Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rizatriptan (MAXALT), a potent, oral 5-HT1B/1D agonist with a rapid onset of action, is available now for the acute treatment of migraine. This study examined the pharmacokinetic and clinical interaction between rizatriptan 10 mg and the components (ethinyl estradiol [EE] 35 micrograms and norethindrone [NET] 1.0 mg) of a well-established oral contraceptive combination product, ORTHO-NOVUM 1/35. Levels of sex hormone binding globulin (SHBG), a protein increased by EE to which NET binds, were also examined. In this two-period crossover study, 20 healthy young female subjects received a coadministration of 8 days of rizatriptan treatment (6 days of single-dose 10 mg rizatriptan and 2 days of multiple-dose rizatriptan, 10 mg q 4 hours for three doses, giving a total daily dose of 30 mg on Days 7 and 8) or matching placebo along with their daily dose (one tablet) of ORTHO-NOVUM 1/35 within their oral contraceptive cycle. Plasma was sampled for EE, NET, and SHBG concentrations. Safety evaluations included routine laboratory safety studies, physical examinations, and monitoring for ECG, vital signs, and adverse events. There were no statistically significant differences in any of the pharmacokinetic parameters of EE or NET between the rizatriptan and placebo treatment periods, thus indicating that rizatriptan had no meaningful effect on the disposition of either the EE or the NET component of ORTHO-NOVUM 1/35. The SHBG concentration did not change throughout the entire study. Clinically, coadministration of rizatriptan with ORTHO-NOVUM 1/35 was well tolerated. Blood pressure, heart rate, and temperature showed no consistent trend or clinically important changes. Adverse events following coadministration of rizatriptan with ORTHO-NOVUM 1/35 were similar to those reported when placebo was given with ORTHO-NOVUM 1/35. The findings of this study indicate that there is little potential for dosages as high as 30 mg/day, the maximum recommended dosing schedule, of rizatriptan to alter the plasma concentrations of oral contraceptives.
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PMID:A double-blind, placebo-controlled evaluation of the effect of oral doses of rizatriptan 10 mg on oral contraceptive pharmacokinetics in healthy female volunteers. 1070 61

Chronic episodic disorders, such as depressive disorders, IBS, migraine, and FMS, have important commonalities, including cormorbidities, an absence of classic anatomic pathology in the tissues, a lack of objective findings on physical examination, and a lack of abnormal findings by routine laboratory and radiologic tests. These CED are more prevalent in women (perhaps due to changes in estrogen levels), are generally worsened by stress (with resultant hyperactivity of the HPA axis), and often improve with aerobic exercise and common classes of medications affecting serotonin function, such as antidepressants. Thus, an increased understanding of the CED may result in improved treatment and functioning of many patients.
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PMID:Chronic episodic disorders in women. 1456 6

The field of migraine genetics has seen an explosion of information over the last year. In a recent breakthrough, missense mutations in a chromosome 1q23 gene, ATP1A2, encoding a Na+, K+-ATPase, have been identified in four distinct pedigrees with a rare form of familial hemiplegic migraine (FHM). ATP1A2 is expressed in the brain, like the voltage gated calcium channel gene, CACNA1A, previously identified as the first hemiplegic migraine gene (FHM1). The shared hemiplegic migraine phenotype of mutations in ATP1A2 and CACNA1A raises the possibility that they coordinately regulate ion homeostasis that determines susceptibility to the initiation of both migraine aura and the pain phase of migraine. For the more common and genetically complex forms of migraine, genome-wide screens have identified several new loci on 4q24, 6p12.2-21.1, 11q24, and 14q21.2-q22.3, suggesting additional migraine genes in these regions. In addition, a recent large case-control association study has linked single nucleotide polymorphisms in the insulin receptor/INSR gene with migraine. However, these polymorphisms do not result in detectable changes in receptor function. The continuing genetic identification of key proteins involved in migraine will refine our understanding of this common and sometimes debilitating disorder, which can strike during the most productive years of a person's life. Given the co-morbidity of migraine with depression and bipolar disorder, our knowledge of the causes of migraine may also contribute to our understanding of these disorders.
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PMID:Update on the genetics of migraine. 1462 54

Chromosomal area 19p13 contains two migraine associated genes: a Ca(v)2.1 (P/Q-type) calcium channel alpha(1) subunit gene, CACNA1A, and an insulin receptor gene, INSR. Missense mutations in CACNA1A cause a rare Mendelian form of migraine, familial hemiplegic migraine type 1 (FHM1). Contribution of CACNA1A locus has also been studied in the common forms of migraine, migraine with (MA) and without aura (MO), but the results have been contradictory. The role of INSR is less well established: A region on 19p13 separate from CACNA1A was recently reported to be a major locus for migraine and subsequently, the INSR gene was associated with MA and MO. Our aim was to clarify the role of these loci in MA families by analyzing 72 multigenerational Finnish MA families, the largest family sample so far. We hypothesized that the potential major contribution of the 19p13 loci should be detected in a family sample of this size, and this was confirmed by simulations. We genotyped eight polymorphic microsatellite markers surrounding the INSR and CACNA1A genes on 757 individuals. Using parametric and non-parametric linkage analysis, none of the studied markers showed any evidence of linkage to MA either under locus homogeneity or heterogeneity. However, marginally positive lod scores were observed in three families, and thus for these families the results remain inconclusive. The overall conclusion is that our study did not provide evidence of a major MA susceptibility region on 19p13 and thus we were not able to replicate the INSR locus finding.
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PMID:Chromosome 19p13 loci in Finnish migraine with aura families. 1544 51

Although migraine is more common in women than men and often linked to the menstrual cycle, few studies have investigated the biological basis of hormonal influences on the trigeminovascular system. In the present study we investigated the effect of physiological levels (10(-9) m) oestrogen on female rat trigeminal ganglia in vitro. Immunocytochemical analysis demonstrated the presence of oestrogen receptor-alpha in a predominantly cytoplasmic location and in neurites. Microarray analysis demonstrated that oestrogen treatment regulates several genes with potential relevance to menstrual migraine. The genes that were upregulated included synapsin-2, endothelin receptor type B, activity and neurotransmitter-induced early gene 7 (ania-7), phosphoserine aminotransferase, MHC-1b, and ERK-1. Down-regulated genes included IL-R1, bradykinin B2 receptor, N-tropomodulin, CCL20, GABA transporter protein, fetal intestinal lactase-phlorizin hydrolase, carcinoembryonic antigen-related protein, zinc finger protein 36, epsin 1 and cysteine string protein. Protein activity assays demonstrated that exposure of the cultured neurons to oestrogen leads to activation of ERK, which has been linked to inflammatory pain. Immunocytochemistry demonstrated that activated ERK was present in neurons containing peripherin, a marker of nociceptive neurons. Several of the genes in the present study may provide potential targets for understanding the association of oestrogen with migraine and other hormone-related orofacial pain.
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PMID:Effects of oestrogen on trigeminal ganglia in culture: implications for hormonal effects on migraine. 1639 64

Fibromyalgia (FMS) is a debilitating disorder characterized by chronic diffuse muscle pain, fatigue, sleep disturbance, depression and skin sensitivity. There are no genetic or biochemical markers and patients often present with other comorbid diseases, such as migraines, interstitial cystitis and irritable bowel syndrome. Diagnosis includes the presence of 11/18 trigger points, but many patients with early symptoms might not fit this definition. Pathogenesis is still unknown, but there has been evidence of increased corticotropin-releasing hormone (CRH) and substance P (SP) in the CSF of FMS patients, as well as increased SP, IL-6 and IL-8 in their serum. Increased numbers of activated mast cells were also noted in skin biopsies. The hypothesis is put forward that FMS is a neuro-immunoendocrine disorder where increased release of CRH and SP from neurons in specific muscle sites triggers local mast cells to release proinflammatory and neurosensitizing molecules. There is no curative treatment although low doses of tricyclic antidepressants and the serotonin-3 receptor antagonist tropisetron, are helpful. Recent nutraceutical formulations containing the natural anti-inflammatory and mast cell inhibitory flavonoid quercetin hold promise since they can be used together with other treatment modalities.
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PMID:Fibromyalgia--new concepts of pathogenesis and treatment. 1656 42

After more than 40 years of clinical use, the mechanisms of action of valproate in epilepsy, bipolar disorder and migraine are still not fully understood. However, recent findings reviewed here shed new light on the cellular effects of valproate. Beyond the enhancement of gamma-aminobutyric acid-mediated neurotransmission, valproate has been found to affect signalling systems like the Wnt/beta-catenin and ERK pathways and to interfere with inositol and arachidonate metabolism. Nevertheless, the clinical relevance of these effects is not always clear. Valproate treatment also produces marked alterations in the expression of multiple genes, many of which are involved in transcription regulation, cell survival, ion homeostasis, cytoskeletal modifications and signal transduction. These alterations may well be relevant to the therapeutic effects of valproate, and result from its enhancement of activator protein-1 DNA binding and direct inhibition of histone deacetylases, and possibly additional, yet unknown, mechanism(s). Most likely, both immediate biochemical and longer-term genomic influences underlie the effects of valproate in all three indications.
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PMID:The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees? 1751 56

One common feature of chronic musculoskeletal pain and headaches are that they are both influenced by stress. Among these, tension-type headache (TTH), fibromyalgia (FMS) and chronic shoulder/neck pain (SNP) appear to have several similarities, both with regard to pathophysiology, clinical features and demographics. The main hypothesis of the present study was that patients with chronic pain (TTH, FMS and SNP) had stress-induced features distinguishing them from migraine patients and healthy controls. We measured pain, blood pressure, heart rate (HR) and skin blood flow (BF) during (1 h) and after (30 min) controlled low-grade cognitive stressor in 22 migraine patients, 18 TTH patients, 23 FMS patients, 29 SNP patients and 44 healthy controls. FMS patients had a lower early HR response to stress than migraine patients, but no differences were found among FMS, TTH and SNP patients. Finger skin BF decreased more in FMS patients compared to migraine patients, both during and after the test. When comparing chronic pain patients (chronic TTH, FMS and SNP) with those with episodic pain (episodic TTH and migraine patients) or little or no pain (healthy controls), different adaptation profiles were found during the test for systolic and diastolic blood pressure, HR and skin BF in the chronic group. In conclusion, these results suggest that TTH, FMS and SNP patients may share common pathophysiological mechanisms regarding the physiological responses to and recovery from low-grade cognitive stress, differentiating them from episodic pain conditions such as migraine.
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PMID:Similarities in stress physiology among patients with chronic pain and headache disorders: evidence for a common pathophysiological mechanism? 1837 56

Central sensitisation phenomena have been well recognized in the development of migraine attacks and tension type headache. It is also known that headache frequency is related to sensitization. Though some studies have focused on the effects of symptomatic treatment on allodynia, few reports have described the action of preventive agents on the facilitating factors for central sensitisation. In this study we aim to review the factors concurrent with an increase in central sensitisation, in view of the choice of preventive agents for primary headaches. Central sensitisation phenomena are increased in pain syndromes with psycho-pathological co-morbidities. For instance, sleep disorders are a frequent symptom in headache, prevailing in chronic forms and in patients with psychiatric comorbidity. Sleep deprivation is also a factor producing hyperalgesic changes. It is known that symptoms attributable to central sensitization are diffusely pronounced in fibromyalgic (FMS) patients, and that FMS co-morbidity is frequent in primary headaches and associated with higher frequency and poorer quality of life. We report our preliminary experience in a group of 20 chronic migraine patients, treated with duloxetine 60 mg/die vs a self-management program including stretching (relaxation training) and exercise (cervical-dorsal flexion and rotation) to decrease strength and flexibility of muscles of cervical and dorsal spine headache patients. Both the treatments were effective on headache frequency and pericranial tenderness, although FMS comorbidity significantly reduced their efficacy on migraine and quality of life. The whole spectrum of action of pharmacological and non pharmacological treatments on central sensitisation mechanisms, and on their facilitating factors, should be taken into account for the best preventive therapeutic approach of primary headaches.
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PMID:Central sensitisation phenomena in primary headaches: overview of a preventive therapeutic approach. 1912 9

Tension - type headache is one of the widely spread types of idiopathic headaches. The pathogenesis of the disease includes depression and change in brain serotonin level. The aim of the research is to study the characteristics of ache and the level of serotonin in blood serum in tension-type headache. The intensity of ache, complex psychometric parameters and the level of serotonin in blood serum were investigated in 100 patients (75% females and 25% males from 17 to 55 years old) with tension-type headache. The average period of the illness was 6-5 years. The diagnosis has been determined according to MKGB (2003) criteria. According to the duration of anamnesis of ache the patients were divided into 3 groups: the first - 66 patients, the second - 24 patients, the third - 10 patients with tension-type headache and migraine. Ache status and its impact on different spheres of activity were assessed according to international 150 millimeters visual analogous scale. The research showed that all patients with tension-type headache had moderate ache syndrome, depression and anxiety of the middle or high rate which were in inverse dependence on serotonin rate in the blood. Intensity of episodic tension-type headache (n=24) was 52 mm according to visual analogous scale, the high rate of anxiety (51,08+/-4,2 scores), moderate rate of depression (12,9 scores according to Bek scale) and tendency of serotonin decreasing in blood (205,72+/-6,74 ng ml) was noted. The research of 76 patients with chronic tension-type headache with cephalgy intensity according to VASH 62 mm the high indicators of reactive (46,81+/-2,68 scores) and personal anxiety, the rate of depression (22,4+/-1,64 according to Bek scale) were associated with the displayed decreasing of serotonin amount in blood (119,38+/-9,42 ng/ml). It was concluded that, tension-type headache and moderate ache syndrome leads to depression decreased self-control of pain and life quality. The quality of serotonin in blood decreases in patients with tension-type headache. The relationship between the intensity of pain syndrome, decrease of work capacity, life quality, and quantity of serotonin in patients with ageing was revealed. It is concluded that serotonin level in blood serum may be considered as pain intensity, degree of depression and index of efficacy of depression treatment. Serotonin is an extremely important neurohormone and its metabolism further study will show new characteristic features of its activity in cerebral neurochemical processes. Scientists thought, that the increased activity caused the psychological disorder, changes in the mood and depression. But the results of the last studies show that the person with the abnormal activity of serotonin does not realize the sense of danger and accordingly the main instinct of self-preservation is broken.
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PMID:[Relationship between serum blood serotonin and tension--type headache]. 1957 13


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