Pitolisant: Pediatric First Approval.

Pitolisant (WAKIX®), a histamine H3 receptor antagonist/inverse agonist that has been developed by Bioprojet Pharma, is approved in the EU and USA and elsewhere for use in adults with narcolepsy with or without cataplexy. In February 2023, based on clinical data in patients aged 6 to < 18 years, pitolisant received its first approval in adolescents and children from the age of 6 years for the treatment of narcolepsy with or without cataplexy in the EU. This article summarizes the milestones in the development of pitolisant leading to this pediatric first approval for narcolepsy with or without cataplexy.

Real-world treatment of pediatric narcolepsy with pitolisant: A retrospective, multicenter study.

BACKGROUND: First symptoms of narcolepsy mostly present during childhood. Pharmacological management options in children are limited, also due to approval status. Pitolisant is an inverse histamine 3 receptor agonist and has been approved for the treatment of adult narcolepsy with or without cataplexy by EMA and FDA. Clinical experience indicates for a beneficial use also in children and adolescents. Our goal was to evaluate the effects and tolerability of pitolisant in narcolepsy children/adolescents in a real-world setting. METHODS: This multicentre retrospective observational study included 55 patients with narcolepsy from three international narcolepsy centers (Germany, France and Italy) who were treated with pitolisant. Patients were eligible if they were at least 6 years old and diagnosed with narcolepsy type 1 or 2. Demographic and clinical characteristics, questionnaires, sleep medicine and laboratory data were collected. RESULTS: 55 children/adolescents (25 girls, 45.45%, 30 boys, 54.55%) aged 6-18 years, with narcolepsy (type 1 = 92.7%, type 2 = 7.3%), were treated with pitolisant. The mean pitolisant dose was 34.1 mg/d. Treatment was effective for excessive daytime sleepiness (EDS) and cataplexy: the pediatric Epworth Sleepiness Scale (ESS) score decreased from 19 to 13.5 (p < 0.001) and the weekly cataplexy frequency improved from 7.9 at baseline to 5.2 (p < 0.001). Treatment with pitolisant was well tolerated. Side effects were mild and mostly short-term. Insomnia was reported most frequently (5.5%). CONCLUSION: First real-world results suggest that pitolisant treatment is effective in improving EDS and cataplexy in children with narcolepsy, and also is well tolerated.

Development of monolithic matrix type transdermal patches containing cinnarizine: Physical characterization and permeation studies

To overcome the problems associated with bioavailability and systemic side effects of the drug by oral administration, monolithic matrix type transdermal patches containing cinnarizine (CNZ) were developed. For this purpose, films based on hydroxypropyl methylcellulose and polyvinylpyrrolidone as matrix-forming polymers were designed. Physical characteristics of transdermal films and drug-excipient compatibility were investigated. Factors affecting in vitro drug release and ex vivo skin penetration and permeation of the drug were studied. It was confirmed that films displayed sufficient flexibility and mechanical strength for application onto the skin for a long time period. Ex vivo penetration experiments gave satisfactory results for transdermal drug delivery through rat skin. The parameters determining good skin penetration were also evaluated. The highest drug permeation rate was obtained with incorporation of Transcutol® (0.102 mg/cm2/h) into the base CNZ formulation, followed by propylene glycol (0.063 mg/cm2/h), menthol (0.045 mg/cm2/h), and glycerin (0.021 mg/cm2/h) as penetration enhancers (p < 0.05). As a result, the developed transdermal patches of CNZ may introduce an alternative treatment for various conditions and diseases such as idiopathic urticarial vasculitis, Ménière's disease, motion sickness, nausea, and vertigo. Thus, the risk of systemic side effects caused by the drug can be reduced or eliminated

Using betahistine in the treatment of patients with Menière's disease: a meta-analysis with the current randomized-controlled evidence.

Background: Betahistine is used worldwide to treat patients with Menière's disease. However, despite it being used for decades, diverging opinions on the effect of betahistine on Menière's symptomatology still exist.Aims: The objective of this systematic review was to provide an overview and rate the certainty of the current evidence base regarding the use of betahistine to treat patients with Menière's disease.Materials and methods: A systematic literature search was conducted in October 2019. The search strategy was subdivided into searches for existing guidelines, systematic reviews and individual randomized controlled trials (RCT) investigating the usage of betahistine as compared to placebo, in patients with Ménière's disease. The primary outcome was the frequency of vertigo attack(s) and occurrence of serious adverse events.Results: We identified three relevant guidelines and three systematic reviews: however, neither included any relevant trials matching our inclusion criteria. An individual search for RCTs identified one trial. The results from this particular trial showed no difference in effects on symptoms following treatment with betahistine.Conclusions and Significance: There is a need for further well-conducted placebo RCTs. Currently, there is still a lack of substantial evidence supporting betahistine as a significant and adequate treatment for patients diagnosed with Menière's disease. Trial registration number: The protocol is registered in PROSPERO. Registration number: CRD42018110127 Accepted 11.10.2018.

Itch and Cough - Similar Role of Sensory Nerves in Their Pathogenesis.

Itch is the most common chief complaint in patients visiting dermatology clinics and is analogous to cough and also sneeze of the lower and upper respiratory tract, all three of which are host actions trying to clear noxious stimuli. The pathomechanisms of these symptoms are not completely determined. The itch can originate from a variety of etiologies. Itch originates following the activation of peripheral sensory nerve endings following damage or exposure to inflammatory mediators. More than one sensory nerve subtype is thought to subservepruriceptive itch which includes both unmyelinated C-fibers and thinly myelinated Adelta nerve fibers. There are a lot of mediators capable of stimulating these afferent nerves leading to itch. Cough and itch pathways are mediated by small-diameter sensory fibers. These cough and itch sensory fibers release neuropeptides upon activation, which leads to inflammation of the nerves. The inflammation is involved in the development of chronic conditions of itch and cough. The aim of this review is to point out the role of sensory nerves in the pathogenesis of cough and itching. The common aspects of itch and cough could lead to new thoughts and perspectives in both fields.

Pitolisant for treating patients with narcolepsy.

Introduction: Narcolepsy is a rare sleep disorder characterized by excessive daytime sleepiness, cataplexy, disturbed nocturnal sleep, hypnagogic hallucinations, and sleep paralysis. Pitolisant is a first-in-class drug acting on histamine 3 receptors and indicated for the treatment of narcolepsy. This article aims to review pitolisant.Areas covered: In this paper the chemical properties, mechanism of action, pharmacokinetics, clinical efficacy and safety of pitolisant was introduced, and the development course of drugs for treating narcolepsy is also briefly described. We performed a systematic review of the literature using PubMed and the following keywords were used: 'pitolisant' and 'narcolepsy', 'cataplexy' and 'excessive daytime sleepiness' and 'histamine 3 receptor'.Expert opinion: Pitolisant is a histamine 3 receptor antagonist/inverse agonist. It can activate histamine release in the brain and enhances wakefulness. Clinical studies showed that pitolisant significantly decreased excessive daytime sleepiness and cataplexy rate versus placebo. Pitolisant was well tolerated, common adverse reactions were headache, insomnia, nausea, and anxiety.

Evaluation of the abuse potential of pitolisant, a selective H3-receptor antagonist/inverse agonist, for the treatment of adult patients with narcolepsy with or without cataplexy.

OBJECTIVES: To evaluate the human abuse potential of pitolisant, a selective histamine 3 (H3)-receptor antagonist/inverse agonist recently approved by the US Food and Drug Administration for the treatment of excessive daytime sleepiness in adult patients with narcolepsy. METHODS: Nondependent, recreational stimulant users able to distinguish phentermine HCl 60 mg from placebo in a drug discrimination test were randomized in a four-period, double-blind, crossover design to receive single doses of pitolisant 35.6 mg (therapeutic dose), pitolisant 213.6 mg (supratherapeutic dose), phentermine HCl 60 mg, and placebo. The primary endpoint was maximum effect (Emax) on the 100-point Drug Liking ("at this moment") visual analog scale. RESULTS: In 38 study completers (73.7% male; 65.8% white; mean age, 33.3 years), mean Drug Liking Emax was significantly greater for phentermine versus pitolisant 35.6 mg (mean difference, 21.4; p < 0.0001) and pitolisant 213.6 mg (mean difference, 19.7; p < 0.0001). Drug Liking Emax was similar for pitolisant (both doses) and placebo. Similarly, for key secondary measures of Overall Drug Liking and willingness to Take Drug Again, mean Emax scores were significantly greater for phentermine versus pitolisant (both doses) and similar for pitolisant (both doses) versus placebo. The incidence of adverse events was 82.1% after phentermine HCl 60 mg, 72.5% after pitolisant 213.6 mg, 47.5% after pitolisant 35.6 mg, and 48.8% after placebo administration. CONCLUSIONS: In this study, pitolisant demonstrated significantly lower potential for abuse compared with phentermine and an overall profile similar to placebo; this suggests a low risk of abuse for pitolisant. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03152123. Determination of the abuse potential of pitolisant in healthy, nondependent recreational stimulant users. https://clinicaltrials.gov/ct2/show/NCT03152123.

Pregnancy outcomes after maternal betahistine exposure: A case series.

OBJECTIVE: To investigate the pregnancy outcomes of women who were exposed to betahistine during their pregnancies. METHODS: We identified and evaluated the outcomes of 27 pregnant women who were referred to Terafar (Teratology Information Service, Izmir, Turkey) for a teratological risk assessment. RESULTS: Of 24 pregnancies with known outcomes, 21 resulted in live births (including two pairs of twins) whereas two ended with miscarriage and three with elective terminations. Among the 20 live births for whom the malformation details were available, there were 17 normal outcomes, one major and two minor congenital malformations. CONCLUSIONS: Despite a number of limitations, this case series may be of value regarding counseling pregnant women with inadvertent betahistine exposure. Further epidemiological studies with larger sample sizes and control groups are necessary to draw more definite conclusions.

What is the long term acid inhibitor treatment in gastroesophageal reflux disease? What are the potential problems related to long term acid inhibitor treatment in gastroesophageal reflux disease? How should these cases be followed?

The meta-analyses of observational studies (OBS) showed the risk of any fracture and hip fracture slightly increased with proton pump inhibitor (PPI) treatment depending on the dose and regardless of time. This was not observed with histamine-2 receptor antagonists (H2RA). The risk of bacterial overgrowth and spontaneous bacterial peritonitis were increased with PPI therapy, but not with H2RA. In meta-analyses of OBS, a slight increase was observed in the risk of community-acquired pneumonia (CAP) in the early stages (<1 month) of PPI use and particularly at high doses. In a five-year LOTUS study, no difference was found in vitamin B12, folic acid, vitamin D, and calcium values in terms of the initial and end of follow-up levels. No increase in the risk of premalignant gastric lesions was observed in the meta-analysis of RCTs in which PPI treatment (≥6 months) was given to Helicobacter pylori negative patients. The risk of hypomagnesemia with PPI use was increased in patients having GFR<60, using diuretics, and over 65 years of age. Quasi-experimental studies showed a reduced zinc absorption with PPI use. In the meta-analysis of OBS, long-term (>1 year) PPI use increased the risk of fundic polyps, but no risk was found in shorter use. The meta-analyses of RCTS showed no difference between PPI and surgery or placebo arms and between the arms of H2RA and placebo in terms of all side effects. No difference was found between the PPI and H2RA arms both in all and serious adverse effects.

Comparison of the Hospital-Acquired Clostridium difficile Infection Risk of Using Proton Pump Inhibitors versus Histamine-2 Receptor Antagonists for Prophylaxis and Treatment of Stress Ulcers: A Systematic Review and Meta-Analysis.

BACKGROUND/AIMS: Although proton pump inhibitors (PPIs) have been widely used for the prevention and treatment of stress gastric ulcers in hospital settings, there are concerns that PPIs increase the risk of Clostridium difficile infection (CDI). However, little is known about the risk of CDI following PPI and histamine-2 receptor antagonist (H2RA) use. We evaluated the comparative hospital-acquired CDI occurrence risk associated with the concurrent use of PPIs versus H2RAs. METHODS: A systematic search of PubMed, MEDLINE/Ovid, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, and Google Scholar through August 19, 2016, identified 12 studies that reported the hospital-acquired CDI occurrence following H2RA and PPI use for the prevention and treatment of stress gastric ulcers. Random-effects pooled odds ratios and 95% confidence intervals were estimated. Heterogeneity was measured using I², and a meta-regression analysis was conducted. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used to assess the overall quality of the evidence. RESULTS: A total of 74,132 patients from 12 observational studies were analyzed. Compared to H2RAs, PPIs increased the risk of CDI by 38.6% (pooled odds ratio, 1.386; 95% confidence interval, 1.152 to 1.668; p=0.001; I²=42.81%). Subgroup analyses of the purpose of study medication use, study site, and study design confirmed the consistency of a greater CDI risk with PPIs than with H2RAs. The overall quality of evidence was rated as low. CONCLUSIONS: The use of PPIs for both the prevention and treatment of stress ulcers was associated with a 38.6% increased risk of hospital-acquired CDI occurrence compared to H2RA use.

Histamine type 1-receptor activation by low dose of histamine undermines human glomerular slit diaphragm integrity.

Histamine has been reported to decrease the ultrafiltration coefficient, which inversely correlates with glomerular permselectivity, however the mechanism(s) underling this effect have never been investigated. This study aimed to assess whether histamine could exert a direct detrimental effect on podocyte permeability and the possible involvement of two key proteins for the glomerular slit diaphragm (SD) integrity, zonula occludens-1 (ZO-1) and P-cadherin. The effect of histamine (100 pM-1000nM) on coloured podocytes junctional integrity was evaluated functionally by a transwell assay of monolayer permeability and morphologically by electron microscopy. Histamine receptor (H1-4R) presence was evaluated at both mRNA (RT-PCR) and protein (immunofluorescence) levels. The Kd and Bmax values for [3H]mepyramine were determined by saturation binding analysis; IP1 and cAMP production evoked by histamine were measured by TR-FRET. ZO-1, P-cadherin and vimentin expression was assessed by qRT-PCR and quantitative immunoblotting. Histamine elicited a time- and sigmoidal dose-dependent (maximum effect at 8h, 10nM) increase in podocyte paracellular permeability widening the paracellular spaces. Only H1R was predominantly localised to the podocyte membrane. Consistently, histamine elicited a sigmoidal dose-dependent increase in IP1, but not in cAMP. Histamine exposure evoked a concentration-dependent reduction in both ZO-1 and P-cadherin and a parallel induction of vimentin mRNA expression with a maximum effect after 6h, and protein expression with a maximum effect after 8h. These effects were prevented by the selective H1R antagonist chlorpheniramine. In conclusion, our data demonstrate that histamine, via the H1R, modifies SD morphological and functional integrity, in part, by decreasing the expression of ZO-1 and P-cadherin.

Conditioning pain stimulation does not affect itch induced by intra-epidermal histamine pricks but aggravates neurogenic inflammation in healthy volunteers.

This study investigated whether itch induced by intra-epidermal histamine is subjected to modulation by a standardized conditioned pain modulation (CPM) paradigm in 24 healthy volunteers. CPM was induced by computer-controlled cuff pressure algometry and histamine was introduced to the volar forearm by skin prick test punctures. Moreover, neurogenic inflammation and wheal reactions induced by histamine and autonomic nervous system responses (heart rate variability and skin conductance) were monitored. CPM did not modulate the intensity of histamine-induced itch suggesting that pruriceptive signaling is not inhibited by pain-recruited endogenous modulation, however, CPM was found to aggravate histamine-induced neurogenic inflammation, likely facilitated by efferent sympathetic fibers.

Interações medicamentosas potenciais com benzodiazepínicos em prescrições médicas de pacientes hospitalizados / Potential drug interactions with benzodiazepines in medical prescriptions of hospitalized patients

A prática de associações medicamentosas é comum em pacientes hospitalizados, Esta prática é muitas vezes necessária, principalmente em pacientes psiquiátricos, uma vez que, juntamente com as doenças neuropsiquiátricas, podem ocorrer outras comorbidades, Entretanto, esta prática pode favorecer a ocorrência de interações medicamentosas com consequente potencialização de diferentes efeitos adversos, Diante deste quadro, o presente trabalho teve como objetivo avaliar a ocorrência de potenciais interações medicamentosas com os benzodiazepínicos, prescritos aos pacientes internados na Clínica Psiquiátrica do Hospital Regional de Assis ? SP, a fim de gerar informações que contribuam para a eficácia do tratamento estabelecido ao paciente, Para isso, foi realizada uma análise de 100 prescrições médicas, nas quais foram avaliadas as possibilidades de ocorrência de interações medicamentosas entre os diferentes fármacos da classe dos benzodiazepínicos administrados concomitantemente, bem como com outras classes de fármacos, Por meio deste estudo, verificou-se que das 100 prescrições médicas analisadas 93 apresentaram a possibilidade de ocorrência de interações farmacológicas entre benzodiazepínicos e com outras classes de fármacos, totalizando 356 possíveis interações, Desse total, destacam-se as associações dos benzodiazepínicos com os antipsicóticos, anti-histamínicos, antiepilépticos e antidepressivos, as quais podem potencializar a manifestação de inúmeros efeitos adversos, em destaque, a exacerbação do efeito depressor do sistema nervoso central, com repercussões que podem variar desde a manifestação clínica leve até risco de êxito letal, Neste contexto, busca-se com este trabalho contribuir para uma melhor compreensão, reconhecimento e intervenção precoce ou profilática em situações clínicas decorrentes de interações farmacológicas entre diferentes classes de fármacos com os benzodiazepínicos...

The practice of drug combinations is common in hospitalized patients. This practice is often necessary, especially in psychiatric patients, since other comorbidities may occur in parallel with neuropsychiatric disorders. However, this practice may favor the occurrence of drug interactions with consequent increase of different adverse effects. Facing this situation, the present study aimed to evaluate the occurrence of potential drug interactions with benzodiazepines prescribed to hospitalized patients at the Psychiatric Clinic of the Hospital Regional de Assis - SP, in order to generate information that contributes to the effectiveness of the treatment provided to patient. To this end, an analysis of 100 medical prescriptions was performed, in which were evaluated the possibility of drug interactions between the different medications from the class of benzodiazepines concomitantly administered, as well as other classes of drugs. By means of this study, it was verified that the 100 analyzed prescriptions 93 presented the possibility of different pharmacological interactions between benzodiazepine, and with other classes of drugs, totaling 356 possible interactions. Of this total stand out the associations of benzodiazepines with antipsychotics, antihistamines, antiepileptics and antidepressants, which can enhance the expression of numerous adverse effects, highlighted the exacerbation of depressant effect on the central nervous system, with effects that can range from mild clinical manifestation until risk of lethal outcome. In this context, it seeks in this work to contribute to a better understanding, recognition and early or prophylactic intervention in clinical situations arising from interactions between different pharmacological classes of drugs with benzodiazepines...

Pharmacokinetic properties and safety profile of histamine dihydrochloride injection in Chinese healthy volunteers: a phase I, single-center, open-label, randomized study.

PURPOSE: Histamine dihydrochloride (HDC) injection has been approved in Europe for the treatment of adults with acute myeloid leukemia, used in combination therapy with the T-cell-derived cytokine interleukin-2. Despite years of clinical applications of HDC in Europe, no data are available on its tolerability and pharmacokinetic properties in Chinese patients. The objective of this study was to determine the safety profile and pharmacokinetic properties of HDC in Chinese healthy volunteers (HVs). METHODS: In this Phase I, single-center, open-label, randomized study, 20 Chinese HVs were randomized to receive a single dose of 0.5 or 1.0 mg HDC via a 10-minute subcutaneous injection. Whole-blood and urine samples were collected at designated time points after dosing. Plasma and urine concentrations of histamine and metabolite N-methyl histamine were measured using a validated HPLC-MS/MS method. Pharmacokinetic parameters were estimated through noncompartmental procedures based on concentration-time data. Adverse events and evaluation of clinical laboratory tests were used to assess the safety profile. The pharmacokinetic profile for a single-dose of 1.0 mg HDC in Chinese HVs was compared with that in Western HVs. FINDINGS: No severe adverse events occurred in this study, and the severity of all adverse events was grade I according to the Common Terminology Criteria for Adverse Events, version 4.0. For the pharmacokinetic parameters of histamine at the 0.5-mg and 1.0-mg dose levels, t½ was 0.50 and 1.02 hours; Tmax was 0.15 and 0.14 hours; mean Cmax was 26.59 and 71.01 nmol/L; AUC0-t was 8.35 and 20.43 nmol/h/L; AUC0-∞ was 9.61 and 22.69 nmol/h/L; accumulated amount excreted in urine within 24 hours was 125.93 and 145.52 nmol; and maximum urine excretion rates were 21.85 and 38.94 nmol/h, respectively. For N-methyl histamine at the 0.5-mg and 1.0-mg dose levels, t½ was 0.58 and 0.66 hours; Tmax was 0.28 and 0.26 hours; mean Cmax was 17.01 and 23.54 nmol/L; AUC0-t was 7.72 and 17.08 nmol/h/L; AUC0-∞ was 9.01 and 19.62 nmol/h/L; accumulated amount excreted in urine within 24 hours was 331.7 and 583.21 nmol; and maximum urine excretion rates were 53.29 and 133.53 nmol/h, respectively. IMPLICATIONS: Both single-dose 0.5 mg and 1.0 mg HDC were well tolerated in Chinese HVs, and the pharmacokinetic profile of HDC in Chinese HVs was characterized in this study. A single dose of 1.0 mg HDC had a more rapid but similar extent of absorption, a wider distribution, and a little more rapid elimination in Chinese HVs compared with Western HVs. Findings from this study support additional clinical trials for HDC using in Chinese patients. Chinese Clinical Trial Registry identifier: ChiCTR-ONC-13003954.

Psychophysical measurements of itch and nociceptive sensations in an experimental model of allergic contact dermatitis.

UNLABELLED: Allergic contact dermatitis (ACD) is a common condition that can significantly affect the quality of life. Contact with allergens results in delayed hypersensitivity reactions involving T lymphocytes, with associated skin inflammation and spontaneous itch and nociceptive sensations. However, psychophysical studies of these sensations are lacking. In the present study, we sensitized 8 healthy volunteers to squaric acid dibutyl ester (SADBE). Two weeks later, 1 volar forearm was challenged with SADBE, and the other with acetone vehicle control. Subsequently, participants rated the maximal perceived intensity of spontaneous itch, pricking/stinging, and burning every 6 to 12 hours for 1 week, using the generalized Labeled Magnitude Scale. In the laboratory, they judged stimulus-evoked sensations within and outside the chemically treated area. The SADBE- but not the acetone-treated skin resulted in 1) localized inflammation, with spontaneous itch and nociceptive sensations peaking at 24 to 48 hours after challenge, 2) alloknesis, hyperknesis, and hyperalgesia to mechanical stimuli that were reduced or eliminated by anesthetic cooling of the SADBE-treated area and restored on rewarming, suggesting that sensations and dysesthesias are dependent on ongoing peripheral neural activity, and 3) enhanced itch to intradermal injection of histamine, BAM8-22, or ß-alanine. This experimental model of T-cell-mediated inflammation may prove useful in evaluating potential treatments of itch from ACD. PERSPECTIVE: In a model of allergic contact dermatitis, experimentally applied in humans, psychophysical measurements were obtained of persistent, spontaneous itch and enhanced stimulus-evoked itch and pain sensations. These sensory measurements will be useful in the identification of the neural mechanisms underlying inflammatory itch and pain.

Phase 2a, randomized, double-blind, placebo-controlled, multicenter, parallel-group study of a H4 R-antagonist (JNJ-39758979) in Japanese adults with moderate atopic dermatitis.

This trial was conducted to evaluate the safety and efficacy of the H4 R-antagonist JNJ-39758979 in adult Japanese patients with moderate atopic dermatitis (AD). Eligible patients were randomly assigned to JNJ-39758979 300 mg, 100 mg or placebo once daily for 6 weeks in this phase 2a, double-blind, multicenter, placebo-controlled study. Primary efficacy was assessed via week-6 Eczema Area and Severity Index (EASI) scores. Secondary efficacy assessments included Investigator's Global Assessment (IGA) and patient-reported outcome (PRO) pruritus assessments (Pruritus Categorical Response Scale [PCRS], Pruritus Numeric Rating Scales [PNRS], Pruritus Interference Numeric Rating Scale [PINRS] and Subject's Global Impressions of Change in Pruritus [SGICP]). Eighty-eight of 105 planned patients were randomized before the study was stopped and unblinded for safety reasons. The study did not meet the primary end-point. However, numerical improvements (i.e. decreases) in median EASI were observed with JNJ-39758979 100 mg (-3.7) and 300 mg (-3.0) versus placebo (-1.3) at week 6. Nominally significant improvements across PRO PCRS, PNRS and SGICP assessments were consistently observed, particularly with JNJ-39758979 300 mg. Safety, including adverse events (AE), was comparable between JNJ-39758979 and placebo with the exception of two patients (both receiving JNJ-39758979 300 mg) with serious AE of neutropenia, leading to premature study discontinuation. No deaths were reported. Except for neutropenia, no clinically relevant changes in laboratory values were observed. Although not conclusive, findings suggest H4 R-antagonism may be beneficial for AD, particularly in controlling pruritus. JNJ-39758979 appears to be associated with drug-induced agranulocytosis, likely an off-target effect.

Effects of pitolisant, a histamine H3 inverse agonist, in drug-resistant idiopathic and symptomatic hypersomnia: a chart review.

OBJECTIVE: To evaluate the benefits and risks of pitolisant (a wake-enhancing drug that increases the histamine release in the brain by blocking presynaptic H3 histamine reuptake) in patients with idiopathic (IH) and symptomatic (SH) hypersomnia plus sleepiness refractory to available stimulants (modafinil, methylphenidate, mazindol, sodium oxybate, and d-amphetamine). METHODS: Through retrospective analyses of patient files, the benefit (the score from the Epworth Sleepiness Scale [ESS], authorization renewal) and tolerance (side-effects) of pitolisant were assessed. RESULTS: A total of 78 patients with IH (n=65%, 78% women) and SH (n=13%, 54% women) received pitolisant 5-50 mg once per day over the course of five days to 37 months. The median (interquartile range) ESS scores of patients with IH decreased from 17 (15.5-18.5) to 14 (12-17). There were 36% responders (ESS fall of > or =3). The improvement in ESS score (-1.9±2.6) was different from 0 in IH without long sleep time (P<0.002) and in IH with a long sleep time (P<0.0001), but not in SH. Forty-four (63%) patients with IH and 12 (77%) patients with SH stopped pitolisant, mostly due to a lack of efficacy. Side-effects included gastrointestinal pain (15.4%), increased appetite and weight gain (14.1%), headache (12.8%), insomnia (11.5%), and anxiety (9%), as well as exceptional reports of depression and persistent genital arousal. CONCLUSION: Pitolisant had a long-term favorable benefit/risk ratio in 23-38% of drug-resistant patients with IH and SH, suggesting that histamine neurons can be stimulated in severe idiopathic and symptomatic hypersomnia.

Sex differences in itch perception and modulation by distraction--an FMRI pilot study in healthy volunteers.

BACKGROUND: Even though itch is a common syndrome of many diseases there is only little knowledge about sex and gender differences in pruritus, especially in central itch perception and modulation. To our knowledge, this is the first fMRI study examining sex differences in perception and its modulation by distraction. METHODS: Experimental itch was induced by application of histamine (0.1 mM) via microdialysis fibers twice at the left forearm and twice at the left lower leg in 33 healthy volunteers (17 females, 16 males). The brain activation patterns were assessed by fMRI during itch without and with distraction (Stroop task). Between the various conditions, subjects were asked to rate itch intensity, desire to scratch and pain intensity. In a second experiment in 10 of the 33 volunteers histamine was replaced by saline solution to serve as control for the 'Stroop' condition. RESULTS: Women generally presented higher itch intensities compared to men during itch over the course of the experiment. A more specific analysis revealed higher itch intensities and desire to scratch in women during experimental induced itch that can be reduced by distraction at the lower legs when itch is followed by 'Stroop'. In contrast, men depicted significant reduction of 'itch' by 'Stroop' at the forearms. Women depicted higher brain activation of structures responsible for integration of sensory, affective information and motor integration/planning during 'itch' and 'Stroop' condition when compared to men. No sex differences were seen in the saline control condition. CONCLUSION: Women and men exhibited localisation dependent differences in their itch perception with women presenting higher itch intensities and desire to scratch. Our findings parallel clinical observations of women reporting higher itch intensities depending on itch localisation and suffering more from itch as compared to men.