinating group of behavioral disturbances that occur in the borderlands between sleep and wakefulness that are often confused with psychiatric disorders. The authors explore a systematic approach for the evaluation and management of these disorders, which can lead to serious injury, and which often disrupt relationships.I am grateful to the contributors of this issue of Focus, all of whom are prominent researchers, educators, and clinicians in the field of sleep medicine. I am confident that you will find their state-of-art papers to be informative and clinically relevant. FiguresReferencesCited byDetailsCited ByNone Volume 12Issue 1 Winter 2014Pages 1-1Disorders of Sleep PDF download

Design and synthesis of novel 3-substituted-indole derivatives as selective H3 receptor antagonists and potent free radical scavengers

A series of novel 3-substituted-indole derivatives with a benzyl tertiary amino moiety were designed, synthesized and evaluated as H3 receptor antagonists and free radical scavengers for Alzheimer’s disease therapy. Most of these synthesized compounds exhibited moderate to potent antagonistic activities in CREs driven luciferase assay. In particular, compound 2d demonstrated the most favorable H3 receptor antagonistic activity with the IC50 value of 0.049μM. Besides, it also displayed high binding affinity to H3 receptor (Ki=4.26±2.55nM) and high selectivity over other three histamine receptors. Moreover, 2d and other two 3-substituted indole derivatives 1d and 3d exerted potent ABTS radical cation scavenging capacities similar to melatonin. Above results illustrate that 2d is an interesting lead for extensive optimization to explore new drug candidate for AD therapy.

Rivastigmine in the Treatment of Hypersexuality in Alzheimer Disease

Inappropriate sexual behaviors (ISB) represent uncommon and often misdiagnosed clinical disorders among patients with Alzheimer disease. So far, no randomized clinical trials regarding the treatment of ISB in demented people have been conducted, but available data from case series and isolated case reports suggest the efficacy of selective serotonin reuptake inhibitors (SSRIs), antipsychotics, antiandrogens, and H2-receptor antagonists. Controversial data exist on the therapeutic influence of cholinesterase inhibitors on sexual disorders. In the present article, we describe the case of an Alzheimer disease patient presenting hypersexuality, successfully treated with rivastigmine. Thus, we perform a revision of the existing literature regarding the therapeutical effect of cholinesterase inhibitors in the treatment of ISB.

A proof-of-concept study of the effect of a novel H3-receptor antagonist in allergen-induced nasal congestion

H1-receptor inverse agonists are used effectively for treating several symptoms of allergic rhinitis, including nasal itching, rhinorrhea, and sneezing, although most agents are not very effective in treating nasal congestion. This study evaluated the relative efficacy of a novel selective H3-receptor antagonist, JNJ-39220675, in preventing nasal congestion induced by exposing participants with ragweed allergy to ragweed allergen in an environmental exposure chamber model. In this single-dose, patient-blind, double-dummy, placebo- and active-controlled, phase IIa cross-over study, 53 participants were randomized to JNJ-39220675 plus placebo, placebo plus pseudoephedrine, or only placebo. The primary efficacy assessment was change in nasal patency assessed by measuring the minimal cross-sectional area of the nasal cavity by using acoustic rhinometry. Secondary assessment included total nasal symptom scores (TNSSs) over the 8-hour environmental exposure chamber exposure period. Smaller decreases in minimal cross-sectional area were observed after JNJ-39220675 (least square mean difference, -0.126; P = .06) and pseudoephedrine (least square mean difference, -0.195; P = .004) treatment compared with placebo. The means for the baseline-adjusted area under the curve of TNSSs were significantly smaller for JNJ-39220675 (P = .0003) and pseudoephedrine (P = .04) versus placebo. JNJ-39220675 was significantly effective in treating all 4 individual symptoms (P ≤ .05 for all scores) compared with placebo, whereas pseudoephedrine only showed a trend for improvement in individual symptom scores of the TNSS. Insomnia was the most frequent adverse event (17.3%) associated with JNJ-39220675 treatment. Prophylactic treatment with the H3-antagonist JNJ-39220675 relieved allergen-induced nasal congestion by using standard nasal symptom scoring; however, in contrast to pseudoephedrine, it only showed a trend for increasing nasal patency by using objective measures.