Evaluating patient and family preferences for acute and preventive pediatric headache treatment.

OBJECTIVE: To describe acute and preventive treatment preferences among youth with migraine and their parents/guardians, and to describe the degree of youth-parent/guardian preference agreement. BACKGROUND: Headache disorders are common in youth, but little is known about patient and family preferences for headache treatments and outcomes. METHODS: In this cross-sectional survey, a headache treatment preferences questionnaire was co-created with stakeholders, piloted, and distributed to consenting youth with migraine aged 9-18 years and parents/guardians at a tertiary care headache clinic in western Canada. Response data were summarized for youth and parents/guardians separately, and agreement rates within a youth-parent/guardian pair were compared to a hypothesized agreement rate of 80% for the primary questionnaire items. RESULTS: Seventy-two youth and n = 94 parents/guardians participated, with n = 63 in youth-parent/guardian pairs. Freedom from pain and rapid relief, and reducing pain severity and headache frequency were top acute and preventive treatment priorities, respectively. More than 90% (69/72) agreed that ≥ 50% reduction in headache frequency was a good target. For both acute and preventive interventions, swallowed pill-based options were most often selected as the preferred first-line treatment, with neuromodulation selected as the preferred second-line treatment. The level of agreement within youth-parent/guardian pairs on preferred treatment modalities was lower than hypothesized for acute (63% [40/63], 95% confidence interval [CI] = 52-75%, χ2 = 10.73, p = 0.001) but not for preventive treatment (73% [46/63], 95% CI = 62-84%, χ2 = 1.92, p = 0.166). Regarding which treatment modalities were perceived as most effective, youth-parent agreement was lower than hypothesized for both acute (48% [30/63], 95% CI = 35-60%, χ2 = 41.29, p < 0.001) and preventive treatment (46% [29/63], 95% CI = 34-58%, χ2 = 45.43, p < 0.001). CONCLUSION: Youth and family preferences aligned qualitatively, but sometimes diverged quantitatively, from typical clinical trial outcomes. The level of agreement within youth-parent/guardian pairs on treatment preferences and perceptions was low. Clinicians should consider both perspectives as they may be divergent.

Guidelines Update: Guidelines of the International Headache Society for controlled trials of preventive treatment of migraine in children and adolescents, 1st edition - An experience-based update.

BACKGROUND: Recent experience in designing and running clinical trials on new medications for the prevention of migraine in children and adolescents highlighted the need for revision of the 1st edition of the International Headache Society Guidelines for clinical trials of preventive treatment of migraine in children and adolescents which were published in 2019. METHODS: The authors of the 1st edition of the guidelines formed an informal focus group with aims of appraising the performance of the guidelines, clarifying any ambiguity and providing improvements, where needed, based on personal experience and expert analysis. RESULTS: This review and the following update were able to address issues related to the classification of migraine, the duration of migraine attacks, the age groups of children and adolescents, the use of electronic diaries, the assessment of outcome measures, the need for an interim analysis and the issues related to placebo response. CONCLUSIONS: This update provides necessary clarifications of the guidelines in order to enable better design and running of future clinical trials for the preventive treatment of migraine in children and adolescents.

Effects of air pollution on human health - Mechanistic evidence suggested by in vitro and in vivo modelling.

Airborne particulate matter (PM) comprises both solid and liquid particles, including carbon, sulphates, nitrate, and toxic heavy metals, which can induce oxidative stress and inflammation after inhalation. These changes occur both in the lung and systemically, due to the ability of the small-sized PM (i.e. diameters ≤2.5 µm, PM2.5) to enter and circulate in the bloodstream. As such, in 2016, airborne PM caused ∼4.2 million premature deaths worldwide. Acute exposure to high levels of airborne PM (eg. during wildfires) can exacerbate pre-existing illnesses leading to hospitalisation, such as in those with asthma and coronary heart disease. Prolonged exposure to PM can increase the risk of non-communicable chronic diseases affecting the brain, lung, heart, liver, and kidney, although the latter is less well studied. Given the breadth of potential disease, it is critical to understand the mechanisms underlying airborne PM exposure-induced disorders. Establishing aetiology in humans is difficult, therefore, in-vitro and in-vivo studies can provide mechanistic insights. We describe acute health effects (e.g. exacerbations of asthma) and long term health effects such as the induction of chronic inflammatory lung disease, and effects outside the lung (e.g. liver and renal change). We will focus on oxidative stress and inflammation as this is the common mechanism of PM-induced disease, which may be used to develop effective treatments to mitigate the adverse health effect of PM exposure.

Tranexamic acid administration practice in otolaryngology head & neck surgery; international survey.

PURPOSE: Tranexamic acid (TXA) is a potent pro-coagulation drug. Pre-operative, preventive TXA administration and TXA use for active bleeding are established treatments in many medical situations; yet, less is known about its use in otolaryngology head and neck surgery practice. The primary study goals were: MATERIALS AND METHODS: This is an international survey exploring TXA administration strategy. The electronic, anonymous, questionnaire was emailed to all registered Israeli and American Otolaryngology Head and Neck Surgery (OHNS) physicians, investigating TXA administration: RESULTS: Overall, 317 otolaryngologists participated in the study. TXA was administered to 40.5 % of the pediatric population and 50 % of the adult patients when needed. Epistaxis was the most common indication for TXA administration (48-55 %). A small number of otolaryngologists, 4-13 %, recommended preventive TXA for various operations. More surgeons include TXA in their practice and adjusted the dose according to renal function in academic compared to non-academic medical centers and among otolaryngologists practicing in Israel compared to the United States. CONCLUSIONS: TXA is provided by many otolaryngologists to treat active epistaxis but to a substantially lesser extent as a preventive measure. TXA is given to children and adults, some with substantial comorbidities. Treatment is more common among surgeons working in academic institutes and medical centers in Israel.

Malaria Infection Is Common and Associated With Perinatal Mortality and Preterm Delivery Despite Widespread Use of Chemoprevention in Mali: An Observational Study 2010 to 2014.

BACKGROUND: In malaria-endemic areas, pregnant women and especially first-time mothers are more susceptible to Plasmodium falciparum. Malaria diagnosis is often missed during pregnancy, because many women with placental malaria remain asymptomatic or have submicroscopic parasitemia, masking the association between malaria and pregnancy outcomes. Severe maternal anemia and low birthweight deliveries are well-established sequelae, but few studies have confirmed the relationship between malaria infection and severe outcomes like perinatal mortality in high transmission zones. METHODS: Pregnant women of any gestational age enrolled at antenatal clinic into a longitudinal cohort study in Ouelessebougou, Mali, an area of high seasonal malaria transmission. Follow-up visits included scheduled and unscheduled visits throughout pregnancy. Blood smear microscopy and polymerase chain reaction (PCR) analysis were employed to detect both microscopic and submicroscopic infections, respectively. Intermittent preventative treatment in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) was documented and prompt treatment regardless of symptoms given upon malaria diagnosis. RESULTS: Of the 1850 women followed through delivery, 72.6% of women received 2 or more IPTp-SP doses, 67.2% of women experienced at least 1 infection between enrollment up to and including delivery. Malaria infection increased the risks of stillbirth (adjusted hazard ratio [aHR] 3.87, 95% confidence interval [CI]: 1.18-12.71) and preterm delivery (aHR 2.41, 95% CI: 1.35-4.29) in primigravidae, and early neonatal death (death within 7 days) in secundigravidae and multigravidae (aHR 6.30, 95% CI: 1.41-28.15). CONCLUSIONS: Malaria treatment after diagnosis, alongside IPTp-SP, is insufficient to prevent malaria-related stillbirth, early neonatal death and preterm delivery (PTD). Although IPTp-SP was beneficial in Mali during the study period, new tools are needed to improve pregnancy outcomes. CLINICAL TRIALS REGISTRATION: NCT01168271.

The relation between the placebo response, observed treatment effect, and failure to meet primary endpoint: A systematic review of clinical trials of preventative pharmacological migraine treatments.

OBJECTIVE: To evaluate the association between the degree of response to placebo in migraine studies and the observed difference between drug and placebo across studies of preventative treatments for migraine. METHODS: A systematic review was performed using MEDLINE and the Cochrane Central Register of Controlled Clinical Trials from January 1988 to June 2019. Randomized, double-blind, parallel-group, placebo-controlled trials on oral or injection preventative treatments for migraine were included. Single- and multi-variable linear regression analyses were performed on the placebo-subtracted response rate (i.e. placebo responders subtracted from active responders), and the proportion of placebo responders. Fisher's exact tests were performed on the level of placebo response and the success in meeting the study's primary endpoint. RESULTS: After adjusting for route of administration and number of randomized subjects, there was a statistically significant association between the proportion of patients who were placebo responders and the placebo-subtracted response rate (b = -0.27, p = 0.02). There was a statistically significant difference in trial success rate (60%) between studies with ≤20% placebo responders and studies with > 30% placebo responders (p = 0.03). CONCLUSION: Considering the detrimental impact that high placebo response can have on clinical trials, it is imperative to find effective solutions to decrease the placebo response and increase assay sensitivity.

Intermittent Preventive Treatment (IPT): Its Role in Averting Disease-Induced Mortality in Children and in Promoting the Spread of Antimalarial Drug Resistance.

We develop an age-structured ODE model to investigate the role of intermittent preventive treatment (IPT) in averting malaria-induced mortality in children, and its related cost in promoting the spread of antimalarial drug resistance. IPT, a malaria control strategy in which a full curative dose of an antimalarial medication is administered to vulnerable asymptomatic individuals at specified intervals, has been shown to reduce malaria transmission and deaths in children and pregnant women. However, it can also promote drug resistance spread. Our mathematical model is used to explore IPT effects on drug resistance and deaths averted in holoendemic malaria regions. The model includes drug-sensitive and drug-resistant strains as well as human hosts and mosquitoes. The basic reproduction, and invasion reproduction numbers for both strains are derived. Numerical simulations show the individual and combined effects of IPT and treatment of symptomatic infections on the prevalence of both strains and the number of lives saved. Our results suggest that while IPT can indeed save lives, particularly in high transmission regions, certain combinations of drugs used for IPT and to treat symptomatic infection may result in more deaths when resistant parasite strains are circulating. Moreover, the half-lives of the treatment and IPT drugs used play an important role in the extent to which IPT may influence spread of the resistant strain. A sensitivity analysis indicates the model outcomes are most sensitive to the reduction factor of transmission for the resistant strain, rate of immunity loss, and the natural clearance rate of sensitive infections.

The headache under-response to treatment (HURT) questionnaire, an outcome measure to guide follow-up in primary care: development, psychometric evaluation and assessment of utility.

BACKGROUND: Headache disorders are both common and burdensome but, given the many people affected, provision of health care to all is challenging. Structured headache services based in primary care are the most efficient, equitable and cost-effective solution but place responsibility for managing most patients on health-care providers with limited training in headache care. The development of practical management aids for primary care is therefore a purpose of the Global Campaign against Headache. This manuscript presents an outcome measure, the Headache Under-Response to Treatment (HURT) questionnaire, describing its purpose, development, psychometric evaluation and assessment for clinical utility. The objective was a simple-to-use instrument that would both assess outcome and provide guidance to improving outcome, having utility across the range of headache disorders, across clinical settings and across countries and cultures. METHODS: After literature review, an expert consensus group drawn from all six world regions formulated HURT through item development and item reduction using item-response theory. Using the American Migraine Prevalence and Prevention Study's general-population respondent panel, two mailed surveys assessed the psychometric properties of HURT, comparing it with other instruments as external validators. Reliability was assessed in patients in two culturally-contrasting clinical settings: headache specialist centres in Europe (n = 159) and primary-care centres in Saudi Arabia (n = 40). Clinical utility was assessed in similar settings (Europe n = 201; Saudi Arabia n = 342). RESULTS: The final instrument, an 8-item self-administered questionnaire, addressed headache frequency, disability, medication use and effect, patients' perceptions of headache "control" and their understanding of their diagnoses. Psychometric evaluation revealed a two-factor model (headache frequency, disability and medication use; and medication efficacy and headache control), with scale properties apparently stable across disorders and correlating well and in the expected directions with external validators. The literature review found few instruments linking assessment to clinical advice or suggested actions: HURT appeared to fill this gap. In European specialist care, it showed utility as an outcome measure across headache disorders. In Saudi Arabian primary care, HURT (translated into Arabic) was reliable and responsive to clinical change. CONCLUSIONS: With demonstrated validity and clinical utility across disorders, cultures and settings, HURT is available for clinical and research purposes.

Current management: migraine headache.

Migraine varies in its frequency, severity, and impact; treatment should consider these variations and the patient's needs and goals. Migraine pharmacologic treatment may be acute (abortive) or preventive (prophylactic), and patients often require both. New medication devices are available or in development, including an intracutaneous, microneedle system of zolmitriptan and sumatriptan, and breath-powered powder sumatriptan intranasal treatment. Lasmiditan, a 5-HT1F receptor agonist, is in development for acute treatment, as are small molecule calcitonin gene-related peptide (CGRP) receptor antagonists (Gepants) for acute and preventive treatment. Antibodies to CGRP and its receptor are being developed for migraine prevention. All 4 treatments are effective and have, as of yet, no safety concerns.

Emerging drugs for migraine treatment.

INTRODUCTION: Migraine is a highly prevalent and disabling neurological condition whose personal, social and economic impact is substantial. Abortive and preventative treatments of this condition are still unsatisfactory, with poor control of the acute symptoms of the single attacks in many cases and a frequent progression towards chronicity. AREAS COVERED: The major drug classes recently developed and/or in current development for migraine treatment are discussed. These include: Calcitonin-Gene-Related Peptide (CGRP) receptor antagonists, mAbs against CGRP or its receptor, selective 5 hydroxytryptamine (5-HT)1F receptor agonists, drugs targeting Acid-Sensing Ion Channels, Transient Receptor Potential channels and Nitric Oxide. EXPERT OPINION: The most convincing results appear those obtained with mAbs against CGRP, particularly in migraine preventative treatment, given the absence of serious adverse events, and the good response in terms of pain relief. If these results are confirmed in larger studies, these compounds have the potential to significantly improve the pharmacological control of migraine and also its evolution towards chronicity.

The pathway to diagnosis and follow-up care for atrial fibrillation in Sri Lanka: a descriptive longitudinal study.

Background: Early diagnosis and continuity of care is vital for atrial fibrillation (AF), to reduce stroke ; There is a lack of understanding of when and how AF is being diagnosed and managed the care pathway) in in low- and middle-income countries (LMICs). We aimed to identify the AF care pathway in Northern Province, Sri Lanka and determine how the COVID-19 pandemic impacted the care pathway. Methods: This descriptive longitudinal study utilised two quantitative questionnaires to evaluate the AF pathway: The first questionnaire (baseline) was used to identify where AF was being diagnosed and the second questionnaire (3 months following baseline) was used to identify where and how often AF follow-up care was being received. How the COVID-19 pandemic impacted the care pathway was asked in the second questionnaire. We aimed to recruit 236 adults (≥18 years) with AF from Jaffna Teaching Hospital. Data were collected between October 2020 and June 2021 and analysed using descriptive statistics. Results: 151 participants were recruited (median age 57 years; 70% female). Most participants were diagnosed in the accident & emergency (38%) or inpatient department (26%), followed by an outpatient department (19%) or private facility (16%). Nearly all (97%) participants received follow-up care during the study period, with an average of 1.3 AF-related healthcare visits per person for a month; most visited an outpatient department (88%). The COVID-19 pandemic negatively impacted 39% of participants' care: healthcare visits were reduced or, delayed or medications were unattainable, and longer intervals between blood tests were experienced; however, 24% of participants were able to receive their medication by ambulance, public health staff or post during lockdowns. Conclusions: Primary care was not involved in the diagnosis of AF, indicating that most diagnoses occurr after a medical emergency. The frequency of blood tests was lower than the guideline recommendations of one per month which could in-part be due to the adverse impacts of the pandemic. Strengthening primary and community-based care may enable early diagnosis and improve continuity of care during and beyond future healthcare crises.

Particulate Matter, an Intrauterine Toxin Affecting Foetal Development and Beyond.

Air pollution is the 9th cause of the overall disease burden globally. The solid component in the polluted air, particulate matters (PMs) with a diameter of 2.5 µm or smaller (PM2.5) possess a significant health risk to several organ systems. PM2.5 has also been shown to cross the blood-placental barrier and circulate in foetal blood. Therefore, it is considered an intrauterine environmental toxin. Exposure to PM2.5 during the perinatal period, when the foetus is particularly susceptible to developmental defects, has been shown to reduce birth weight and cause preterm birth, with an increase in adult disease susceptibility in the offspring. However, few studies have thoroughly studied the health outcome of foetuses due to intrauterine exposure and the underlying mechanisms. This perspective summarises currently available evidence, which suggests that intrauterine exposure to PM2.5 promotes oxidative stress and inflammation in a similar manner as occurs in response to direct PM exposure. Oxidative stress and inflammation are likely to be the common mechanisms underlying the dysfunction of multiple systems, offering potential targets for preventative strategies in pregnant mothers for an optimal foetal outcome.

Collect Once, Use Many Times: Attaining Unified Metrics for Tuberculosis Preventive Treatment for People Living With HIV.

The World Health Organization (WHO) recommends providing tuberculosis preventive treatment (TPT) to all persons living with HIV and to all household contacts of persons with bacteriologically confirmed pulmonary tuberculosis disease. Regrettably, the absence of a harmonized data collection and management approach to TPT indicators has contributed to programmatic challenges at local, national, and global levels. However, in April 2020, the WHO launched the Consolidated HIV Strategic Information Guidelines, with an updated set of priority indicators. These guidelines recommend that Ministries of Health collect, report, and use data on TPT completion in addition to TPT initiation. Both indicators are reflected in the WHO's list of 15 core indicators for program management and are also required by the US President's Emergency Plan for AIDS Relief's Monitoring, Evaluation, and Reporting (MER) guidance. Although not perfectly harmonized, both frameworks now share essential indicator characteristics. Aligned indicators are necessary for robust strategic and operational planning, resource allocation, and data communication. "Collect once, use many times" is a best practice for strategic information management. Building harmonized and sustainable health systems will enable countries to successfully maintain essential HIV, tuberculosis, and other health services while combatting new health threats.

Dynamic changes of interferon gamma release assay results with latent tuberculosis infection treatment.

OBJECTIVES: Using QuantiFERON-TB Gold In-Tube (QFT-GIT) for monitoring tuberculosis (TB) and latent TB infection treatment effect is controversial. The present study aimed to evaluate the dynamic changes of interferon gamma (IFN-γ) levels along with latent TB infection treatment via a randomized controlled study. METHODS: A total of 910 participants treated with 8 weeks of once-weekly rifapentine plus isoniazid (group A), 890 treated with 6 weeks of twice-weekly rifapentine plus isoniazid (group B) and 818 untreated controls (group C) were followed for 2 years to track active TB development. QFT-GIT tests were repeated three times for all groups: before treatment (T0), at completion of treatment (T1) and 3 months after completion of treatment (T2). RESULTS: Similar rates of persistent QFT-GIT reversion were observed in groups A (19.0%, 173/910), B (18.5%, 165/890) and C (20.7%, 169/818) (p 0.512). The dynamic changes of IFN-γ levels were not statistically significant among the three groups. In treated participants, individuals with higher baseline IFN-γ levels showed increased TB occurrence (1.0%, 9/896) compared to those with lower baseline levels (0.2%, 2/904) (p 0.037). A similar but statistically insignificant trend was also observed in untreated controls (1.8% (7/400) vs. 0.5% (2/418), p 0.100). When TB cases were matched with non-TB cases on baseline IFN-γ levels, no significant differences were found with respect to the dynamic changes in IFN-γ levels with time, regardless of whether they received treatment. CONCLUSIONS: QFT-GIT reversion or decreased IFN-γ levels should not be used for monitoring host response to latent TB infection treatment.

Assessing the Value of Antibiotics on Farms: Modeling the Impact of Antibiotics and Vaccines for Managing Lawsonia intracellularis in Hog Production.

Increasing awareness of antibiotic resistance has correspondingly increased efforts to identify and reduce the causal behaviors that led to this severe public health threat. The consequences of these efforts are regulatory and market pressures limiting antibiotic use by livestock farmers which may lead to significant financial and welfare challenges on the farm, even if antibiotics can be substituted by vaccines. The purpose of this study is to measure the relative cost-effectiveness of antibiotics vs. vaccines for controlling L. intracellularis on a Canadian farrow-to-finish pig farm. This is done by modeling the production and economic impact of different antibiotics and vaccines available for managing this disease, listed in the Canadian Compendium of Veterinary Products. The economic impacts (in Canadian dollars) of the disease are estimated and the net benefits of alternative prevention and treatment options are compared to determine the relative cost-effectiveness of each strategy. Of the 12 options analyzed, four were preventative (antibiotic and vaccine) and eight were antibiotic treatments. Prophylactic chlortetracycline (an antibiotic) is the most cost-effective option for managing L. intracellularis, while Porcilis Ileitis (a vaccine) is the least cost-effective strategy. This result remains robust considering sensitivity analysis of the production parameters, which indicates that preventative antibiotics are more cost-effective than vaccines. This implies that banning preventative antibiotic treatments harms the bottom line of farmers under current market conditions.

Early diagnosis of tuberous sclerosis complex: a race against time. How to make the diagnosis before seizures?

BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic disorder with an incidence of 1:6000 live births and associated with the development of benign tumors in several organs. It is also characterized by high rates of neurological and neuropsychiatric abnormalities, including epilepsy affecting 70-90% of patients and being one of the major risk factors of intellectual disability. The first seizures in TSC patients appear usually between the 4th and the 6th months of life. Recent studies have shown the beneficial role of preventative antiepileptic treatment in TSC patients, with the possibility for improvement of cognitive outcome. Moreover, European recommendations suggest early introduction of Vigabatrin if ictal discharges occur on EEG recordings, with or without clinical manifestation. The aim of this study was to define the most useful approach to make the diagnosis of TSC before seizure onset (before age 4th months), in order to start early EEG monitoring with possible preventative treatment intervention. METHODS: We performed a retrospective review of children who were suspected of having TSC due to single or multiple cardiac tumors as the first sign of the disease. We analyzed the medical records in terms of conducted clinical tests and TSC signs, which were observed until the end of the 4th month of age. Subsequently, we described the different clinical scenarios and recommendations for early diagnosis. RESULTS: 82/100 children were diagnosed with TSC within the first 4 months of life. Apart from cardiac tumors, the most frequently observed early TSC signs were subependymal nodules (71/100, 71%), cortical dysplasia (66/100, 66%), and hypomelanotic macules (35/100, 35%). The most useful clinical studies for early TSC diagnosis were brain magnetic resonance imaging (MRI), skin examination and echocardiography. Genetic testing was performed in 49/100 of the patients, but the results were obtained within the first 4 months of life in only 3 children. CONCLUSIONS: Early diagnosis of TSC, before seizure onset, is feasible and it is becoming pivotal for epilepsy management and improvement of cognitive outcome. Early TSC diagnosis is mostly based on clinical signs. Brain MRI, echocardiography, skin examination and genetic testing should be performed early in every patient suspected of having TSC.

Identification and modification of amyloid-independent phenotypes of APOE4 mice.

BACKGROUND: Over 70 million Americans inherit the strongest genetic risk factor for Alzheimer's disease (AD), apolipoprotein E4 (APOE4), but have no course for reducing their risk. The association of non-steroidal anti-inflammatory drug (NSAID) use with reduced risk of AD for APOE4-carriers suggests that NSAIDs may be useful in AD prevention. METHODS: We identified phenotypes associated with APOE4 in APOE knock-in mice in order to define modifiable measures that correlate with risk of AD. RESULTS: APOE4 mouse brains showed altered post-translational modifications and biochemical distribution of APOE compared to APOE3 mice; these differences were also observed in brains of human APOE4 carriers. Two-month treatment with ibuprofen significantly altered the expression pattern of APOE in APOE4 mice to that of APOE3 mice; PPAR-γ agonist pioglitazone also had a significant effect. APOE4 mice also show deficits in dendritic spine density, and ibuprofen and pioglitazone significantly increased dendritic spine density. CONCLUSIONS: We report new phenotypes associated with APOE4 in human and APOE knock-in mice and their mitigation with NSAID treatment, through COX-2 inhibition and PPAR-γ activation.

Preventative and therapeutic effects of a GABA transporter 1 inhibitor administered systemically in a mouse model of paclitaxel-induced neuropathic pain.

BACKGROUND: There is a dearth of drugs to manage a dose-limiting painful peripheral neuropathy induced by paclitaxel in some patients during the treatment of cancer. Gamma-aminobutyric acid transporter-1 (GAT-1) whose expression is increased in the brain and spinal cord during paclitaxel-induced neuropathic pain (PINP) might be a potential therapeutic target for managing PINP. Thus, our aim was to evaluate if systemic administration of a GAT-1 inhibitor ameliorates PINP. METHODS: The reaction latency to thermal stimuli (hot plate test; at 55 °C) and cold stimuli (cold plate test; at 4 °C) of female BALB/c mice was recorded before and after intraperitoneal treatment with paclitaxel, its vehicle, and/or a selective GAT-1 inhibitor NO-711. The effects of NO-711 on motor coordination were evaluated using the rotarod test at a constant speed of 4 rpm or accelerating mode from 4 rpm to 40 rpm over 5 min. RESULTS: The coadministration of paclitaxel with NO-711 3 mg/kg prevented the development of paclitaxel-induced thermal hyperalgesia and cold allodynia at day 7 after drug treatment. NO-711 at 3 mg/kg produced antihyperalgesic activity up to 1 h and antiallodynic activity up to 2 h in mice with established paclitaxel-induced thermal hyperalgesia and cold allodynia. No motor deficits were observed with NO-711 at a dose of 3 mg/kg, whereas a higher dose 5 mg/kg caused motor impairment and reduced mean time spent on the rotarod at a constant speed of 4 rpm. However, at a rotarod accelerating mode from 4 rpm to 40 rpm over 5 min, NO-711 3 mg/kg caused motor impairment up to 1 h, but had recovered by 2 h. CONCLUSIONS: These results show that systemic administration of the GAT-1 inhibitor NO-711 has preventative and therapeutic activity against paclitaxel-induced thermal hyperalgesia and cold allodynia. NO-711's antiallodynic effects, but not antihyperalgesic effects, were independent of its motor impairment/sedation properties. Thus, low doses of GAT-1 inhibitors could be useful for the prevention and treatment of PINP with proper dose titration to reduce motor impairment/sedation side effects.

Sodium channel antagonists for the treatment of migraine.

INTRODUCTION: Migraine has a strong social impact, influencing both quality of life and work productivity. Therapeutic approach of migraine consists of a multimodal program of pharmacotherapy and behavioral therapy in order to reduce the risk of chronification. Indications for the use of preventive therapy are three or more attacks per month, significant disability, attack duration that is > 90 min. AREAS COVERED: In this review, studies conducted on sodium channel antagonists for the prophylaxis of migraine are selected using the International Classification of Headache Disorders (ICHD)-I and -II diagnostic criteria for migraine and are open-label and placebo-controlled studies. EXPERT OPINION: Several sodium channel antagonists, such as valproic acid, topiramate, lamotrigine, zonisamide, carbamazepine and oxcarbazepine, are widely used in migraine although without similar level of efficacy. Among these antiepileptic drugs, valproic acid and topiramate seem to be more effective in migraine, as reported in the majority of controlled studies. In spite of their high efficacy rate, important side effects should be always monitored, especially depression, cognitive functions, weight gain, sleepiness and dizziness. The usefulness of this class drug will be dramatically improved by using ongoing data on individual pharmacogenomics profile.

The application of the preventative treatment theory in common cold disease / 国际中医中药杂志

The preventative treatment theory is a very important part of traditional Chinese medicine. When this theory is used in the treatment of common cold disease, it focuses on the prevention of common cold disease. The preventative treatment theory is very important and can be applied in the whole process of the treatment common cold disease.