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Background: Migraine is a common cause of primary headaches that may interfere with normal daily activities for which different modalities of treatment had been used. In the present study different types of analgesics and prophylactic medications had been evaluated for their efficacy and tolerability. Objective: To evaluate the efficacy and tolerability of: 1. Combined analgesic, Excedrin (aspirin with paracetamol and caffeine) in comparison with single analgesic, diclofenac, as a therapy for severe migraine attack. 2. Combined prophylactic, amitriptyline, or propranolol with pizotifen in comparison with pizotifen alone as prophylactic drugs for severe migraine. Materials & Methods: Part (1): 80 patients with severe migraine were enrolled and randomly assigned to receive an oral tablet of either Excedrin (aspirin 250 mg, acetaminophen 250mg, caffeine 65mg) four times daily when needed (n=40) or diclofenac 50mg twice daily when needed as abortive treatment for migraine attack, in addition to the use of pizotifen twice a day in both subgroups for 10 days duration. Part (2): 46 patients who showed good response from part one of the study were divided randomly into three subgroups with different prophylactic regimens. 1. oral pizotifen 0.5mg tablet twice a day, n=16. 2. oral pizotifen 0.5mg twice a day with propranolol 20mg tablet twice a day, n=15. 3. oral pizotifen 0.5mg tablet twice a day with amitriptyline 10mg tablet once at night. n=15. Efficacy was assessed by determining the patients' number exhibiting improvement with no or mild headache. Tolerability is no or minimal side effects or interactions. Results: Part (1): A good response to treatment was obtained in 30% of the diclofenac group vs 85% of the Excedrin group (P<0.01). Part (2): A good response to treatment was obtained in 33.3% of the pizotifen group vs 60% of pizotifen with propranolol group (P< 0.05) vs 87.5% of pizotifen with amitriptyline group (P< 0.01). Conclusion: Combined medications are more effective than single medications in the treatment & prophylaxis of severe migraine. [ABSTRACT FROM AUTHOR]

Purpose: Abdominal migraine (AM) is a very common functional gastrointestinal disorder in children. This study reports the clinical features and response of AM to prophylactic treatment in children. Methods: This retrospective study was conducted between January 2010 and December 2019 at the Royal Hospital in the Sultanate of Oman. This study included children aged ≤ 13 years with a diagnosis of AM based on the Rome IV criteria for functional diagnoses. Clinical, demographic, and treatment data were collected. Results: Seventy-four children were identified, of which 43 were eligible for inclusion in this study. The median age at the onset of symptoms was 7 years (range, 2-12 years). The most frequent symptoms were headache (81.4%), nausea (79.1%), and vomiting (72.1%). Of the total cohort, 46.5%, 23.3%, and 6.9% received riboflavin, pizotifen, and propranolol monotherapy, respectively. Combination therapy was also used; 16.3% of children received pizotifen and propranolol, 4.7% received riboflavin and pizotifen, and 2.3% received riboflavin and propranolol. Patients treated with propranolol monotherapy showed 100% clinical improvement and those treated with riboflavin or pizotifen monotherapy showed 90% clinical improvement. Response to combination therapy with pizotifen and propranolol was 71.4%, and with riboflavin and pizotifen was 100%. In addition, treatment response was significantly associated with the presence of vomiting ( p=0.039). Conclusion: We found a favorable response to various modalities and combination treatments with riboflavin, pizotifen, and propranolol in children with AM. In addition, the presence of vomiting may predict treatment response. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Arterial blood pressure (BP) is regulated by a complex network of peripheral and central (brain) mechanisms. Research suggests that gut bacteria-derived compounds may affect the circulatory system. We evaluated hemodynamic effects of indole, a gut bacteria-derived product of tryptophan, and indoxyl sulfate (indoxyl), a liver metabolite of indole. BP and heart rate (HR) were recorded in anesthetized, male, Wistar rats at baseline and after the administration of either a vehicle, indole, or indoxyl into the femoral vein (IV) or into the lateral ventricle of the brain (ICV). Besides, we evaluated the effect of pretreatment with flupentixol, a non-selective D 1 , D 2 , α 1 and 5 HT 2A receptor blocker; pizotifen, a non-selective 5-HT 1 , 5-HT 2A and 5HT 2C receptor blocker; and ondansetron, a 5-HT 3 blocker, on hemodynamic responses to indole and indoxyl. Vehicle infused IV and ICV did not affect hemodynamics. Indole administered IV produced a dose-dependent increase in BP but not HR. In contrast, the ICV infusion of indole produced a decrease in BP and HR. Indoxyl infused IV produced an increase in BP and HR, whereas indoxyl infused ICV did not affect BP and HR. The hemodynamic effects of indole and indoxyl were inhibited by pretreatment with ondansetron and pizotifen but not flupentixol. In conclusion, indole and indoxyl sulfate affect arterial blood pressure via peripheral and central mechanisms dependent on serotonin signalling. We propose that indole and indoxyl sulfate may be mediators in the interaction between gut bacteria and the circulatory system. [ABSTRACT FROM AUTHOR]

The aim of this study was to develop and evaluate a transdermal delivery system of pizotifen malate. Pizotifen is frequently used in the preventive treatment of migraine, but is also indicated in eating disorders. In the course of the project, the effects of chemical enhancers such as ethanol, 1,8-cineole, limonene, azone and different fatty acids (decanoic, decenoic, dodecanoic, linoleic and oleic acids) were determined, first using a pizotifen solution. Steady state flux, diffusion and partition parameters were estimated by fitting the Scheuplein equation to the data obtained. Among the chemical enhancers studied, decenoic acid showed the highest enhancement activity, which seemed to be due to the length of its alkyl chain and unsaturation at the 9th carbon. The influence of iontophoresis and the involvement of electrotransport in said process was determined. The absorption profile obtained with iontophoresis was similar to that obtained with fatty acids and terpenes, though skin deposition of the drug was lower with the former. Transdermal delivery systems (TDS) of pizotifen were manufactured by including chemical enhancers, decenoic acid or oleic acid, and were subsequently characterized. When the results obtained with solutions were compared with those obtained with the TDS, a positive enhancement effect was observed with the latter with respect to the partitioning and diffusion of the drug across the skin. Our findings endorse the suitability of our TDS for delivering therapeutic amounts of pizotifen malate. [ABSTRACT FROM AUTHOR]

A new simple, rapid, and sensitive stability-indicating high-performance liquid chromatography method has been developed and validated for the simultaneous determination of pizotifen, methylparaben, propylparaben, and synthesis impurities A and B of pizotifen in syrup. The separation of these compounds was achieved within 14 min on a Waters X-terra RP18 column using an isocratic mobile phase consisting of acetonitrile/tetrahydrofuran/potassium dihydrogenophosphate 0.1 M at pH 3.5 containing 4.59 mM heptane sulfonate (38:1.5:62, v/v/v). The analysis was performed at a flow rate of 1 mL min−1and a detection wavelength of 220 nm. The selectivity, linearity, and calibration range, accuracy, within and between-days precision, limit of detection and quantification, and recovery were examined as part of method validation. Forced degradation showed that pizo does not undergo degradation under heat, acidic, and basic conditions, but that it was susceptible to oxidation with first-order kinetic degradation. Liquid chromatography coupled with mass spectrometry was used to analyze the degraded samples and tentative structural identification were assigned based upon known reactivity of the drug and molecular weight measurements. [ABSTRACT FROM AUTHOR]

Abstract: Propranolol is a non-selective beta-adrenergic receptor blocker used in the treatment of cardiovascular diseases and migraine prophylaxis. Although it has been shown that propranolol dilates the peripheral arteries of rat, its action in the central nervous system vasculature has not been investigated. In this study, the effects of propranolol in rat basilar artery were investigated. Basilar arteries from male Wistar rats were examined in a myograph system. The relaxant effects of propranolol, pindolol, atenolol, pizotifen and methysergide were examined in basilar arteries precontracted by serotonin or PGF2α. Only propranolol and pizotifen induced vasorelaxations; the pD2 values were 5.23±0.13 and 5.94±0.03; respectively. The vasorelaxation induced by propranolol and pizotifen was not affected by endothelium or the presence of l-NOARG and/or indomethacin. The calcium channel blocking activity of propranolol and pizotifen was compared with that of nifedipine in a calcium free solution with high K+ (60mM) concentration. These drugs shifted the concentration–response curves of calcium induced contractions with pA2 values of 5.45±0.04; 7.14±0.09; and 9.22±0.06 respectively. The P2Y receptor agonist UTP was used to induce sustained and stable contractions in basilar artery segments. Nifedipine caused a marked, but an incomplete relaxation. Cyclopiazonic acid, an inhibitor of sarcoplasmic reticulum calcium channels, but not propranolol or pizotifen abolished the remaining tonus after partial relaxations obtained with nifedipine. These results suggest that propranolol causes vasorelaxation by blocking the L-type voltage-gated calcium channels in the rat basilar artery. [Copyright &y& Elsevier]

• Intrathecal 5-HT2R antagonist pizotifen alleviates neuropathic pain and inflammatory pain. • The antihyperalgesic effect of pizotifen derived from enhanced GABAergic inhibition. • Pizotifen affect motor performance weakly without sedative activity. 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 GABA A R 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. [ABSTRACT FROM AUTHOR]

Abstract: MDMA (N-methyl-3,4-methylenedioxyamphetamine) produces a discriminative stimulus (DS) effect in animals, but attempts to completely block this action with selective neurotransmitter antagonists have not been very successful. Biochemically, MDMA can increase synaptic levels of serotonin, dopamine, and norepinephrine that, conceivably, might interact with multiple populations or subpopulations of neurotransmitter receptors. The present study attempted to antagonize the DS effects of MDMA using the nonselective agents clozapine, cyproheptadine, and pizotyline. An extensive and comparative radioligand binding profile was also obtained for the latter two agents. The purported antagonists were administered in combination with the training dose of MDMA to groups of Sprague–Dawley rats trained to discriminate 1.5 mg/kg of MDMA from saline vehicle in a standard two-lever operant paradigm using a VI-15s schedule of reinforcement. Clozapine was without effect at the doses evaluated, and cyproheptadine only partially attenuated MDMA-appropriate responding. In contrast, pizotyline (AD50 =2.5 mg/kg), in combination with the MDMA training dose, resulted in a dose related decrease in percent drug-appropriate responding to saline levels. In a separate group of animals trained to discriminate the structurally-related agent N-methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA) from vehicle, pretreatment with pizotyline also resulted in a substantial decrease in drug-appropriate responding. The results with cyproheptadine and pizotyline in the binding assays confirmed that these agents display high affinity for multiple subpopulations of serotonergic, dopaminergic, adrenergic, histaminergic, and cholinergic receptors. The overall results of the present investigation indicate that pizotyline, which is clinically available in some countries, might be of clinical utility in the treatment of MDMA overdose. [Copyright &y& Elsevier]

Migraine is common during pregnancy, but fortunately this combination of conditions obviously exists for only a finite period. The greatest frequency of migraine attacks occurs during the first trimester. Accurate diagnosis is a sine qua non in this setting as in any headache patient. It is in the first trimester that the fetus is at greatest risk from abortifacient and teratogenic drugs, and when very early pregnancy may be undiagnosed. Ergot alkaloids (including methysergide) should be avoided during pregnancy because of their teratogenicity, and most other drug classes should be used only when unavoidable. The use of prophylactic agents during pregnancy should be the exception, not the rule, and preferably only during the second and third trimesters; propranolol is probably safest in this situation. De novo headache during pregnancy usually requires expert review of the patient. Treatment tactics for uncomplicated migraine in pregnancy depend on the concurrent clinical situation. Paracetamol (acetaminophen) is the mainstay for the patient whose typical attacks continue into the first trimester. If paracetamol is insufficient, then partial agonist opioids may be used if typical migraine attacks persist in the second and third trimesters (which is uncommon). 'Chronic migraine' in pregnancy, i.e. >or=15 headache days per month, is rare, and is the greatest therapeutic challenge. Co-morbidities such as depression or epilepsy require specialised approaches. The complexities associated with these tactics are discussed in this article, and it is emphasised that none has the specific approval of regulatory authorities. Heightened pharmacovigilance will better inform the future pregnant migraineur. However, this type of information is less likely to be available for novel classes of neuropharmacological agents than for existing ones. [ABSTRACT FROM AUTHOR]

Abstract: The photostability of selected benzocycloheptane antihistaminic agents, namely, loratadine (I), pizotifen (II), ketotifen fumarate (III) and cyproheptatidine (IV), was investigated. Both I and II were photolabile while III and IV were photostable. To perform stability studies on the photolabile compounds (I and II), specific stability-indicating high performance liquid chromatographic (HPLC) methods were established. The accuracy, precision and reliability of the developed HPLC methods for the assay of I and II in their pharmaceutical dosage forms were reported. Assay results for both drugs were within R.S.D. values <2%. The stability-indicating power of the developed methods was validated through study of UV-degraded solutions of I and II contained in quartz cells. The photostability of both drugs was studied under UV-irradiation at 254nm. The photodegradation kinetics of both drugs, studied in different solvents, are also reported. TLC fractionation of photodegraded solutions of both drugs, revealed two fluorescent photodegradates of drug I. The use of UV-absorbers (ascorbic acid and p-aminobenzoic acid (PABA)) enhanced the photostability of both drugs possibly through a spectral-overlay effect. [Copyright &y& Elsevier]

We report a case of a teenage boy with cyclical vomiting syndrome (CVS) who was referred to the anesthesia-run postoperative pain service for symptom management. His symptoms were uncontrolled by oral pizotifen prophylaxis and acute therapy with intravenous (IV) hydration and ondansetron. A continuous low dose IV midazolam infusion was added to his treatment regimen (as is instituted for recalcitrant postoperative nausea and vomiting) with benefit, but not total symptom resolution. Recent literature review suggested links between migraine, CVS and adrenergic autonomic dysfunction. Consequently, IV clonidine was administered, in addition, with recovery. This combination was reinstituted successfully on subsequent admissions and emergency department presentations with shortened episode durations from 4–5 days to 16–48 h. It is uncertain if clonidine's sympatholytic effects were significantly beneficial or if associated sedation or natural resolution were contributors. Many agents have been used in CVS therapy but no trials have been done. Neither midazolam nor clonidine has been reported previously as used in the treatment of CVS. The apparent success of this combination raises possibilities both for future trials and research into the pathogenesis of CVS. [ABSTRACT FROM AUTHOR]

Analytical validation of a new liquid chromatographic–mass spectrometric (LC–MS) method for determination of total amount of ketotifen (unchanged and conjugated) in human plasma is presented. Pizotifen was used as an internal standard. An enzyme hydrolysis of conjugated ketotifen was conducted with a combination of β-glucuronidase and aryl sulfatase. After enzyme hydrolysis a liquid–liquid extraction was performed as a cleaning step. The quantitative determination was obtained using selected ion monitoring (SIM) LC–MS. Chromatographic condition was a combination of reverse phase gradient system and a switching column technique. A satisfactory hydrolysis, acceptable accuracy, improved precision in the linear range from 0.5 to 20.0 ng/ml plasma, absolute recovery of 98.04% for ketotifen and 95.13% for pizotifen and stability for 7 months at −20 °C have been achieved. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]