Enhancing Outpatient Dihydroergotamine Infusion With Interdisciplinary Care to Treat Refractory Pediatric Migraine: Preliminary Outcomes From the Comprehensive Aggressive Migraine Protocol ("CAMP").

OBJECTIVE: To determine preliminary outcomes of a treatment for refractory pediatric migraine that integrates outpatient dihydroergotamine (DHE) infusion with interdisciplinary adjunctive care. BACKGROUND: Limited data are available to inform treatment of refractory migraine in children. Intravenous DHE therapy has shown promise but has been implemented in costly inpatient settings and in isolation of nonpharmacological strategies shown to enhance analgesia and functional improvement. METHODS: We conducted a retrospective chart review of 36 patients ages 11-18 with refractory migraine who underwent a pilot treatment program in an outpatient neurology clinic. The treatment integrated up to 5 days of outpatient DHE infusion with adjunctive nonpharmacological care (pain coping skills training, massage, aromatherapy, and school reintegration support). Changes in headache, healthcare utilization, and functional limitations were assessed as indicators of treatment response through 3-month follow-up. RESULTS: On average, headache intensity declined (M = 5.8 ± 2.5 to M = 2.4 ± 2.7; P < .0001) during the treatment period and remained statistically significantly improved through 3-month follow-up. Headache frequency decreased by a mean of 1.5 days per week (M = 6.7 ± 1.0 vs M = 5.2 ± 2.7, P = .012) through 3-month follow-up, with a 27% reduction (from 0.91 to 0.66) in the proportion of patients reporting a continuous headache (P = .009). Over this same follow-up period, there was a reduction in school days missed per month (median [25th, 75th percentile]: 4.5 [0, 21.0] vs 0 [0.0, 0.5]). There also were reductions in headache-related visits per month to the emergency department and medical providers. Adverse effects were common but typically minor and transient. CONCLUSIONS: Combining outpatient DHE infusion with interdisciplinary adjunctive care has promise as an effective treatment option for adolescents with refractory migraine.

Development and in vitro/in vivo evaluation of dihydroergotamine mesylate loaded maltodextrin-pullulan sublingual films.

Dihydroergotamine mesylate (DHE), ergotamine derivative, has been offered for clinical use to stop or treat symptoms of an emerging migraine as injection for more than a half century. It is shown that bioavailability of DHE greatly changes between the subjects and up to 99% of the orally absorbed dose may be cleared by first pass metabolism. The aim of this study was to design and optimize DHE fast-dissolving sublingual films for migraine treatment. For this purpose pullulan and maltodextrin was chosen as film-forming polymers and propylene glycol as plasticizer. For optimization process Box Behnken design was used. The formed films were free from air bubbles, cuttings, or cracks. Disintegration, mechanical strength and dissolution of films were compared. It is found that pullulan and maltodextrin formed films with the most desired properties at the concentration of 1.5% and 2%. The application of optimum formulation to rabbits showed that bioavailability of formulation is about 23.35% with a tmax 20 min. Due to this fast onset of action and higher bioavailability than oral administration, it is suggested that the polymer combinations of pullulan and maltodextrin formed successful films and were considered as an alternative dosage form for DHE in migraine therapy.

A Systematic Review and Meta-Analysis of Nonpharmacological Interventions for Moderate to Severe Dementia

OBJECTIVE: Due to limited efficacy of medications, non-pharmacological interventions (NPI) are frequently co-administered to people with moderate to severe dementia (PWMSD). This systematic review and meta-analysis investigated the effects of NPI on activities of daily living (ADL), behavioral and psychological symptoms of dementia (BPSD), and cognition and quality of life (QoL) of PWMSD. METHODS: A literature search was conducted in the following databases: Cochrane CENTRAL, EMBASE, Medline, CIHNAL, PsycINFO, KoreaMED, KMbase, and KISS. We conducted a meta-analysis on randomized controlled trials and used the generic inverse variance method with a fixed-effects model to calculate the standardized mean difference (SMD). The protocol had been registered (CRD42017058020).

Effects of Two Music Therapy Methods on Agitation and Anxiety among Patients Weaning off Mechanical Ventilation: A Pilot Study / 기본간호학회지

PURPOSE: The feasibility and differential effects of two music therapy methods (interventions with preferred music vs. classical relaxation music) were done to examine the effects on agitation and anxiety in patients weaning off mechanical ventilation. METHODS: This pilot study was conducted using a crossover design. Six patients listened to preferred music choices and classical relaxation music. Anxiety scores were measured using the Richmond Agitation Sedation Scale (RASS), State-Trait Anxiety Inventory (STAI), and visual analog scale (VAS). RESULTS: Patients showed a significant decrease in agitation and anxiety after both the preferred and classical relaxation music interventions. The difference in the effects of preferred music and that of classical relaxation music was not significant. As for feasibility, patients exhibited a change in agitated behaviors after the music interventions by not trying to take off medical devices and quietly listening to the music, and by smiling and moving lips along with the lyrics while listening. CONCLUSION: Music interventions which centered on either patients' preferences or classical relaxation music to enhance relaxation, helped reduce agitation and anxiety during the mechanical ventilation weaning process.

Effects of Aromatherapy on Agitation in Patients with Dementia: A Systematic Literature Review and Meta-analysis

PURPOSE: The purpose of this study is to identify the effects of aromatherapy on agitation in patients with dementia using a meta-analysis and systemic literature review. METHODS: The EMBASE, CINAHL, MEDLINE, and other databases were searched up to November 2017. RESULTS: Of 419 publications identified, 12 met inclusion criteria, and 9 studies were used to estimate the effect size of aromatherapy. A total of 837 participants across all studies were included. The commonly applied methods were massage (50%), type of oil lavender (75%), and instrument Cohen-Mansfield Agitation Inventory (75%). A medium effect size of aromatherapy on agitation was identified (d=−0.56, I2=65.0%, p=.001). The massage group has lower effect size than the other group (d=−0.98, I2=0.0%, p=.001). CONCLUSION: Aromatherapy appears to be effective in improving agitation in patients with dementia. However, further studies for home-dwelling patients with dementia and with different types of aroma oil should be conducted in the future. In addition, research with well-designed are needed to assess the effects or aromatherapy on agitation.

Acute and chronic triptan exposure neither alters rodent cerebral blood flow nor worsens ischemic brain injury.

Although it is still debated whether vasoconstriction underlies migraine resolution by triptans, they are not recommended in patients at cardiovascular risk. However, relationship between stroke incidence and triptan use is unclear, and it is unknown whether acute or chronic use of these drugs worsens ischemic brain injury. To address this issue, we investigated the effect of clinically-relevant doses of the potent cerebral artery vasoconstrictor eletriptan on cerebral blood flow (CBF) and brain infarct volumes, as well as on expression of genes involved in cerebrovascular regulation. We report that acute treatment of rats or mice with eletriptan did not reduce basal CBF, which promptly dropped upon treatment with prazosin or dihydroergotamine. Acute of chronic (1month) eletriptan also did not affect CBF changes and infarct volumes in mice undergoing brain ischemia/reperfusion. Finally, chronic eletriptan reduced brain mRNAs for PACAP and VIP, leaving unaffected those for 5HT1B/DR and CGRP. No significant transcript changes were found in dura mater. Data suggest that the impact of triptans on cerebral hemodynamic should be re-evaluated, as well as their propensity to increase stroke risk in migraineurs.

In Vitro Metabolism Evaluation of the Ergot Alkaloid Dihydroergotamine: Application of Microsomal and Biomimetic Oxidative Model.

Dihydroergotamine is a semisynthetic natural product derived from ergotamine, an ergot alkaloid. It is used to treat migraines, a neurological disease characterized by recurrent moderate to severe headaches. In this work, the in vitro metabolism of dihydroergotamine was evaluated in a biomimetic phase I reaction, aiming to verify all possible formed metabolites. Dihydroergotamine was submitted to an in vitro metabolism assay using rat liver microsomes, and the metabolites were analyzed by HPLC-MS/MS. The biomimetic reactions were performed with Jacobsen catalyst for scaling up production of oxidized metabolites. Two hydroxylated metabolites were isolated and characterized by MS/MS and 1H NMR analysis.

Severe hyponatremia and seizures after bowel preparation with low-volume polyethylene glycol plus ascorbic acid solution / 영남의대학술지

The widely used polyethylene glycol (PEG)-based solutions have been proven effective for bowel preparation when 4 L of the solution is administered before colonoscopy. However, large volumes of the solutions are generally poorly tolerated. A new PEG-based solution consisting of 2 L of PEG and a high dose of ascorbic acid has recently become available. Electrolyte abnormalities caused by PEG-based solutions have rarely been reported. We report on a case of acute severe hyponatremia with associated generalized tonic-clonic seizures after bowel preparation with a low-volume PEG plus ascorbic acid solution in a 74-year-old woman with no history of seizures. She took a beta blocker, an angiotensin-converting enzyme inhibitor, and glimepiride for hypertension and diabetes mellitus. She showed general weakness, nausea, agitation, muscle cramping, and seizures after ingestion of the PEG plus ascorbic acid solution. Her serum sodium level was 112 mEq/L. Her symptoms improved after intravenous administration of hypertonic saline. Physicians should pay attention to screening for electrolytes and development of neurological symptoms during bowel preparation.

Effect of commercial alcoholic drinks on sound enamel surface of bovine teeth / 대한구강보건학회지

OBJECTIVES: The purpose of this study was to evaluate the change in surface microhardness of sound enamel of bovine teeth due to commercial alcoholic drinks. METHODS: The experiment group comprised of wines, makgeollis, and beers with low pH, while distilled water was used as the control. The two experiment groups were administered soju having the highest (SojuH) and lowest (SojuL) pH. Drinking wines were classified into 2 groups: agitated (wine A) and non-agitated (wine NA) wines. The pH values, buffering capacity, and concentrations of fluorine, calcium, and phosphorus of both the wine groups were measured. Eighty-four bovine specimens were divided into seven groups (N=12) and were immersed for 1, 3, 5, 10, 30, 60, and 120 min, respectively. The surface microhardness was measured using a microhardness tester before and after treatment with each alcoholic drink. After 120 min, the enamel surface was examined using a scanning electron microscope (SEM). The statistical methods used in this study were one-way analysis of variance (ANOVA) and repeated-measure ANOVA. RESULTS: The differences in the surface microhardness (DeltaVHN) values obtained before and after treatment for 120 min were statistically significant among groups. Makgeolli, wine A, and wine NA significantly eroded the enamel after 120 min. However, sojuH and sojuL had an effect similar to that of distilled water, which was used in the control group. Beer caused slight enamel erosion. SEM images revealed that makgeolli, wine A, and wine NA caused significant erosion of the enamel surface, while beer caused slight erosion. SEM observation results were similar to those obtained after surface microhardness evaluation. CONCLUSIONS: The study findings suggest that alcoholic drinks, such as makgeolli and wine, with organic acids and a pH value less than 4.0 can cause tooth enamel erosion. Therefore, alcoholic drinks with low pH values and organic acid composition should not be retained for long periods in the mouth.

Evidence-based stress management: focusing on nonpharmacological procedure which reduce stress and promote health

In modern society, stress is one of the most significant problems affecting physical as well as mental health. Stress, which is defined as a situation in which the homeostasis of the physiological system of one's mind and body is threatened, is composed of two concepts: stressors and stress reactions. A stressor is the stimulus that is perceived as a threat and arouses a stress reaction, such as a disaster or serious life event. Stress reactions are physical and mental symptoms, for example, chest tightness, dizziness, abdominal pain, dyspepsia, headache, and agitation, which are mediated by the sympathetic nervous system and stress hormones such as cortisol. These reactions, along with stress-related unhealthy behaviors, result in serious chronic diseases, including cancers and cardiovascular disease. Stress coping methods are classified into two components: cognitive behavioral interventions for stressors and mind-body interventions to reduce the stress response. Various interventions have been identified: progressive muscle relaxation, autogenic training, relaxation response, biofeedback, the emotional freedom technique, guided imagery, diaphragmatic breathing, transcendental meditation, and mindfulness-based stress reduction. Meditation and progressive muscular relaxation are well-known and widely used procedures to reduce the stress response and to improve quality of life. Further studies to establish an evidence-based standardized program that can be easily applied at the individual level are needed.

What Is the Evidence to Support the Use of Therapeutic Gardens for the Elderly?

Horticulture therapy employs plants and gardening activities in therapeutic and rehabilitation activities and could be utilized to improve the quality of life of the worldwide aging population, possibly reducing costs for long-term, assisted living and dementia unit residents. Preliminary studies have reported the benefits of horticultural therapy and garden settings in reduction of pain, improvement in attention, lessening of stress, modulation of agitation, lowering of as needed medications, antipsychotics and reduction of falls. This is especially relevant for both the United States and the Republic of Korea since aging is occurring at an unprecedented rate, with Korea experiencing some of the world's greatest increases in elderly populations. In support of the role of nature as a therapeutic modality in geriatrics, most of the existing studies of garden settings have utilized views of nature or indoor plants with sparse studies employing therapeutic gardens and rehabilitation greenhouses. With few controlled clinical trials demonstrating the positive or negative effects of the use of garden settings for the rehabilitation of the aging populations, a more vigorous quantitative analysis of the benefits is long overdue. This literature review presents the data supporting future studies of the effects of natural settings for the long term care and rehabilitation of the elderly having the medical and mental health problems frequently occurring with aging.

Toxicological assessment of dihydroergotamine after chronic inhalation in dogs.

The objective was to determine the respiratory toxicity of MAP0004, orally inhaled dihydroergotamine (DHE), via inhalation for six months. Forty beagle dogs (twenty females, twenty males) were treated by nose-only inhalation for 182 days. Groups 2 through 5 received MAP0004 (mean doses: 0.045, 0.154, 0.44, 0.825 mg/kg); Group 1 received vehicle only. Groups 1 through 4 received single thirty-minute exposures, whereas Group 5 was exposed twice daily for thirty minutes. Toxicity was assessed from clinical observations, objective evaluations, and clinical and anatomical pathology. Systemic effects were scabbing of ear tips in Groups 3, 4, and 5 and excessive salivation and emesis, observed in Group 5. No changes were observed in the lungs in any dose group. Minimal treatment-related microscopic changes were observed in the respiratory nasal epithelium only in Group 5. No plexiform, vascular media, or fibroproliferative changes in any heart valves were observed in any group. Expected systemic pharmacologic effects were observed only at MAP0004 target doses ≥ 0.224 mg/kg (achieved doses > 0.154 mg/kg), which was more than five times the maximum daily intravenous (IV) human clinical dose of DHE, and more than twenty times the systemic equivalent dose of MAP0004. The no-observed adverse effect level (NOAEL) was the achieved inhaled dose of 0.045 mg/kg, or four times the human clinical dose of MAP0004.

Sundown Syndrome in Persons with Dementia: An Update

"Sundowning" in demented individuals, as distinct clinical phenomena, is still open to debate in terms of clear definition, etiology, operationalized parameters, validity of clinical construct, and interventions. In general, sundown syndrome is characterized by the emergence or increment of neuropsychiatric symptoms such as agitation, confusion, anxiety, and aggressiveness in late afternoon, in the evening, or at night. Sundowning is highly prevalent among individuals with dementia. It is thought to be associated with impaired circadian rhythmicity, environmental and social factors, and impaired cognition. Neurophysiologically, it appears to be mediated by degeneration of the suprachiasmatic nucleus of the hypothalamus and decreased production of melatonin. A variety of treatment options have been found to be helpful to ameliorate the neuropsychiatric symptoms associated with this phenomenon: bright light therapy, melatonin, acetylcholinesterase inhibitors, N-methyl-d-aspartate receptor antagonists, antipsychotics, and behavioral modifications. To decrease the morbidity from this specific condition, improve patient's well being, lessen caregiver burden, and delay institutionalization, further attention needs to be given to development of clinically operational definition of sundown syndrome and investigations on etiology, risk factors, and effective treatment options.

New therapeutic developments in chronic migraine.

PURPOSE OF REVIEW: Chronic migraine is a common cause of chronic daily headache, which is often refractory to standard treatment. New research has increased our understanding of this disorder and its treatment. This review focuses on recent clinical trials and advances in our understanding of migraine pathophysiology. RECENT FINDINGS: Migraine research has traditionally focused on the more common episodic form of the disorder, but recent clinical trials have started to focus on chronic migraine or chronic daily headache. Topiramate, onabotulinum toxin type A, gabapentin, petasites and tizanidine are among the agents that appear to be effective in the treatment of chronic migraine. New acute medications including an inhaled form of dihydroergotamine will soon be available and neuromodulatory procedures such as occipital nerve stimulation may be effective for the most disabled patients. In the past few years, other studies have shed light on potential risk factors for chronic migraine such as medication-overuse headache, temporomandibular disorders, obstructive sleep apnea and obesity. SUMMARY: This review explains advances in the treatment of chronic migraine, a common disorder seen in neurological practice. These new advances in preventive treatment and a better understanding of its risk factors will allow clinicians to better identify individuals at greatest risk and prevent the development of chronic migraine.

Cluster headache: diagnosis and treatment.

Cluster headache is a rare yet exquisitely painful primary headache disorder occurring in either episodic or chronic patterns. The unique feature of cluster headache is the distinctive circadian and circannual periodicity in the episodic forms. The attacks are stereotypic--they are of extreme intensity and short duration, occur unilaterally, and are associated with robust signs and symptoms of autonomic dysfunction. Although the pathophysiology of cluster headache remains to be fully understood, there have been a number of recent seminal observations. To exclude structural mimics, patients presenting with symptoms suggestive of cluster headache warrant at least a brain magnetic resonance imaging (MRI) scan in their work-up. The medical treatment of cluster headache includes acute, transitional, and maintenance prophylaxis. Agents used for acute therapy include inhalation of oxygen, triptans, such as sumatriptan, and dihydroergotamine. Transitional prophylaxis refers to the short-term use of fast-acting agents. This typically involves either corticosteroids or an occipital nerve block. The mainstay of prophylactic therapy is verapamil. Yet, other medications, including lithium, divalproex sodium, topiramate, methysergide, gabapentin, and even indomethacin, may be useful when the headache fails to respond to verapamil. For medically refractory patients, surgical interventions, occipital nerve stimulation, and deep brain stimulation remain an option. As the sophistication of functional neuroimaging increases, better insight into the pathophysiological mechanisms that underlie cluster headache is expected.

Drug dependence associated with triptans and ergot derivatives: a case/non-case study.

INTRODUCTION: The aim of this case/non-case study was to assess and compare the risk of drug dependence associated with different migraine-specific drugs, i.e., ergot derivatives and triptans, using the French pharmacovigilance database. METHODS: Reports on drug side effects recorded in this database between January 1985 and June 2007 were analyzed, and triptans (almotriptan, eletriptan, naratriptan, sumatriptan, and zolmitriptan) as well as ergot derivatives used in acute migraine were examined. For all reports, cases were defined as those reports corresponding to "drug abuse," "physical or mental drug dependence," and "pharmacodependence," whereas "non-cases" were defined as all the remaining SED reports. The method's reliability was assessed by calculating the risk associated with a negative (amoxicillin) and a positive (benzodiazepines) control. The risk of dependence associated with each drug and control was evaluated by calculating the odds ratio (OR) with a confidence interval of 95%. RESULTS: Among the 309,178 reports recorded in the database, drug dependence accounted for 0.8% (2,489) of the reports, with 10.9% (449) involving a triptan, and 9.33% (332) an ergot derivative. The risk of dependence was similar for triptans and ergot derivatives and did not differ from that of benzodiazepines. In the triptan group, the risk (odds ratio [95% CI]) ranged from 10.3 [4.8-22.3] for sumatriptan to 21.5 for eletriptan [10.1-45.6], while in the ergot derivative group, it ranged from 12 [8-17.9] for ergotamine to 20.6 [8-53] for dihydroergotamine. CONCLUSIONS: These findings confirm the hypothesis that triptans and ergot derivatives are associated with an increased risk of drug dependence.

Effect of intrathecal glycine and related amino acids on the allodynia and hyperalgesic action of strychnine or bicuculline in mice / 대한마취과학회지

BACKGROUND: The intrathecal (IT) administration of glycine or GABAA receptor antagonist result in a touch evoked allodynia through disinhibition in the spinal cord. Glycine is an inhibitory neurotransmitter that appears to be important in sensory processing in the spinal cord. This study was aimed to evaluate the effect of glycine-related amino acids on antagonizing the effects of IT strychnine (STR) or bicuculline (BIC) when each amino acid was administered in combination with STR or BIC. METHODS: A total of 174 male ICR mice were randomized to receive an IT injection of equimolar dose of glycine, betaine, beta-alanine, or taurine in combination with STR or BIC. Agitation in response to innocuous stimulation with a von Frey filament after IT injection was assessed. The pain index in hot-plate test were observed after it injection. The effect of it muscimol in combination with str or bic were also observed. RESULTS: The allodynia induced by STR was relieved by high dose of glycine or betaine. But, allodynia induced by BIC was not relieved by any amino acid. Whereas the STR-induced thermal hyperalgesia was only relieved by high dose of taurine at 120 min after IT injection, the BIC-induced one was relieved by not only high dose of taurine at 120 min but also low dose of glycine or betaine at 60 min after IT injection. The BIC-induced allodynia and thermal hyperalgesia was relieved by IT muscimol. CONCLUSIONS: This study suggests that IT glycine and related amino acids can reduce the allodynic and hyperalgesic action of STR or BIC in mice.

Cardiac arrest after position change in a morbidly obese patient: A case report / 대한마취과학회지

Morbid obesity presents many clinical problems. Especially, morbid obesity has a significant effect on airway management and pulmonary function. We experienced a cardiac arrest of a morbidly obese (Body Mass Index of about 62 kg/m2). 21-year-old male patient that necessitated cardiopulmonary resuscitation (CPR). The patient was scheduled for an emergency cystoscopy under local anesthesia. After change to supine position in the operation room, dyspnea, tachypnea, agitation, and, subsequently, cardiac arrest developed.

Cardiovascular excitatory effect on rats of a fraction isolated from the eyestalk of shrimp: Peneaus vanameii.

The crustacean nervous system is an important source of substances with diverse biological activities, particularly affecting invertebrate cardiocirculatory physiology. However, the effects of these substances on the cardiovascular system of higher vertebrates are not very well documented. The purpose of this study was to evaluate the effects of a cardioexcitatory substance (CES) isolated from the eyestalk of the shrimp Peneaus vanameii on rat cardiovascular function. The administration of a purified fraction of this substance raised mean arterial pressure by 37.33 +/- 5.00 mm Hg, pulse pressure 35.00 +/- 4.93 mm Hg and heart rate 80.00 +/- 12.83 beats/min over basal values (p < 0.01). Evaluation of the possible underlying mechanisms of this hypertensive and tachycardic effect reveled that dihydroergotamine pretreatment (20 microg/0.2 mL) reduced the effect of CES on mean blood pressure, but not on heart rate. Propranolol pretreatment (4 microg/0.2 mL) reduced the tachycardia, but not the hypertensive response. Enalapril pretreatment (5 microg/0.2 mL) did not modify the effects induced by CES on heart rate or blood pressure, and the verapamil pretreatment (1 microg/0.2 mL) reduced both cardiovascular changes by 85% (p < 0.01). These results indicate that CES isolated from the shrimp eyestalk produces hypertension and tachycardia mediated by adrenergic receptors in association to calcium channels activation.