Repurposed pizotifen malate targeting NRF2 exhibits anti-tumor activity through inducing ferroptosis in esophageal squamous cell carcinoma.

Targeted therapy attempts are needed to enhance esophageal squamous cell carcinoma (ESCC) patients' overall survival and satisfaction of life. Nuclear factor erythroid 2-related factor 2 (NRF2), as a high-confidence cancer driver gene, controls the antioxidant response, metabolic balance and redox homeostasis in cancer and is regarded as a potent molecular target for cancer treatment. Here, we attempted to find a new NRF2 inhibitor and study the underlying molecular mechanism in ESCC. We found that up-regulated NRF2 protein was negatively correlated with patient prognosis and promoted tumor proliferation in ESCC. Moreover, Pizotifen malate (PZM), a FDA-approved medication, bound to the Neh1 domain of NRF2 and prevented NRF2 protein binding to the ARE motif of target genes, suppressing transcription activity of NRF2. PZM treatment suppressed tumor development in ESCC PDX model by inducing ferroptosis via down-regulating the transcription of GPX4, GCLC, ME1 and G6PD. Our study illustrates that the over expression of NRF2 indicates poor prognosis and promotes tumor proliferation in ESCC. PZM, as a novel NRF2 inhibitor, inhibits the tumor growth by inducing ferroptosis and elucidates a potent NRF2-based therapy strategy for patients with ESCC.

Intrathecally administered pizotifen alleviates neuropathic and inflammatory pain in mice by enhancing GABAergic inhibition.

Chronic pain, such as chronic neuropathic pain and chronic inflammatory pain, is often difficult to manage and bring great trouble to patients. 5-HT plays a key role in the process of pain transmission both in centrally and peripherally. Tricyclic antidepressants (TCA) such as amitriptyline are classical 5-HT reuptake inhibitors, are recommended as the first-line treatment for chronic pain. Pizotifen, a 5-HT2 receptor antagonist, is currently used in the prevention of vascular headaches. However, the antinociceptive effect of pizotifen on non-headache pain especially chronic pain in the spinal level is still unknown. Here we find that intrathecal pizotifen attenuates neuropathic and inflammatory pain mainly due to elevated GABAergic synaptic inhibition. Neuropathic pain is induced by segmental spinal nerve ligation (SNL), and inflammatory pain is induced by intraplantar injection of complete Freund's adjuvant (CFA). Both in SNL and CFA mice, spinally administered pizotifen reduced mechanical and thermal hyperalgesia dose-dependently. Since the levels of GAD65/67 were increased, and the frequency of mIPSCs in the spinal dorsal horn was increased, together with the antinociceptive effect being reversed by both GABAAR and GAD blockade, this antinociceptive effect might be generated from strengthened GABAergic inhibition. Furthermore, high dose of pizotifen (5 µg) weakly affected motor performance and did not influence the locomotor activity in normal animals. In summary, our findings suggest that pizotifen strengthens the inhibitory synaptic transmission and exerts antinociceptive effect on both neuropathic pain and inflammatory pain in the spinal cord, and may serve as a promising remedy for chronic pain.

Headaches in over 12s: diagnosis and management

This guideline covers advice on the diagnosis and management of tension-type headache, migraine (including migraine with aura and menstrual-related migraine), cluster headache and medication overuse headache in young people (aged 12 years and older) and adults. It aims to improve the recognition and management of headaches, with more targeted treatment to improve the quality of life for people with headaches, and to reduce unnecessary investigations. MHRA advice on antiepileptic drugs in pregnancy: In May 2021, we amended our recommendation on topiramate for migraine prophylaxis to include discussion of the potential benefits and risks, and the importance of effective contraception for women and girls of childbearing potential when taking topiramate.

Early-Onset Shapiro Syndrome Variant Treated with Pizotifen: A Case Report.

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.

Efficacy of amitriptyline, pizotifen and propranolol in the prevention of migraine.

This intervention study conducted in the Neurology outpatient Department of Mymensingh Medical College Hospital (MMCH) from January 2006 to December 2007 to compare efficacy of amitriptyline, pizotifen and propranolol in the prophylaxis of migraine. Ninety cases were selected following certain inclusion and exclusion criteria. Result showed that the differences in duration, frequency and severity of attack were reduced in all groups but the differences among the groups were not significant (p>0.05). However, compared with amitriptyline and pizotifen, the propranolol group needed tablet paracetamol as abortive therapy less frequently which was statistically significant (p<0.05). All the drugs were well tolerated with minimum adverse effects.

Pharmacological interventions for recurrent abdominal pain (RAP) and irritable bowel syndrome (IBS) in childhood.

BACKGROUND: Between 4% and 25% of school-age children complain of recurrent abdominal pain (RAP) of sufficient severity to interfere with daily activities. For the majority no organic cause for their pain can be found on physical examination or investigation and although most children are likely managed by reassurance and simple measures, a large range of interventions have been recommended. OBJECTIVES: To determine the effectiveness of medication for recurrent abdominal pain in school-age children. SEARCH STRATEGY: The Cochrane Library (CENTRAL) 2006 (Issue 4), MEDLINE (1966 to Dec 2006), EMBASE (1980 to Dec 2006), CINAHL (1982 to Dec 2007), ERIC (1966 to Dec 2006), PsycINFO (1872 to Dec 2006), LILACS (1982 to Dec 2006), SIGLE (1980 to March 2005), and JICST (1985 to 06/2000) were searched with appropriate filters SELECTION CRITERIA: Studies on school age children with RAP (Apley or the Rome II criteria for gastrointestinal diseases) allocated by random or quasi-random methods to a drug treatment vs. placebo/ no treatment were included. DATA COLLECTION AND ANALYSIS: References identified by the searches were screened against the inclusion criteria by two independent reviewers. Data was extracted and analysed using RevMan 4.2.10. MAIN RESULTS: Three trials met the inclusion criteria. Symon et al report a cross-over trial comparing pizotifen and placebo in 16 children with "abdominal migraine". Data before cross-over was not available. Results for 14 children showed Mean fewer days in pain of 8.21 (95% CI 2.93, 13.48) while taking the active drug. Kline et al compared peppermint oil capsules with placebo in a randomised trial in 50 children with RAP and IBS. 42 children completed the study. OR for improvement was 3.33 (95% CI 0.93-12.1)See et al compared famotidine with placebo in a randomised cross-over trial in 25 children with RAP and dyspepsia. OR for improvement before cross-over was 11 (95%CI 1.6, 75.5). AUTHORS' CONCLUSIONS: This review provides weak evidence of benefit on medication in children with RAP. The lack of clear evidence of effectiveness for any of the recommended drugs suggests that there is little reason for their use outside of clinical trials. Clinicians may choose to prescribe drugs in children with severe symptoms that have not responded to simple management. However, if using drugs as a "therapeutic trial", clinicians should be aware that, RAP is a fluctuating condition and any "response" may reflect the natural history of the condition or a placebo effect rather than drug efficacy.

Pharmacological prevention of migraine: to be considered case by case.

(1) Migraines are characterized by recurrent headaches generally lasting between 4 and 72 hours and disappearing without complication. They can be incapacitating, owing to their frequency and/or intensity. (2) Many drugs have been used to prevent migraines. One of the most common outcome measures used in clinical trials is the proportion of responder patients, defined as those in whom the monthly frequency of migraines is at least halved. On average, about one-third of patients respond to placebo in clinical trials. (3) Propranolol is the betablocker with the best-documented efficacy: in absolute terms the response rate is about 30% higher than with placebo. The adverse effects of betablockers are mainly cardiovascular and neuropsychological. (4) Valproic acid, an anticonvulsant, is about as effective as propranolol, and its adverse effects are generally acceptable. (5) Amitriptyline is the antidepressant with the best-documented preventive effects, with a response rate about 20% higher than placebo. Its principal adverse effects are due to its atropinic action. Amitriptyline can also have a sedative effect. (6) Flunarizine also has documented efficacy, but this "hidden neuroleptic" can cause extrapyramidal disorders and weight gain. (7) Among the serotonergic antagonists, methysergide has documented efficacy but long-term treatment can lead to serious retroperitoneal, pulmonary or cardiac fibrosis. Pizotifen causes drowsiness or weight gain in about 50% of patients. (8) The choice of preventive treatment for migraine must be based on the balance between efficacy (compared to placebo) and adverse effects. In practice, the first choice drug is propranolol. (9) Because the frequency of migraines fluctuates over time, withdrawal of prophylaxis should be attempted on a regular basis, with the patient's consent.

Raynaud phenomena and migraine in two children: inclusion within a family of related disorders.

UNLABELLED: We report a case of two siblings with Raynaud phenomena and migraine, whose symptoms were successfully treated with pizotifen. CONCLUSION: To our knowledge, this is the first case documenting the association between Raynaud phenomena and migraine in two siblings with a family history of Raynaud phenomena and ischaemic heart disease.

Systematic review of treatments for recurrent abdominal pain.

OBJECTIVE: To conduct a systematic review of evaluated treatments for recurrent abdominal pain (RAP) in children. METHODS: Online bibliographic databases were searched for the terms "recurrent abdominal pain," "functional abdominal pain," "children," or "alternative therapies" in articles classified as randomized controlled trials. The abstracts or full text of 57 relevant articles were examined; 10 of these met inclusion criteria. Inclusion criteria required that the study involve children aged 5 to 18 years, subjects have a diagnosis of RAP, and that subjects were allocated randomly to treatment or control groups. The methodology and findings of these articles were evaluated critically, and data were extracted from each article regarding study methods, specific interventions, outcomes measured, and results. RESULTS: Studies that evaluated famotidine, pizotifen, cognitive-behavioral therapy, biofeedback, and peppermint oil enteric-coated capsules showed a decrease in measured pain outcomes for those who received the interventions when compared with others in control groups. The studies that evaluated dietary interventions had conflicting results, in the case of fiber, or showed no efficacy, in the case of lactose avoidance. CONCLUSIONS: Evidence for efficacy of treatment of RAP in children was found for therapies that used famotidine, pizotifen, cognitive-behavioral therapy, biofeedback, and peppermint oil enteric-coated capsules. The effects of dietary fiber were less conclusive, and the use of a lactose-free diet showed no improvement. There seemed to be greater improvement when therapy (famotidine, pizotifen, peppermint oil) was targeted to the specific functional gastrointestinal disorder (dyspepsia, abdominal migraine, irritable bowel syndrome). The behavioral interventions seemed to have a general positive effect on children with nonspecific RAP. Many of these therapies have not been used widely as standard treatment for children with RAP. Although the mechanism of action for each effective therapy is not fully understood, each is believed to be safe for use in RAP.

[Effectiveness of tolfenamic acid in the prevention of migraine]. / Tolfenamines rugsties veiksmingumas migrenos profilaktikai.

The migraine prophylactic effect of tolfenamic acid 300 mg versus pizotifen 1.5 was evaluated in a prospective, randomized, double-blind, parallel group study. 192 patients were included with a frequency of 4-8 moderate to severe migraine attacks monthly, with or without aura, fulfilling the diagnostic criteria for migraine as defined by the International Headache Society. A four-week baseline period without medication was followed by 12 weeks of treatment with tolfenamic acid 300 mg or pizotifen 1.5 mg. In both periods patients were allowed to take escape medication (paracetamol and codeine) if the treatment was inefficient. All the patients had a headache diary before and during treatment. The primary criterion of efficacy was reduction in attack frequency per 4 weeks. Also reduction in intensity or duration of migraine attacks in hours at the end of 12 weeks treatment compared to the baseline period was measured. Both groups exhibited significant reduction in attack frequency (p < 0.001). Tolfenamic acid significantly reduced severity compared to the run-in period (p = 0.009). Patients treated with pizotifen needed more escape medication when compared to the run-in period (p < 0.01). Tolerance, especially weight gain, was a major drawback with pizotifen. Because of its high efficacy, excellent tolerability and low cost, tolfenamic acid is an interesting option for migraine prophylaxis.

Pharmacological interventions for recurrent abdominal pain (RAP) in childhood.

BACKGROUND: Between 4% and 25% of school age children complain of recurrent abdominal pain (RAP) of sufficient severity to interfere with daily activities. For the majority of such children no organic cause for their pain can be found on physical examination or investigation. Although most children are likely managed by reassurance and simple measures, a large range of interventions has been recommended. OBJECTIVES: To determine the effectiveness of medication for recurrent abdominal pain in school-age children. SEARCH STRATEGY: The Cochrane Library (CENTRAL), MEDLINE, EMBASE, CINAHL, ERIC, PsycLIT, LILACS and JICST were searched using a strategy combining (Recurrent OR synonyms) AND (Abdomen OR synonyms) AND (Pain OR synonyms). Where appropriate search filters were employed. In addition, researchers working in this area were asked to identify relevant studies. SELECTION CRITERIA: Any study in which the majority of participants were school age children fulfilling standard criteria for RAP, and who were allocated by random or quasi-random methods to any drug treatment compared with a placebo or no treatment. DATA COLLECTION AND ANALYSIS: References identified by the searches were screened against the inclusion criteria by two independent reviewers. MAIN RESULTS: Only one trial met the inclusion criteria. This cross-over trial in 14 children who met suggested criteria for "abdominal migraine" compared pizotifen and placebo, each given for one month with no washout period. Participants reported a mean of 8.21 (95% CI 2.93, 13.48) fewer days of pain while taking the active drug. They also reported that the mean difference on an "Index of Severity" was -16.21 (95% CI -26.51, -5.90) and on an "Index of Misery" was -56.07 (95% CI -94.07, -18.07). REVIEWER'S CONCLUSIONS: There is little evidence to suggest that recommended drugs are effective in the management of RAP. At present there seems little justification for the use of these drugs other than in clinical trials. There is an urgent need for trials of all suggested pharmacologic interventions in children with RAP.

Abdominal migraine: evidence for existence and treatment options.

There is evidence to suggest that, in children, episodic abdominal pain occurring in the absence of headache may be a migrainous phenomenon. There are four separate strands of evidence for this: the common co-existence of abdominal pain and migraine headaches; the similarity between children with episodic abdominal pain and children with migraine headaches, with respect to social and demographic factors, precipitating and relieving factors, and accompanying gastrointestinal, neurological and vasomotor features; the effectiveness of nonanalgesic migraine therapy (such as pizotifen, propanolol, cyproheptadine and the triptans) in abdominal migraine; and the finding of similar neurophysiological features in both migraine headache and abdominal migraine. Abdominal migraine is rare, but not unknown, in adults. Many families are content with a diagnosis and reassurance that the episodes, though distressing, are not the result of serious pathology. Some patients respond to simple dietary and other prophylactic measures. There is scant evidence on which to base recommendations for the drug management of abdominal migraine. What little literature exists suggests that the antimigraine drugs pizotifen, propanolol and cyproheptadine are effective prophylactics. Nasal sumatriptan (although not licensed for pediatric use) may be effective in relieving abdominal migraine attacks.

Episodios recidivantes de estupor como manifestación insólita de migraña / Recurrent episodes of stupor as an unusual manifestation of migraine

Episodios recidivantes de afectación de la conciencia ocurren en la epilepsia y en algunas metabolopatías, pero también en el contexto de migrañas, como el caso que se refiere, un niño que desde los 3 años padece episodios paroxísticos de estupor de hasta más de 24 horas de duración, con trastornos vegetativos y, ocasionalmente, movimientos desordenados de un hemicuerpo. Sin antecedentes personales, con migraña en madre y abuela. Durante los episodios y en las intercrisis son normales la exploración clínica y neurológica, el fondo de ojo, y los exámenes complementarios: hemograma, coagulación, glucosa, transaminasas, amilasa, aminoácidos, amonio, lactato, iones, equilibrio ácido-base, ácido úrico, urea y creatinina. TAC y RM cerebral normales. EEG con grupos generalizados de ondas lentas y agudas (sharp waves) de hasta 20 minutos de duración. Tratado sin éxito con todos los antiepilépticos, durante una crisis se detecta en orina 65 mmol/mol de creatinina de 5-hidroxiindolacético (normal < 10). Suspendiendo el antiepiléptico y administrando pizotifeno se reduce la frecuencia y la duración de los episodios, que desaparecen tras la toma de flunarizina. A los seis meses de iniciado este último tratamiento se realiza nueva determinación de indolacético en orina con resultado normal (6 mmol/mol de creatinina).En conclusión, aunque existan datos electroclínicos sugestivos de epilepsia, la resistencia al tratamiento específico justifica descartar otros diagnósticos, en ocasiones tan singulares como el de este paciente (AU)

Cortical hyperexcitability is cortical under-inhibition: evidence from a novel functional test of migraine patients.

Recent studies of the visual cortex in patients with migraine have generally concluded that migraine (particularly migraine with aura) is associated with a state of functional cortical hyperexcitability. The mechanisms giving rise to this hyperexcitability have hitherto been unclear. This paper reports two studies that used a novel investigative technique, derived from basic research in vision science, to examine specific deficits of inhibitory processing in primary visual cortex. The technique is termed the metacontrast test, and it examines visual masking under highly specified conditions. In Study 1, 12 migraine with aura patients (MA), 12 age-matched migraine without aura patients (MO) and 12 age- and sex-matched headache-free control subjects (C) were compared using the metacontrast test. MA patients were significantly less susceptible to visual masking in the metacontrast test than both MO and C groups: this result is highly consistent with a deficit in cortical inhibitory processing in MA patients. Study 2 examined MA patients taking a variety of migraine prophylactics, again using the metacontrast test. Test results normalized in those MA patients taking sodium valproate, but not in those taking other prophylactics. Sodium valproate is a GABA-A agonist that is known to cross the blood-brain barrier: GABA-ergic networks act as the primary inhibitory mechanism in visual cortex. Taken together, the results of these studies argue that cortical hyperexcitability, at least in MA patients, is likely to be a result of deficient intracortical inhibitory processes.

[Abdominal migraine in adults]. / Migrena brzuszna u doroslych.

A case of a 35-year-old woman with abdominal migraine is presented. For four years she had been suffering from abdominal pains occurring only at night, always between 1 and 3 a.m. The patient always woke with abdominal pains and nausea. Each time she had diarrhoea and vomited and found that this gave her relief from the pain. Sometimes she lost consciousness for 1-2 minutes. After the attack she felt very weak, her legs and feet became numb and she found it difficult to get to sleep. The attacks and the fainting fits increased in frequency until she had several a month. Numerous gastrological examinations did not reveal any deviations from the normal. At the anti- epileptic consulting unit, abdominal epilepsy was excluded (no abnormalities were found in the eeg and CT examinations of the cranium). As a child she had paroxysmal abdominal pains. When the patient was 10 years old, she had an attack lasting one week and though the pain was severe on the left side, appendectomy was performed. Her mother suffers from migraine with very severe head pains. The patient was referred to our consulting unit where she was treated with Pizotifen in doses of 0.5 mg morning and noon and 1 mg in the evening for three months during which time she had no attacks. A few weeks after discontinuing this treatment, the nocturnal attacks again occurred though the pains were not so severe. She was then prescribed Nitrendipine, 5 mg nightly, and the attacks ceased. However, the patient said that she had felt better when taking Pizotifen.