A rare case of migrainous left bell抯 palsy after migrainous right external ophthalmoplegia - A case report

Migraine increased the risk of Bell palsy in the total population. Among migraine patients, between ?30 and <60 years old are at an increased risk of Bell palsy. A migraine is a primary headache characterized by recurrent headache attacks triggered by various factors. As much as 10% of the global population is thought to experience migraine headaches. It was earlier considered that migraine headaches were triggered by the dilation of cerebral vessels, and the recent evidence supports that migraine attacks can also occur in the absence of vasodilation. According to the researchers, the direct neural effects from the trigeminal nerve to the facial nerve could contribute to the risk of facial palsy among patients with migraine. An alteration of the trigeminovascular function has been suggested to trigger migraines. The neurogenic inflammation of the facial nerve trunk caused by its proximity to the dilated posterior auricular/ stylomastoid/ occipital and superficial temporal arteries during a migraine attack leads to a temporary lower motor neuron type of paresis of the muscles supplied by the facial nerve. We herewith report a rare case of migrainous left Bell抯 palsy after migrainous right external ophthalmoplegia, treated with Sumatriptan.

Clinical observation on the treatment of Middle-Aged Chronic Migraine with Qiye Shenan tablet and Sumatriptan / 中国生化药物杂志

Objective To observe the clinical effect of Qiye Shenan tablet combined with sumatriptan in the treatment of middle-aged and elderly patients with chronic migraine.MethodsA total of 124 elderly patients with chronic migraine treated in our hospital from July 2015 to December 2015 were selected.The patients were divided into two groups according to the principle of randomization, with 62 cases in each group.The control group was treated with sumatriptan, The observation group was treated with Qiye Shenan tablet on this basis.The curative effect of the two groups, the relevant indicators and adverse reactions were analyzed.ResultsThe effective rate was 95.16% in the observation group, which was higher than that in the control group (80.65%, P<0.05).After treatment, the VAS score and the main symptom scores of the observation group were (1.86±0.42,3.48±0.59), respectively, which were lower than those in the control group (3.19±0.50,5.06±0.64) (P<0.05).The level of nitric oxide (NO) in the observation group was (33.04±3.86)μmol/L, which was lower than that in the control group (40.92±4.28)μmol/L(P<0.05).The adverse reaction rate was 11.29% in the observation group, which was lower than that in the control group (17.74%), but there was no significant difference between the two groups.ConclusionQiye Shenan tablet can improve the therapeutic effect of chronic migraine in the elderly, reduce the pain of the patients and improve the related symptoms, and the safety of medication.

Determination of sumatriptan in human plasma using liquid chromatography-mass spectrometry for pharmacokinetic study in healthy Korean volunteers

This study describes the development of an analytical method to determine sumatriptan levels in human plasma using high performance liquid chromatography (HPLC) coupled with triple quadrupole tandem mass spectrometry (MS/MS) and its application to a pharmacokinetic study in healthy Korean volunteers. A single 50 mg dose of sumatriptan was orally administered to twelve healthy volunteers (nine women and three men). The HPLC-MS/MS analytical method was validated with respect to its specificity, linearity, sensitivity, accuracy, precision, recovery, and stability. The calibration curve was linear over a concentration range of 0.3–100 ng/mL (r > 0.999). The lower limit of quantitation for sumatriptan in plasma was 0.3 ng/mL. The accuracy and precision of the analytical method were acceptable within 15% at all quality control levels. We compared plasma concentration-time curves as well as pharmacokinetic parameters such as the area under the curve (AUC) and maximum plasma concentration (C(max)). Both the mean AUC and C(max) of sumatriptan were 1.56 times higher in women than in men. These differences could be largely explained by the difference in body weight (44%) between women and men. The outcomes may provide insights into developing appropriate individualized treatment strategies.

Stability Indicating RP-HPLC Method Development and Validation for the Estimation of Sumatriptan in Bulk and Pharmaceutical Dosage Form.

A simple, highly sensitive stability indicating reverse phase high-performance liquid chromatographic (RP-HPLC) method was developed and validated for the determination of sumatriptan succinate in bulk and tablet dosage form. The analysis was performed on reverse phase C18 ODS Inertsil (250×4.6mm, 5μm) column, with a mobile phase containing buffer: aetonitrile: methanol (80:10:10 v/v/v), pH was adjusted to 2.5 with orthophosphoric acid (OPA) at 221nm, by an isocratic elution mode with 1ml/min flow rate using photo diode array (PDA) detector at ambient temperature. The injection volume and retention time was found 20 μl and 4.4 minutes respectively. The method produced linear responses in the concentration range of 5-150 μg/ml, with a correlation coefficient of 0.999. The limit of detection (LOD) and limit of quantification (LOQ) values for HPLC method were found to be 1.967 and 5.961 μg/ml respectively. The recovery of the method was 98% of the labelled value. This method was validated for accuracy, precision, linearity and robustness. Sumatriptan subjected to different ICH prescribed stress conditions of acid, alkali, peroxide, reduction, thermal, photolytic and humidity degradation. This method can easily and conveniently take up for routine quantitative analysis of sumatriptan in bulk and pharmaceutical dosage form by easily available materials with low cost.

Population pharmacokinetic analysis of the multiple peaks phenomenon in sumatriptan

The objective of this study was to develop a population pharmacokinetic (PK) model for sumatriptan, which frequently shows an atypical absorption profile with multiple peaks. Sumatriptan, a selective agonist for the vascular serotonin (5-HT1) receptor that causes vasoconstriction of the cerebral arteries, is used for the acute treatment of migraine attack with or without aura. Despite its relatively high between-subject variability, few reports have addressed PK modeling of sumatriptan. Plasma data obtained after a single 50-mg oral dose of sumatriptan in 26 healthy Korean male subjects were used. Blood samples were collected 0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 12 h after dosing. Plasma sumatriptan concentrations were analyzed using UPLC/MS/MS. Population PK analysis was performed using plasma concentration data for sumatriptan with NONMEM (ver. 7.2). A total of 364 concentrations of sumatriptan were captured by a one-compartment model with first-order elimination, and a combined transit compartment model and first-order absorption with lag time was successful in describing the PK with multiple peaks in the absorption phase of sumatriptan. The creatinine clearance as a covariate significantly (P < 0.01) influenced the absorption fraction (f ). The final model was validated through a visual predictive check and bootstrapping with no serious model misspecification.

Formulation and Evaluation of Oral Elementary Osmotic Pump Tablets of Sumatriptan Succinate.

Aim: In the present study, Sumatriptan succinate was formulated as oral elementary osmotic pump with a zero-order drug release profile. Methodology: The effect of different formulation variables i.e. different types of osmogens, concentrations of osmogen and concentration of coating solution were studied. The in vitro evaluation was carried out in different release media. Result: Highest percentage of drug release was observed at high concentration of mannitol i.e., 1:3 (drug: mannitol). Osmogen with low osmotic pressure (38 atm) showed 71.01% zero-order drug release for 12 hours when compared to that of the osmogen with high osmotic pressure (356 atm) which showed 67.38% of release by zero order. Conclusion: Elementary osmotic pump tablets of Sumatriptan succinate were able to deliver zero-order release up to 12 hours independent of pH of dissolution media and have overcome the problem of chronotherapeutic effect.

Effect of formulation parameters on Sumatriptan succinate Buccal Mucoadhesive Tablet: Quality by Design approach.

The present investigation was focused on application of QbD approach to see the effect of formulation variables on buccal mucoadhesive tablets containing anti migraine drug, Sumatriptan succinate to circumvent the first pass effect and to provide sustained release. Risk assessment of critical material and process parameters are linked to critical quality attributes (CQAs) of the product with respect to obtain total quality product profile (TQPP). The effect of critical parameters (polymer: drug ratio, carbopol: HPMC E5 ratio and diluent quantity) were investigated by executing design of experimentation (DoE) using Box-Behnken statistical model. DR10 hr (drug release after 10 hrs), mucoadhesive strength and mucoadhesion time were considered critical quality attributes (CQAs). Sumatriptan succinate buccal mucoadhesive (SBM) tablets were prepared by direct compression method and were evaluated as per pharmacopoeia procedure. Multiple regression analysis and ANOVA were employed to identify and estimate the effect of important parameters and establish their relationship with CQAs and to obtain design space for optimization purpose. The best in-vitro drug release profile, mucoadhesive strength, mucoadhesion time and desired product quality was achieved with the formulation prepared in the region of design space. FDS graph, 3D response graph and Overlay plot were successfully implemented to interpret effects and selection of significant parameters on CQAs. Hence, it can be concluded that formulation parameters affects the SBM tablet and can be successfully optimized using the QbD a novel approach resulting into the SBM tablets which could provide sustained effect and avoid first pass effect.

Cluster Headache.

Cluster headache causes severe unilateral temporal or periorbital pain, lasting 15 to 180 minutes and accompanied by autonomic symptoms in the nose, eyes, and face. Headaches often recur at the same time each day during the cluster period, which can last for weeks to months. Some patients have chronic cluster headache without remission periods. The pathophysiology of cluster headache is not fully understood, but may include a genetic component. Cluster headache is more prevalent in men and typically begins between 20 and 40 years of age. Treatment focuses on avoiding triggers and includes abortive therapies, prophylaxis during the cluster period, and long-term treatment in patients with chronic cluster headache. Evidence supports the use of supplemental oxygen, sumatriptan, and zolmitriptan for acute treatment of episodic cluster headache. Verapamil is first-line prophylactic therapy and can also be used to treat chronic cluster headache. More invasive treatments, including nerve stimulation and surgery, may be helpful in refractory cases.

Development and Evaluation of Mouth Dissolving Films of Sumatriptan Succinate for Better Therapeutic Efficacy.

The present investigation was undertaken with an objective of formulating mouth dissolving films (MDFs) of an anti-migraine drug, Sumatriptan Succinate (SUM) to enhance convenience and compliance to the elderly and pediatric patients for better therapeutic efficacy. Film former, Hydroxy Propyl Methyl Cellulose along with film modifier/solubilizing agents, Polyvinyl pyrrolidone K30 (PVP K30) and Sodium Lauryl Sulphate (SLS) were used to formulate MDFs. The MDFs were prepared by wet film applicator technique and were evaluated for in vitro dissolution characteristics, in vitro disintegration time, and their physico-mechanical properties. MDFs with 13% (w/w) of HPMC E5 gave better dissolution properties when compared to HPMC E15. MDFs with PVP K30 and SLS gave superior dissolution properties when compared to MDFs without PVP K30 and SLS. The dissolution properties of MDFs with PVP K30 were superior when compared to MDFs with SLS. Overall, SUM MDFs showed good mechanical properties like tensile strength, folding endurance and % elongation and dissolution properties. These results suggest that the HPMC is an excellent film former which gives rapid drug release.

Sumatriptan down-regulates calcitonin gene-related peptide expression via extracellular signalregulated 1/2 and c-Jun N-terminal kinase signaling transduction pathways in rat trigeminal ganglion after organ culture / 中华神经科杂志

Objective To explore the effects of sumatriptan on the modulation of calcitonin generelated peptide(CGRP) expression and its involving intracellular signaling transduction mechanisms in rat trigeminal ganglion(TG) after organ culture.Methods Using organ culture in vitro model,54 isolated TGs of SD rats were randomly divided into fresh group ( n =6 ),control group ( n =6 ) and experimental group (n =42,6 TGs for each subgroup).Experimental group included seven subgroups,which were respectively pretreated with four different concentrations of sumatriptan,specific inhibitors of extracellular signalregulated kinases 1/2 (ERK1/2) pathway (U0126 and PD98059 ),and the inhibitor of c-Jun N-terminal kinase (JNK) (SP600125).After co-cultured with above intervention agents for 24 h,CGRP-immunoreactivity (CGRP-ir) positive neurons and CGRP-mRNA expression levels were quantified by immunohistoehemistry stain and real-time polymerase chain reaction,respectively.Phosphorylated ERK1/2 (pERK1/2) and JNK (pJNK) proteins levels were determined by Western-blotting method.Results The CGRP-ir ( + ) neurons expression levels were significantly increased after 24 h organ culture.However,0.10 and 0.50 mg/ml concentrations of sumatriptan remarkably decreased the CGRP-ir ( + ) neurons expression levels.The positive cell percentage,positive optic area,integrated optical density,mean optical density and CGRP-mRNA expression level in TG were significantly reduced than control groups (tPCP =8.652,26.382; tarea =6.220,13.917; tIA =5.606,15.904; tM14 =2.661,21.748; tmRNA =8.032,15.675.P ＜ 0.05 ).The CGRP-mRNA expressions were significantly down-regulated after co-incubation with concentration of 0.50 mg/ml sumatriptan for 24 h in TG of SD rat ( P ＜0.05 ).The levels of pERK1/2 and pJNK protein kinase detected by Western-blotting were significantly reduced by 0.50 mg/ml concentration of sumatriptan,the degrees of which were closed to the ERK1/2 and JNK pathway specific blockers.Conclusion It suggests that the optimal concentration of sumatriptan significantly down-regulates CGRP over-expression via intracellular ERK1/2 and JNK signaling transduction pathways in TG after organ culture.

Estimation of sumatriptan succinate in bulk and formulations by visible spectrophotometry using aromatic aldehydes.

Two simple and sensitive visible spectrophotometric methods (A and B) have been developed for the determination of sumatriptan succinate in bulk and tablet dosage forms. Methods (A and B) are based on the reaction of drug with aromatic aldehydes such as Vanillin or Para dimethyl amino cinnamaldehyde(PDAC) in the presence of sulphuric acid in non aqueous medium and formed purple red colored condensation products with an absorption maximum of 565nm for method A and 560nm for method B. The Beer’s law obeyed in the concentration range of 10-50μg/ml for method A and 20-60μg/ml for method B. The proposed methods are applied to commercial available tablets and the results are statistically compared with those obtained by the reference method and validated by recovery studies.

Comparative Efficacy and Tolerability of Sumatriptan, Ergotamine, Naproxen and Rizatriptan in Moderate to Severe Acute Attack of Migraine.

A double-blind, randomized, parallel study was done to compare sumatriptan, ergotamine, naproxen and rizatriptan in 40 outpatients treating a single migraine attack of moderate to severe intensity. Among these groups, significantly more number of patients had headache relief at 2 hours postdose in naproxen and rizatriptan group as compared to ergotamine. Naproxen, rizatriptan and sumatriptan were better than ergotamine in causing freedom from the associated symptoms of nausea, vomiting, photophobia and phonophobia at 2 hour postdose. Naproxen, rizatriptan and sumatriptan were also efficacious in causing functional normalization at 2 hours postdose as compared to ergotamine. The overall results of the study suggest that naproxen is as efficacious as triptan group of drugs but better than ergotamine group in treatment of moderate-severe acute migraine attack. It is more cost effective than triptans and also a well tolerated drug.

The influence of NF-κB protein expression in the periaqueductal gray matter induced by sumatriptan in migraine animal model / 中华神经科杂志

Objectiye To investigate the possible mechanism of sumatriptan in treating migraine.Methods Migraine model rat was electrically stimulated at cerebral dura mater in superior sagittal sinus (SSS) to induce migraine.Each of 10 male SD rats were randomly selected into groups of normal control (no intervention), pseudo-stimulation group ( no electrical stimulation), stimulation group ( no treatment after stimulation), saline group (treated with saline after migraine stimulation ) and sumatriptan group ( treated with sumatriptan after migraine stimulation).The neurons expressing NF-κB in periaqueductal gray matter (PAG) were evaluated in each group by immnunostaining.Results The numbers of NF-κB immunoreactive positive neurons were 179.5 ± 14.9 in sumatriptan group, 497.8 ± 20.6 in saline group,508.7 ± 30.8 in stimulation group, 112.9 ± 10.7 in pseudo-stimulation group and 111.7 ± 15.7 in normal group.The stimulation group was higher than normal group, pseudo-stimulation group and sumatriptan group (F=944.78, P <0.05).Conclusions The NF-κB positive neurons were activated in the PAG by electric stimulation of the dura mater near the SSS.Sumatriptan can reduce the expression of NF-κB protein.

A Case of Vasospastic Angina Pectoris Occurring Following Administration of Oral Imigran(R) for Migraine

Imigran(R) (sumatriptan), a 5-hydroxytryptamine (HT) derivative, is highly effective in aborting attacks of migraine and cluster headache. The drug is generally well tolerated. However tolerated, although up to 8% of patients consistently have demonstrate chest symptoms, including chest pressure, tightness, and pain, often mimicking angina pectoris. It has been suggested that these chest symptoms are caused by coronary vasoconstriction, and that this effect may be mediated by endothelial dysfunction. This can be reversed by the administration of glyceryl trinitrate. We report a case of vasospastic angina pectoris occurring after the administration of oral sumatriptan in a patient with migraine.

A Case of Cyclic Vomiting Syndrome Improved by Sumatriptan / 대한소화관운동학회지

Cyclic vomiting syndrome is a rare disorder characterized by recurrent, prolonged episodes of severe nausea and vomiting with no apparent cause. The vomiting is self-limited and patients have asymptomatic periods of variable duration between episodes. This affects mainly in infancy and childhood, but some cases in adulthood were rarely reported. Cyclic vomiting syndrome remains poorly understood, but shares some of the same features as abdominal migraine and migraine. It seems to have a relationship of biochemical or neuraphysiological mechanism based on brain-gut interaction and some of hormonal disturbance. We describe the case of a 24-year-old female patient with several years history of recurrent episodes of severe vomiting diagnosed as cyclic vomiting syndrome. The patient was treated by sumatriptan and ceased vomiting dramatically. Gastric emptying time and electtogastrogram at the time of stopped vomiting revealed marked gastroparesis and follow-up test during prophylactic therapy in symptom-free interval was found to be normalized.

Responses of Trigeminal Ganglion Neurons to Electrical and Mechanical Stimulation of the Middle Meningeal Artery, Superior Sagittal Sinus and Transverse Sinus in Rats

The intracranial blood vessels of the dura and the pia receive sensory afferent innervations from trigeminal nerve which has been believed to play a critical role in the mediation of vascular headache such as migraine. The purpose of this study was to discover the mechanism by which the interaction between trigeminal ganglion neurons and the function of cerebral blood vessels. Using electrophysiological recording, we studied the responses of trigeminal ganglion neurons to electrical stimulation of middle meningeal artery(MMA), superior sagittal sinus(SS) and transverse sinus(TS) in rats. Sumatriptan is a highly selective agonist for 5-HT1D receptor subtype which mediates vasoconstriction of cerebral blood vessels. We observed responses to electrical stimulation in trigeminal ganglion neurons and meningeal blood flow(MBF) after intravenous injection of sumatriptan. The results were as follows: 1) The presumed mean conduction velocities of the cells activated MMA, SS and TS by electrical stimulation were approximately 1.5, 2.9 and 2.9m/s, respectively. These were presumed to be nociceptive small myelinated or unmylinated sensory fibers. 2) The action potential discharges of trigeminal ganglion neurons on MMA, SS and TS in the experimental control groups were 671+/-39.49, 856+/-63.95 and 494+/-21.54microV, respectrely. The action potential discharges of sumatriptan groups on MMA, SS and TS(393+/-20.10, 562+/-32.26 and 262+/-18.94microV, respectively) were significantly decreased compared to that of the experimental control groups. 3) The mean MBF of normal control group was 63.29+/-7.54ml/100g/min. The mean MBF of the experimental control groups on MMA, SS and TS were 97.13+/-9.91, 104.28+/-12.54 and 91.82+/-6.41ml/100g/min, respectively(p<0.05). MBF of sumatriptan group before stimulation was significantly decreased(compared to normal: 37.17+/-4.76ml/100g /min vs 63.29+/-7.54ml/100g/min). The mean MBF of sumatriptan groups on MMA, SS and TS were 57.11+/-4.48, 66.56+/-6.23 and 56.07+/-5.00ml/100g/min, respectively. Compared to that of the experimental control groups, the MBF of the sumatriptan groups were significantly decreased. In conclusion, the activation of trigeminal sensory afferents by the electrical stimulation of the dural vessel may create vasodilatation and increase cerebral blood flow which may lead to vascular headaches via trigeminal ganglion to brain stem This pathway can be important for understanding the neural mechanism for the development of pharmacological and surgical approach to alleviate vascular headache.

A Comparative Trial of Oral and Subcutaneous Sumatriptan in Acute Treatment of Migraine: a multicenter trial

BACKGROUND: The efficacy of sumatriptan(SMN) in acute management of migrane has been well established. In Korea, however, a clinical study comparing the utility of oral(PO) and subcutaneous(SQ) regimen had not been conducted yet. This study was directed to compare the two regimens of SMN in terms of the efficacy as well as the adverse events in a singed-out Korea patient group. METHODS: The 91 migrane patients were recruited and randomly assigned to either PO or SQ regimen as the initial treatment of acute migrane attack. Then, they were forwarded to the other regimen as an open cross-over trial. The treatment responses and adverse events were assessed and rated by the subjects. RESULTS: Eighty one patient successfully tried at least one regimen of SMN. Overall, the proportion of excellent treatment response was 90.7%(PO) and 94.1%(SQ), with the occurrence of adverse events being 67.4%(PO) and 76.5%(SQ) respectively. In 18 patients who were able to complete cross-over procedure, the efficacy was 94.4% both in PO and SQ regimen, with the occurrence of adverse events 72.2% in both of two regimen. Although the SQ regimen tends to induce faster treatment response regardless of the cross-over completion, it bears no statistical significance. CONCLUSION: We conclude that the PO and SQ regimens of SMN show very comparable clinical utility in achieving therapeutic responses as well as in producing adverse events. The treatment efficacy was excellent but higher occurrence of side effects in this study, although mostly in mild degree, suggests that optimal dose adjustment strategy needs to be elaborated in Korea.