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Background: Plant lectins have shown promising biological activities in the central nervous system (CNS). Objective: This study evaluated the effect of DAL, a lectin isolated from the seeds of the Dioclea altissima species, having binding affinity to D-glucose or D-mannose residues, on mice behavior. Methods: Mice (n=6/group) were treated (i.p.) with DAL (0.25, 0.5 or 1 mg/kg) or vehicle and subjected to several tests (open field/OFT, marble-burying/MBT, hole-board/HBT, elevated plus maze/PMT, tail suspension/ TST, forced swimming/FST or rotarod/RRT). Pizotifen, cyproheptadine, flumazenil, L-NAME, 7-NI, Larginine or yohimbine were administered 15 min before DAL (0.5 mg/kg) and the animals were evaluated on PMT. It was also verified whether the DAL effect depended on its structural integrity and ability to interact with carbohydrates. Results: The results showed there were no neurobehavioral changes in the mice at the RRT, FST and locomotion in the OFT. DAL (0.25, 0.5 or 1 mg/kg) increased the behavior of grooming and rearing in the OFT, head dips in the HBT, pedalling in the TST and decreased the number of marbles hidden in the MBT. In the PMT, DAL (0.25, 0.5 and 1 mg/kg) and Diazepam increased the frequency of entries in the open arms and the time of permanence in the open arms without affecting the locomotor activity. The effect of DAL was dependent on carbohydrate interaction and protein structure integrity and it prevented by pizotifen, cyproheptadine, flumazenil, L-NAME and 7-NI, but not by L-arginine or yohimbine. Conclusion: DAL was found to have an anxiolytic-like effect mediated by the 5-HT and GABAergic receptors and NO pathway.

Screening for drugs that disrupt embryonic development in zebrafish can help identify treatments that suppress metastasis.

Background Vestibular Migraine (VM) and the migraine variant Benign Paroxysmal Vertigo of childhood (BPV) are the commonest causes of vertigo in childhood (Langhagen et al., 2016). Studies suggest VM and BPV are the cause in between 24–56% of childhood vertigo (Brodsky et al., 2016). Between 2–10.6% of school age children are affected by VM/BPV (O’Reilly et al, 2012). VM is a clinical diagnosis with no specific vestibular diagnostic features or other biomarkers (Langhagen et al, 2016). Whilst there are numerous studies on VM in adult patients, there is a paucity of evidence in paediatric patients, particularly on clinical characterisation. Currently diagnosis and management strategies are largely based on evidence from adult populations (Kacperski and Bazarsky, 2017). Objectives This study aims to describe a large cohort of patients diagnosed with VM at a tertiary Audiovestibular Medicine unit, describing clinical presentation, examination, diagnosis, and management. We hope to raise awareness of this common and treatable condition in children and young adults. Methods This is a retrospective electronic case note review of all patients presenting to Audiovestibular Medicine clinics in a tertiary unit between January and December 2018. All patients who were given a diagnosis of vestibular migraine/migraine variant during this time, or who were patients being followed up with a known diagnosis of vestibular migraine/migraine variant, were identified. Clinical letters were reviewed looking specifically at: presenting symptoms (including headache and vertigo, other symptoms, medical comorbidities and impact of symptoms); clinical examination findings; diagnostic test findings (including vestibular diagnostics, blood tests and neuroimaging); treatment and overall outcome. Results 81 children were identified with a mean age at presentation of 10.3 ±3.8 years (range 2–17). 53% were female. 65% reported episodes beginning ≥2 years ago. No headache was reported in 29 children, however photophobia and phonophobia were common (68 and 54 children respectively). Otological symptoms were not uncommon with tinnitus present in 22 children. Comorbidities often included neurodevelopmental difficulties. Impact on schooling and extra-curricular activities was high for a subgroup of children. 31 children had episodes weekly or more frequently. Clinical examination showed abnormal oculomotor signs in 5/77 children tested (2 central and 3 peripheral) and abnormal neuro-vestibular findings in 14/78 children tested. Videonystagmography showed abnormalities in 30/75 patients tested (8 central and 8 peripheral oculomotor; 28 neuro-vestibular). Video Head Impulse Test showed significant saccades in 11/94 tests. 37% of children showed normal examination and diagnostic findings. Treatment included lifestyle measures, medication (for acute treatment or for migraine prophylaxis) and vestibular rehabilitation. The most commonly used medications in this cohort were Pizotifen (44), Propranolol (29) and Topiramate (10). Symptoms fully resolved or improved in most patients (79%) with treatment. Conclusions VM and migraine variants are a common diagnosis in children. Early recognition of clinical symptoms, appropriate diagnosis and treatment are important for effective management of these children.

Benzodiazepines are highly effective in combating anxiety; however, they have considerable adverse effects, so it is important to discover new safe anxiolytic agents. This study was designed to investigate the anxiolytic and anticonvulsant effect of natural product 2-hydroxy-3,4,6-trimethoxyacetophenone (HTMCX) and its possible mechanisms of action in adult zebrafish. The open field and light / dark tests (n = 6 animals/group) were used to assess anxiety and pentylenetetrazole (PTZ) as a seizure inducer. The 96-hour acute toxicity of HTMCX was also investigated. HTMCX (1, 3, and 10 mg / kg; v.o.) was not toxic and affected locomotor activity. The highest doses (3 and 10 mg / kg; v.o.) produced signs of anxiolytic action in the light / dark test, and this effect was abolished by the pizotifen (antagonist 5HTR1 and 5HTR2A / 2C), having the potential to form a complex in the same region of the site indicating that the anxiolytic effect via the serotonergic mechanism. However, the anxiolytic effect of HTMCX has not been abolished by flumazenil (antagonist GABARA), cyproheptadine (antagonist 5HTR2A), and granisetron (antagonist 5HTR3A / 3B). Therefore, HTMCX demonstrated an anxiolytic effect, suggesting that the 5HTR1 and 5HTR / 2C receptors may be involved in the pharmacological performance of this acetophenone in the central nervous system.

Metastasis is responsible for approximately 90% of cancer-associated mortality but few models exist that allow for rapid and effective screening of anti-metastasis drugs. Current mouse models of metastasis are too expensive and time consuming to use for rapid and high-throughput screening. Therefore, we created a unique screening concept utilizing conserved mechanisms between zebrafish gastrulation and cancer metastasis for identification of potential anti-metastatic drugs. We hypothesized that small chemicals that interrupt zebrafish gastrulation might also suppress metastatic progression of cancer cells and developed a phenotype-based chemical screen to test the hypothesis. The screen used epiboly, the first morphogenetic movement in gastrulation, as a marker and enabled 100 chemicals to be tested in five hours. The screen tested 1280 FDA-approved drugs and identified Pizotifen, an antagonist for serotonin receptor 2C (HTR2C) as an epiboly-interrupting drug. Pharmacologic and genetic inhibition of HTR2C suppressed metastatic progression in a mouse model. Blocking HTR2C with Pizotifen restored epithelial properties to metastatic cells through inhibition of Wnt-signaling. In contrast, HTR2C induced epithelial to mesenchymal transition (EMT) through activation of Wnt-signaling and promoted metastatic dissemination of human cancer cells in a zebrafish xenotransplantation model. Taken together, our concept offers a novel platform for discovery of anti-metastasis drugs.

Migraines are a chronic problem that some people face in all aspects of life at least each week, if not every day. Some types affect the front and back of the head, each headache has special symptoms and a treatment method because migraines are one of those most difficult types and can be caused by a variety of reasons, such as fatigue, malnutrition, and other medical conditions. The frequency and location of migraine attacks can vary. The concept of a migraine also differs between patients and can be caused by mere stress, fever, or other health disturbances. However, opioid recovery is the most common treatment alternative. A variety of drugs and brands are aimed at overcoming migraine problems, including paracetamol, Nadolol, timolol, metoclopramide, botulinum toxin, domperidone, pizotifen, and sumatriptan. It may be difficult to evaluate and select the medications from a larger group of medications considering the criteria such as medication prices, toxicity, concentration, and the performance of medications. This study aims to use TOPSIS methodology for clinicians to accurately compare 24 alternative migraine drugs that help control productive migraine drugs in general and/or in a particular patient situation. It helps one to understand the medications' biologic, therapeutic, and chemical properties, and their treatment costs.

ObjectivesProphylactic drugs currently used for migraine treatment are not specific. Furthermore, few studies in existing literature describe drugs utilisation patterns and adherence to migraine prophylactic treatment. This study is aimed to describe utilisation patterns of migraine drugs, evaluate adherence to prophylactic medications and investigate drug-related costs.DesignRetrospective population-based study using an administrative health-related database.SettingPrimary care setting in the Campania region, Southern Italy.ParticipantsThis study was carried out between 1 January 2016 and 31 December 2018, involving 12 894 subjects with any primary or secondary hospital discharge with migraine diagnosis, or at least two medical dispensations of migraine-specific acute or prophylactic medications (triptans or pizotifen). Subjects were classified into four treatment cohorts: no treatment, acute, prophylactic and both acute and prophylactic. Subjects were followed-up for 1 year.Outcome measuresUtilisation patterns of migraine drugs at treatment initiation; adherence to prophylactic treatment; discontinuation, restart and switching rates; annual migraine drug costs per patient.ResultsOverall, 81.1% of subjects received acute treatment as their initial migraine treatment regimen, 10.7% prophylactic treatment, 8.2% both acute and prophylactic treatment. 599 patients were treated prophylactically; of these, 26.2% adhered to their initial treatment while 73.8% reported interruptions in treatment. Among the latter, 46.4% of patients discontinued the treatment completely within 103 days (IQR 89.0), 31% restarted treatment 46 days after interruption (IQR 60.0) and 22.6% switched to another treatment within 98 days (IQR 57.5) (pConclusionsMigraine treatment with acute medications is still prevalent in Italy; only few patients received prophylactic treatment with poor adherence to treatment. These findings reflect an unmet need for improved prophylactic therapies in order to provide a better disease management.

Background: Plant lectins have shown promising neuropharmacological activities in animal models. Objective: This study evaluated the effect of Dioclea altissima seed lectin (DAL) on adult zebrafish behavior. Method: Zebrafish (n=6/group) were treated (i.p.; 20 μL) with DAL (0.025; 0.05 or 0.1 mg/mL), vehicle or diazepam (DZP) and submitted to several tests (open field, light/dark preference or novel tank). Flumazenil, pizotifen or granisetron were administered 15 min before DAL (0.05 mg/mL), and the animals were evaluated on light/dark preference test. It was also verified whether the DAL effect depended on its structural integrity and ability to interact with carbohydrates. Results: DAL decreased the locomotor activity of adult zebrafish (0.025; 0.05 or 0.1 mg/mL), increased the time spent in the upper region of the aquarium (0.025 mg/mL), and decreased the latency time of adult zebrafish to enter the upper region on the novel tank test. DAL (0.05 mg/mL) also increased their permanence in the light zone of the light/dark preference test. The effect of DAL was dependent on carbohydrate interaction and protein structure integrity and was prevented by pizotifen, granizetron and flumazenil. Conclusion: DAL was found to have an anxiolytic-like effect mediated by the 5-HT and GABAergic receptors.

This retrospective review aims to survey the clinical characteristics and management of vestibular migraine (VM) patients seen in a tertiary hospital multi-disciplinary balance disorders clinic, and how this aligns with the evidence base in the literature. A single investigator reviewed the medical records of the patients who presented to a tertiary hospital balance disorders clinic over a four month period and identified 90 cases of VM. The mean age of patients with a diagnosis of VM was 50 years (range of 17–84) and 72 (80%) were female. Vertigo (96%) and headache (60%) were the predominate symptoms. Vestibular function testing abnormalities included six (5%) with a positive video head impulse test and seven (6%) with oculomotor abnormalities. Pizotifen (30%) and amitriptyline (21%) were the two most commonly used medications whilst only 14 (16%) received vestibular physiotherapy. This study suggests that VM is a very common presentation to a tertiary balance disorders clinic, but there is little consensus in choice of initial management and vestibular rehabilitation is underutilized. This data may be valuable in informing the practice of neuro-otology as well as in the planning of future service provision.

Shapiro Syndrome is a rare entity defined by the triad of recurrent spontaneous hypothermia, hyperhidrosis, and agenesis of the corpus callosum. Fewer than 100 cases have been reported so far and there are only few cases without a complete agenesis of corpus callosum ("Shapiro Syndrome Variant"). In this article, we report the clinical, electroencephalographic, and neuroimaging data of a patient with early-onset Shapiro Syndrome Variant. The case study describes a 4-year-old patient with episodes characterized by generalized hyperhidrosis, hypotonia, impaired consciousness, and hypothermia with onset before the first year of age. We captured an event during which the EEG showed rhythmic low- to medium-voltage theta waves without clear epileptiform activity. Brain MRI was normal and Shapiro Syndrome Variant was hypothesized. We started treatment with pizotifen, and after 2 years, the patient showed a reduction in frequency and duration of episodes. Shapiro Syndrome, although rare, should be considered in the differential diagnosis in patients with neurovegetative symptoms which suggest epileptic attacks at first. Our case is of particular interest to specialists because Shapiro SyndromeVariant is a rare syndrome and our patient had a very early onset of symptoms.In addition, we report our experience with pizotifen therapy, which produced a good response.

Background and aims Ketamine+xylazine mixture is a widely used anaesthetic in animal experiments. In rats anaesthetized with this mixture, we have shown that injection of carrageenan, a standard proinflammatory stimulus, into the cheek (intra-oral injection) induced oedema. A likely mediator of this oedema is substance P (SP), a major transmitter of sensory nerves in orofacial tissue. We have assessed the effects of intra-oral injection of SP in rats. Experimental approach SP (50–1 μg per rat) was injected intra-orally in male adult Holtzman or Wistar rats, anaesthetized with ketamine+xylazine. For comparison, histamine (50 μg) and 5-HT (5 μg) were similarly injected. Antagonists of SP (SR140333, 2 mg/kg), of histamine (pyrilamine, 2 mg/kg) or of 5-HT (pizotifen, 2 mg/kg) were subcutaneously (s.c.) injected, 30 min before the corresponding agonist. Oedema in the cheek was assessed by measuring tissue thickness with calipers. Results Intra-oral injection of SP (1–50 μg per rat) in Holtzman or Wistar rats anaesthetized with ketamine+xylazine induced, dose-dependently, death within 15 min, accompanied by signs of excessive salivation. Rats pretreated with SR140333 were protected against SP-induced lethality and the excessive salivation. However, intra-oral injection of either histamine or 5-HT did not induce death, only a characteristic cheek oedema. These doses of SP injected into the hindpaws of conscious Holtzman and Wistar rats only induced oedema with no deaths. In rats anaesthetized with inhaled isoflurane, intra-oral SP (50 μg) induced only cheek oedema, with no deaths or excessive salivation. This oedema was prevented by pre-treating rats with SR140333, pyrilamine and pizotifen. Conclusion It is likely that the deaths were due to excessive salivation induced by the particular combination of ketamine and SP. Our results are presented as a warning to other experimenters who might use these two otherwise non-toxic conditions and the consequent unexpected and needless loss of experimental animals.

Cluster headache is characterised by attacks of excruciating unilateral headache or facial pain lasting 15 min to 3 h and is seen as one of the most intense forms of pain. Cluster headache attacks are accompanied by ipsilateral autonomic symptoms such as ptosis, miosis, redness or flushing of the face, nasal congestion, rhinorrhoea, peri-orbital swelling and/or restlessness or agitation. Cluster headache treatment entails fast-acting abortive treatment, transitional treatment and preventive treatment. The primary goal of prophylactic and transitional treatment is to achieve attack freedom, although this is not always possible. Subcutaneous sumatriptan and high-flow oxygen are the most proven abortive treatments for cluster headache attacks, but other treatment options such as intranasal triptans may be effective. Verapamil and lithium are the preventive drugs of first choice and the most widely used in first-line preventive treatment. Given its possible cardiac side effects, electrocardiogram (ECG) is recommended before treating with verapamil. Liver and kidney functioning should be evaluated before and during treatment with lithium. If verapamil and lithium are ineffective, contraindicated or discontinued because of side effects, the second choice is topiramate. If all these drugs fail, other options with lower levels of evidence are available (e.g. melatonin, clomiphene, dihydroergotamine, pizotifen). However, since the evidence level is low, we also recommend considering one of several neuromodulatory options in patients with refractory chronic cluster headache. A new addition to the preventive treatment options in episodic cluster headache is galcanezumab, although the long-term effects remain unknown. Since effective preventive treatment can take several weeks to titrate, transitional treatment can be of great importance in the treatment of cluster headache. At present, greater occipital nerve injection is the most proven transitional treatment. Other options are high-dose prednisone or frovatriptan.

Purpose: Population-based data are sparse on utilization of prophylactic versus acute therapies for newly diagnosed migraine. We examined initial migraine treatment patterns and associated patient characteristics in Denmark. Methods: We used population-based health databases to assemble a nationwide cohort of adult migraine patients in 2005 to 2013. Migraine was defined as a first hospital diagnosis of migraine or a second redeemed outpatient prescription for triptans, ergots, pizotifen, or flunarizine. We classified the initial migraine treatment received after migraine onset as “no treatment,” “acute only,” “prophylactic only,” and “both acute and prophylactic” and described distributions of sex, age, comorbidities, and comedications. Results: Among 97 431 migraine patients (78% women, median age of 41 y [interquartile range of 32-50 y]), the initial migraine treatments received were “acute only” (88.2%), “prophylactic only” (1.9%), and “both acute and prophylactic” (5.2%) whereas 4.6% had no record of treatment. Initiators of prophylactic treatment—with or without acute treatment—were less likely than initiators of acute treatment to be women (71% and 77% versus 79%), were older (median ages: 45 and 44 y versus 41 y), and had more comorbidities (including hypertension [31% and 24% versus 7%] and diabetes [6% and 5% versus 3%]). Nonpersistence with initial prophylactic treatment was common: within the first year, 35% of initiators stopped therapy fully, 50% stopped and restarted, and 15% switched drugs. Conclusions: For 88% of patients with incident migraine, the initial migraine treatment was acute treatment only. Use of prophylactic medication as initial treatment was low and correlated with higher age and comorbidity.

Initially there was some concern that ergots could cause malformations, notably such due to vascular disruption. This may be true but has neither been detected in the cohort studies published, nor in the data from the Swedish health registers. No teratogenic effect has been seen from triptans in spite of relatively large number of exposures studied. Little is known on the use of pizotifen during pregnancy. Available data do not indicate a teratogenic risk but more information is needed.

Gastric cancer is the fifth most common malignancy and the third highest cause of cancer-associated mortality worldwide. Therefore, research on the pathogenesis of gastric cancer is of utmost importance. It has been reported that aberrant activation of the Wnt/β-catenin signaling pathway is involved in the occurrence and development of gastric cancer. In the present study, it was found that pizotifen could inhibit the viability of gastric cancer cell lines MNK45 and AGS cells in a dose-dependent manner. Pizotifen treatment suppressed cell migration and invasion in MNK45 and AGS cells, whilst also inducing apoptosis. Western blot analysis demonstrated that pizotifen blocked the expression of Wnt3a, β-catenin and N-cadherin, whilst increasing E-cadherin expression. In addition, BML-284, a pharmacological Wnt signaling activator, partially reversed the changes in the expression levels of β-catenin, N-cadherin and E-cadherin in MNK45 and AGS cells induced by pizotifen. Collectively, these findings suggested that pizotifen demonstrates potential as a novel anti-cancer drug for the treatment of gastric cancer by inhibiting the Wnt/β-catenin pathway.

Background and aims This study aimed to assess the potential of calcitonin-gene related peptide (CGRP), a neuropeptide released from sensory nerves, to induce oedema in orofacial tissue. Experimental approach Wistar rats (150–200 g) anesthetized with isoflurane were injected intraorally with CGRP (100 μl; 8–33 pmol) in the right side of the mouth. The contralateral side was injected with the same volume of physiological saline. Increased cheek thickness (in mm), as a measure of oedema formation, was assayed bilaterally with a digital caliper before ( T = 0) and up to 24 h following injection of CGRP. Pretreatment with antagonists (CGRP 8–37, 10 nmol; pizotifen, 2 mg/kg) was given by intra-oral or subcutaneous injection, 10 or 30 min, respectively, before the inflammatory stimulus. CGRP and CGRP 8–37 were also injected into the rat hind paw to induce oedema. Data are presented as the mean (±SEM) difference in thickness between the right and the left sides at each time. Results Following intra-oral injection, CGRP induced a rapidly developing (5–15 min) and long-lasting (6 h), dose-dependent oedema in the rat cheek, blocked by pre-treatment with CGRP 8–37 or pizotifen. CGRP induced a smaller oedematogenic effect in the rat hind paw also blocked by the CGRP antagonist. CGRP (16 pmol) potentiated the oedema induced by co-injected substance P (3.7 nmol) and contributed to the oedema following intraoral injection of carrageenan (100 μg). Injection of CGRP 8–37 alone induced an early but short-lasting oedema. Conclusion Local injection of CGRP potently induced oedema in the orofacial tissue of rats which was blocked by a CGRP receptor antagonist. The overall inhibition of carrageenan-induced oedema by CGRP 8–37 suggests that endogenous CGRP contributes to an oedematogenic response in orofacial tissues.

Background and objectives: Migraine is now ranked as number 19 among all diseases causing disability by WHO1 which is characterized by recurrent attacks of various combinations of headache and neurological, gastrointestinal and autonomic symptoms2 accompanied by photophobia, phonophobia and vomiting3. The treatment of migraine involves acute, preventive drugs and non-pharmacological strategies. The basic principle in management of migraine is avoiding the trigger factors, blocking the mediators and splinting the end organ4. Though there is no significant curable treatment but there are some internationally proven and well accepted prophylactic medication which reduces headache severity, frequency, duration and risk for rebound5. Sodium valproate and pizotifen are commonest of them6, where sodium valproate is more effective than pizotifen in the prophylaxis of migraine patients. Methods: This study was a single blind randomized clinical trial carried out in the neurology outpatient department of Bangabandhu Sheikh Mujib Medical University, Dhaka (BSMMU) for the period of 2 years, among adult patients between the age of 16-50 years. Results: A total of 120 patients were included & divided into two groups such as group-A(60 patients) treated by sodium valproate & group-B(60 patients) treated by pizotifen for a period of 6 months and followed up every two months for 3 times and showed sodium valproate is more effective than pizotifen. Conclusion: This study permit to conclude that efficacy of sodium valproate is more than pizotifen in the prophylaxis of migraine patients. DOI: http://dx.doi.org/10.3329/bjn.v28i2.17174 Bangladesh Journal of Neuroscience 2012; Vol. 28 (2): 81-87

This chapter describes methods of synthesis, pharmacological properties and use of derivatives of piperidin-4-ylidene substituted tricyclic compounds such as cyproheptadine, azatadine, loratadine, rupatadine, ketotifen, pizotifen, alcaftadine, and ritanserin.

Aim The purpose of this retrospective multicenter study was to evaluate the use and the self-perceived efficacy and tolerability of pharmacological and non-pharmacological treatments in children and adolescents with primary headaches. Methods Study of a cohort of children and adolescents diagnosed with primary headache, consecutively referred to 13 juvenile Italian Headache Centers. An ad hoc questionnaire was used for clinical data collection. Results Among 706 patients with primary headaches included in the study, 637 cases with a single type of headache (migraine 76% – with and without aura in 10% and 67% respectively; tension-type headache 24%) were selected (mean age at clinical interview: 12 years). Acetaminophen and non-steroidal anti-inflammatory drugs (in particular ibuprofen) were commonly used to treat attacks, by 76% and 46% of cases respectively. Triptans were used overall by 6% of migraineurs and by 13% of adolescents with migraine, with better efficacy than acetaminophen and non-steroidal anti-inflammatory drugs. Preventive drugs were used by 19% of migraineurs and by 3% of subjects with tension-type headache. In migraineurs, flunarizine was the most frequently used drug (18%), followed by antiepileptic drugs (7%) and pizotifen (6%), while cyproheptadine, propanolol and amitriptyline were rarely used. Pizotifen showed the best perceived efficacy and tolerability. Melatonin and nutraceuticals were used by 10% and 32% of subjects, respectively, both for migraine and tension-type headache, with good results in terms of perceived efficacy and tolerability. Non-pharmacological preventive treatments (i.e. relaxation techniques, biofeedback, cognitive-behavioral therapy, acupuncture) were used only by 10% of cases (migraine 9%, tension-type headache 15%). Discussion Non-steroidal anti-inflammatory drugs, especially ibuprofen, should be preferred to acetaminophen for acute attacks of migraine or tension-type headache, because they were usually more effective and well tolerated. Triptans could be used more frequently as first or almost second choice for treating migraine attack in adolescents. Non-pharmacological preventive treatments are recommended by some pediatric guidelines as first-line interventions for primary headaches and their use should be implemented in clinical practice. Prospective multicenter studies based on larger series are warranted to better understand the best treatment strategies for young people with primary headaches.

Ethnopharmacological relevance Maerua angolensis DC (Capparaceae) has been employed in the management of several central nervous system (CNS) disorders including anxiety. This study evaluated the anxiolytic effects of the petroleum ether/ethyl acetate fraction stem bark extract and its possible mechanism(s) using zebrafish anxiety models. Methods Adult zebrafish, tested in the novel tank and light dark tests, have shown by previous authors to be sensitive to the anxiolytic effects of known anxiolytic drugs. Adult zebrafish were treated with M. angolensis extract, fluoxetine, desipramine, and diazepam followed by testing in the novel tank and light dark tests. We further assessed the effect of the extract on anxiety after inducing an anxiogenic phenotype using the ethanol-withdrawal and chronic unpredictable stress (CUS) tests. The anxiolytic effect was further investigated after pretreatment with flumazenil, granisetron, cyproheptadine, methysergide and pizotifen. Results M. angolensis extract, similar to fluoxetine and desipramine, demonstrated significant anxiolytic behaviour at doses that did not reduce locomotor activity significantly. Similar anxiolytic effects were recorded in the ethanol withdrawal-induced anxiety test. Furthermore, the anxiogenic effects induced by the CUS paradigm were significantly reversed by treatment M. angolensis extract and fluoxetine. The anxiolytic effects of M. angolensis extract were however reversed after pre-treatment with flumazenil, granisetron, cyproheptadine, methysergide and pizotifen. Conclusions Taken together, this suggests that the petroleum ether/ ethyl acetate fraction of M. angolensis possesses significant anxiolytic activity, which could partly be accounted for by an interaction with the serotoninergic system and the GABA A receptor.

Hemiplegic migraine (HM) is a rare subtype of migraine with aura, characterized by transient hemiparesis during attacks. Diagnosis is based on the International Classification of Headache Disorders criteria (ICHD-II). Two types of HM are recognized: familial (FHM) and sporadic hemiplegic migraine (SHM). HM is genetically heterogeneous. Three genes have been identified (CACNA1A, ATP1A2, and SCN1A) but more, so far unknown genes, are involved. Clinically, attacks of the 3 subtypes cannot be distinguished. The diagnosis can be confirmed but not ruled out by genetic testing, because in some HM patients other, not yet identified, genes are involved. The presence of additional symptoms (such as chronic ataxia or epilepsy) may increase the likelihood of identifying a mutation. Additional diagnostics like imaging, CSF analysis, or an EEG are mainly performed to exclude other causes of focal neurological symptoms associated with headache. Conventional cerebral angiography is contraindicated in HM because this may provoke an attack. Because HM is a rare condition, no clinical treatment trials are available in this specific subgroup of migraine patients. Thus, the treatment of HM is based on empirical data, personal experience of the treating neurologist, and involves a trial-and-error strategy. Acetaminophen and NSAIDs often are the first choice in acute treatment. Although controversial in HM, triptans can be prescribed when headaches are not relieved sufficiently with common analgesics. An effective treatment for the severe and often prolonged aura symptoms is more warranted, but currently no such acute treatment is available. Prophylactic treatment can be considered when attack frequency exceeds 2 attacks per month, or when severe attacks pose a great burden that requires reduction of severity and frequency. In no strictly preferred order, flunarizine, sodium valproate, lamotrigine, verapamil, and acetazolamide can be tried. While less evidence is available for prophylactic treatment with topiramate, candesartan, and pizotifen, these drugs can also be considered. The use of propranolol in HM is more controversial, but evidence of adverse effects is insufficient to contraindicate beta-blockers.

A simple, selective, linear, precise, and accurate RP-HPLC method was developed and validated for rapid assay of Pizotifen in pharmaceutical dosage form. Isocratic elution at a flow rate of 1.0 mL/min was employed on Chromosil C18 (250 mm × 4.6 mm, 5 μm) column at ambient temperature. The mobile phase consists of methanol : acetonitrile in the ratio of 10 : 90 v/v. The UV detection wavelength was 230 nm, and 20 μL sample was injected. The retention time for Pizotifen was 2.019 min. The percent RSD for accuracy of the method was found to be 0.2603%. The method was validated as per the ICH guidelines. The method can be successfully applied for routine analysis of Pizotifen in the rapid and reliable determination of Pizotifen in pharmaceutical dosage form.

Huntington's disease (HD) is a dominantly inherited neurodegenerative condition characterized by dysfunction in striatal and cortical neurons. There are currently no approved drugs known to slow the progression of HD.To facilitate the development of therapies for HD, we identified approved drugs that can ameliorate mutant huntingtin-induced toxicity in experimental models of HD.A chemical screen was performed in a mouse Hdh(Q111/Q111) striatal cell model of HD. This screen identified a set of structurally related approved drugs (pizotifen, cyproheptadine, and loxapine) that rescued cell death in this model. Pizotifen was subsequently evaluated in the R6/2 HD mouse model.We found that in striatal Hdh(Q111/Q111) cells, pizotifen treatment caused transient ERK activation and inhibition of ERK activation prevented rescue of cell death in this model. In the R6/2 HD mouse model, treatment with pizotifen activated ERK in the striatum, reduced neurodegeneration and significantly enhanced motor performance.These results suggest that pizotifen and related approved drugs may provide a basis for developing disease modifying therapeutic interventions for HD.

Pizotifen malate is an antihistamine and serotonin inhibitor used in the preventive treatment of migraine and eating disorders. A simple, rapid, accurate and precise high-performance liquid chromatography (HPLC) method involving ultraviolet detection was validated for the quantitative analysis of pizotifen malate in samples from in vitro transdermal diffusion studies. The method was validated for specificity, linearity, accuracy, precision, limit of detection, limit of quantification and robustness. Drug stability in the solution was also determined under different conditions. Separation was carried out using a 250 × 4.0 mm Kromasil(®) C(18) column at room temperature. The detector response, fitted at 254 nm, was found to be linear in a concentration range between 0.24 and 24.0 µg/mL. The limit of detection was 0.02 µg/mL and the limit of quantification was 0.07 µg/mL. Finally, in vitro transdermal diffusion of pizotifen malate was characterized using the validated HPLC method.