interacts_with DB00998?
The low-potency , voltage-dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high-affinity human ether-a-go-go-related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower-affinity Q12809 blockers may be different . In this study , alanine-substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . DB01182 's blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open-channel model ) . These findings are supported by very slow recovery of wild-type Q12809 channels from block at -120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open-state propafenone binding-site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi-stacking interactions with two or more Phe656 side-chains ) is either perturbed or becomes less accessible because of closed-channel gating . This provides further evidence for the existence of gating-induced changes in the spatial location of Phe656 side chains . DB00171 -sensitive potassium channels ( K( DB00171 ) ) in retina : a key role for delayed ischemic tolerance . The objectives of the present study were to determine the localization of K( DB00171 ) channels in normal retina and to evaluate their potential roles in ischemic preconditioning ( IPC ) in a rat model of ischemia induced by increased intraocular pressure ( IOP ) . Brown Norway rats were subjected to sublethal 3- , lethal 20- and 40-min ischemia and the functional recovery was evaluated using electroretinography . The time interval between ischemic insults ranged from 1 to 72 h . The effects of K( DB00171 ) channel blockade on IPC protection were studied by treatment with 0.01 % glipizide . IPC was mimicked by injection of K( DB00171 ) channel openers of 0.01 % (-)cromakalim or 0.01 % P1060 72 h before 20-min ischemia . Co-expression of K( DB00171 ) channel subunits Kir6.2/ Q09428 was observed in the retinal pigment epithelium , inner segments of photoreceptors , outer plexiform and ganglion cell layers and at the border of the inner nuclear layer . In contrast to a 20- or 40-min ischemia , a 3-min ischemia induced no alteration of the electroretinogram ( ERG ) and constituted the preconditioning stimulus . An ischemic challenge of 40 min in preconditioned rats induced impairment of retinal function . However , animals preconditioned 24 , 48 and 72 h before 20-min ischemia had a significant improvement of the ERG . (-)Cromakalim and P1060 mimicked the effect of IPC . DB01067 significantly suppressed the protective effects of preconditioning . In conclusion , activation of K( DB00171 ) channels plays an important role in the mechanism of preconditioning by enhancing the resistance of the retina against a severe ischemic insult . Serotonergic modulation of the acoustic startle response in rats during preweaning development . The involvement of serotonin ( 5-HT ) in modulating the acoustic startle response ( ASR ) is well established in adult rats , but 5-HT involvement during the preweaning period , when 5-HT neurons undergo extensive development , has not previously been described . Three 5-HT receptor subtypes are reported to modulate the ASR in adult rats : P08908 and 5-HT2 receptor agonists facilitate the ASR , whereas P28222 agonists decrease the response . In the present study , the effects of 5-HT agonists and generalized 5-HT depletion on the ASR were studied in preweanling animals , using independent groups of Long-Evans rats tested on postnatal day ( P01160 ) 13 , 17 and 21 . 8-Hydroxy-2-(di-n-propylamino) tetralin ( 8OHDPAT , 62-1000 micrograms/kg ) , a P08908 receptor agonist , and 5-methoxy-N,N-dimethyl tryptamine ( MeODMT , 2-4 mg/kg ) , a nonselective 5-HT agonist , had no effect on P01160 13 and then increased the ASR on P01160 17 and 21 . The 5-HT2 receptor antagonists cyproheptadine ( 5 mg/kg ) and ketanserin ( 5 mg/kg ) blocked the effect of MeODMT at both ages , providing some evidence that MeODMT increased the ASR through 5-HT2 receptors . 1-(m-Chlorophenyl) piperazine ( mCPP , 1-5 mg/kg ) , a P28222 agonist , had no effect on ASR amplitude on P01160 13 or 17 and then produced a dose-related decrease in the response on P01160 21 . Generalized depletion of 5-HT by 80-90 % in whole-brain and spinal cord , using p-chlorophenylalanine ( PCPA , 300 mg/kg 24 hr prior to testing ) , did not alter ASR amplitude at any age. ( ABSTRACT TRUNCATED AT 250 WORDS ) Differences in transcript levels of ABC transporters between pancreatic adenocarcinoma and nonneoplastic tissues . OBJECTIVES : The aim of this study was to evaluate transcript levels of all 49 human DB00171 -binding cassette transporters ( ABCs ) in one of the most drug-resistant cancers , namely , the pancreatic ductal adenocarcinoma ( PDAC ) . Association of ABCs levels with clinical-pathologic characteristics and P01116 mutation status was followed as well . METHODS : Tumors and adjacent nonneoplastic tissues were obtained from 32 histologically verified PDAC patients . The transcript profile of ABCs was assessed using quantitative real-time polymerase chain reaction with a relative standard curve . P01116 mutations in exon 2 were assessed by high-resolution melting analysis and sequencing . RESULTS : Most ABCs were deregulated in PDAC and 10 ABCs were associated with clinical-pathologic characteristics . P01116 mutations did not change the global expression profile of ABCs . CONCLUSIONS : The expression of ABC transporters was significantly deregulated in PDAC tumors when compared to nonmalignant tissues . The observed up-regulation of P21439 , O95342 , P33527 , O15438 , O15440 , Q5T3U5 , and Q9UNQ0 in tumors may contribute to the generally poor treatment response of PDAC . The up-regulation of O95477 , Q8IZY2 , and P45844 implicates a serious impairment of cellular cholesterol homeostasis in PDAC . On the other hand , the observed down-regulation of Q99758 , O95255 , P13569 , and Q09428 suggests a possible role of stem cells in the development and progression of PDAC . A DNA hypermethylation profile reveals new potential biomarkers for prostate cancer diagnosis and prognosis . BACKGROUND : DNA hypermethylation has emerged as a novel molecular biomarker for the evaluation of prostate cancer diagnosis and prognosis . Defining the specific gene hypermethylation profile for prostate cancer could involve groups of genes that specifically discriminate patients with indolent and aggressive tumors . METHODS : Genome-wide methylation analysis was performed on 83 tumor and 10 normal prostate samples using the GoldenGate Methylation Cancer Panel I ( Illumina , Inc. ) . All clinical stages of disease were considered . RESULTS : We found 41 genes hypermethylated in more than 20 % of the tumors analyzed ( P < 0.01 ) . Of these , we newly identified P28161 and P01210 as being genes that are hypermethylated in prostate cancer and that were simultaneously methylated in 40.9 % of the tumors analyzed . We also identified panels of genes that are more frequently methylated in tumor samples with clinico-pathological indicators of poor prognosis : a high Gleason score , elevated Ki-67 , and advanced disease . Of these , we found simultaneous hypermethylation of P13569 and P28222 to be common in patients with a high Gleason score and high Ki-67 levels ; this might indicate the population at higher risk of therapeutic failure . The DNA hypermethylation profile was associated with cancer-specific mortality ( log-rank test , P = 0.007 ) and biochemical recurrence-free survival ( log-rank test , P = 0.0008 ) . CONCLUSIONS : Our findings strongly indicate that epigenetic silencing of P28161 and P01210 is a common event in prostate cancer that could be used as a molecular marker for prostate cancer diagnosis . In addition , simultaneous P28222 and P13569 hypermethylation could help discriminate aggressive from indolent prostate tumors . Very early-onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early-onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 -3B , P01160 , and P36382 from 192 early-onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7.6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0.1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4.1 % ; with minor allele frequency < 0.1 ; P = .0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early-onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF . A review of the use of frovatriptan in the treatment of menstrually related migraine . Menstrual migraine ( MM ) is a highly prevalent condition associated with considerable disability . Migraine attacks occur exclusively around the menstrual period in approximately 10 % of women with migraine , that is , pure menstrual migraine , while at least 50 % of them also experience migraine at other times of the month , that is , menstrually related migraine ( MRM ) . The therapeutic approach to patients with MRM is based on treatment of the attack , or prophylactic strategies . Triptans are recommended as first-line treatments for moderate to severe migraine attacks , including MM . DB00998 is one of the newest triptans . Its high affinity for P28222 /1D receptors and long half-life contribute to its distinctive clinical effect , characterized by a more sustained and prolonged effect than other triptans . Indeed , frovatriptan proved to be effective in treating the acute attack , but was particularly effective in the short-term preventive therapy of MM . In addition , frovatriptan is one of the safest triptans , with the lowest risk of treatment-emergent adverse events . Following extensive evidence from randomized pharmacological trials , frovatriptan has now gained a grade A recommendation from the guidelines for short-term prophylaxis of MM . Recent post-hoc analyses of direct comparative trials also suggest that frovatriptan might have an important role in the acute treatment of MRM . In these studies , frovatriptan showed pain relief and pain-free rates similar to those of zolmitriptan , rizatriptan , and almotriptan , but with significantly lower recurrence rates . More well-designed , randomized , prospective studies , specifically enrolling women with MM , will be needed in the near future to confirm the efficacy of frovatriptan in this migraine subtype . DB00998 : a selective type 1B/1D serotonin receptor agonist for the treatment of migraine headache . DB00998 belongs to an innovative family of compounds aimed at breaking through the long-standing barrier of migraine headache understanding and treatment . While a typology of headaches has been recognized for some time , and a number of therapies have been introduced for reduction of headache pain and duration , the causes of migraine remain a subject of debate . Those prone to attacks continue to endure them and suffer the related symptoms such as nausea and disorientation . DB00998 , like all the triptans , acts by inducing vasoconstriction of the meningeal arteries . It has been shown in pharmacological tests to act selectively as a potent agonist of serotonin P28222 /1D receptors . DB00998 has been well tolerated in humans and efficacious in reducing headache pain and duration in clinical trials , which have also indicated that dose adjustments for age or gender are not necessary for the drug . Patients have found the use of frovatriptan acceptable over the long-term , and overall a low-incidence of adverse effects has been reported . Though not a prophylactic , frovatriptan has demonstrated the potential to significantly improve the therapeutic approaches to the treatment of migraine . DB00998 . black triangle DB00998 , a new serotonin receptor agonist developed for the acute treatment of migraine , has high affinity for serotonin P28222 and P28221 receptor subtypes and is a potent stimulator of contraction in human basilar arteries. black triangle A long terminal elimination half-life ( approximately 26 hours ) is a distinctive pharmacokinetic feature of frovatriptan which appears to be independent of dose , age , gender and renal function. black triangle A single oral dose of frovatriptan 2.5mg was effective in the acute treatment of migraine providing meaningful relief within 2 hours to approximately twice as many recipients as placebo in clinical trials. black triangle Consistent relief of migraine symptoms was achieved in patients who treated a number of consecutive attacks with frovatriptan and the incidence of 24-hour migraine recurrence was reduced. black triangle DB00998 was well tolerated in clinical trials , with the overall incidence of adverse events occurring with frovatriptan 2.5mg only slightly higher than that reported with placebo . Mild to moderate fatigue , nausea and paraesthesia were the most commonly reported drug-related adverse events . DB00998 Vernalis . Vanguard ( now Vernalis ) has developed frovatriptan , a selective P28222 /1D partial agonist licensed from GlaxoSmithKline as a potential treatment for migraine [ 188478 ] , [ 194382 ] , [ 377863 ] . Structure functional expression and spatial distribution of a cloned cDNA encoding a rat P28221 -like receptor . Using polymerase chain reaction ( PCR ) a complementary DNA ( cDNA ) encoding a 5-hydroxytryptamine ( 5-HT ) receptor was isolated from rat forebrain . The amplified cDNA specifies an open reading frame of 374 amino acids comprising seven putative transmembrane regions . Expression of the cloned cDNA in human embryonic kidney cells ( P29320 293 ) was used to establish the pharmacological profile of the encoded receptor polypeptide . Membranes containing the cloned receptor showed high affinity binding of [ 3H ] -5-HT . Competition binding experiments with a variety of serotonin receptor ligands displayed a rank order of affinities corresponding to a P28221 subtype : 5-CT > 5-HT = metergoline > CGS 12066 > methysergide > sumatriptan > mianserin = (-)alpha-Me-5-HT = yohimbine > 8-OH-DPAT > or = rauwolscine > spiperone > DOI > propranolol > or = 2-Me-5-HT > or = ICS 205930 . Ketanserin and ritanserin displaced [ 3H ] -5-HT-binding in a biphasic manner . In situ hybridization revealed highest expression of the corresponding mRNA in the pyramidal layer of the olfactory tubercle and the nucleus caudatus and accumbens . DB00175 -induced proangiogenic effects depend upon extracellular P09038 . The P04035 inhibitors ( statins ) have been shown to exert several protective effects on the vasculature that are unrelated to changes in the cholesterol profile , and to induce angiogenesis . The proangiogenic effect exerted by statins has been attributed to the activation of the PI3K/Akt pathway in endothelial cells ; however , it is unclear how statins activate this pathway . DB00175 -mediated activation of Akt and MAPK occurs rapidly ( within 10 min. ) and at low doses ( 10 nM ) . Here , we hypothesized that P09038 contributes to the proangiogenic effect of statins . We found that pravastatin , a hydrophilic statin , induced phosphorylation of the FGF receptor ( FGFR ) in human umbilical vein endothelial cells . SU5402 , an inhibitor of FGFR , abolished pravastatin-induced PI3K/Akt and MAPK activity . Likewise , anti- P09038 function-blocking antibodies inhibited Akt and MAPK activity . Moreover , depletion of extracellular P09038 by heparin prevented pravastatin-induced phosphorylation of Akt and MAPK . Treatment with P09038 antibody inhibited pravastatin-enhanced endothelial cell proliferation , migration and tube formation . These observations indicate that pravastatin exerts proangiogenic effects in endothelial cells depending upon the extracellular P09038 . Estrogen regulation of uterine genes in vivo detected by complementary DNA array . INTRODUCTION : In the present study , our aim was to identify differentially expressed genes involved in estrogen actions at the endometrium level in rats . METHODS : Thirty adult rats were ovariectomized four days prior to drug administration for 48 days . Rats were divided in 2 groups : I , control and II , conjugated equine estrogens ( CCE ) . Total RNA was isolated from uterus , and differential expression was analyzed by array technology and RT-PCR . RESULTS : A total of 32 candidate genes were shown to be upregulated or downregulated in groups I or II . Among them , differential expression was already confirmed by RT-PCR for P24593 , P28222 , c-kit , and P15692 , genes whose expression was up regulated during CCE therapy , and casein kinase II and serine kinase expression was the same level in both groups . CONCLUSION : We have demonstrated that cDNA array represents a powerful approach to identify key molecules in the estrogens therapy . A number of the candidates reported here should provide new markers that may contribute to the detection of target estrogen receptor . This information may also aid the development of new approaches to therapeutic intervention . Correcting human mitochondrial mutations with targeted RNA import . Mutations in the human mitochondrial genome are implicated in neuromuscular diseases , metabolic defects , and aging . An efficient and simple mechanism for neutralizing deleterious mitochondrial DNA ( mtDNA ) alterations has unfortunately remained elusive . Here , we report that a 20-ribonucleotide stem-loop sequence from the H1 RNA , the RNA component of the human RNase P enzyme , appended to a nonimported RNA directs the import of the resultant RNA fusion transcript into human mitochondria . The methodology is effective for both noncoding RNAs , such as tRNAs , and mRNAs . The RNA import component , polynucleotide phosphorylase ( Q8TCS8 ) , facilitates transfer of this hybrid RNA into the mitochondrial matrix . In addition , nucleus-encoded mRNAs for mitochondrial proteins , such as the mRNA of human mitochondrial ribosomal protein P28222 ( O15235 ) , contain regulatory sequences in their 3'-untranslated region ( UTR ) that confers localization to the mitochondrial outer membrane , which is postulated to aid in protein translocation after translation . We show that for some mitochondrial-encoded transcripts , such as P35354 , a 3'-UTR localization sequence is not required for mRNA import , whereas for corrective mitochondrial-encoded tRNAs , appending the 3'-UTR localization sequence was essential for efficient fusion-transcript translocation into mitochondria . In vivo , functional defects in mitochondrial RNA ( mtRNA ) translation and cell respiration were reversed in two human disease lines . Thus , this study indicates that a wide range of RNAs can be targeted to mitochondria by appending a targeting sequence that interacts with Q8TCS8 , with or without a mitochondrial localization sequence , providing an exciting , general approach for overcoming mitochondrial genetic disorders . Shared and unique genetic contributions to attention deficit/hyperactivity disorder and substance use disorders : a pilot study of six candidate genes . The shared genetic basis of attention deficit/hyperactivity disorder ( ADHD ) and substance use disorders ( SUDs ) was explored by investigating the association of candidate risk factors in neurotransmitter genes with both disorders . One hundred seven methadone maintenance treatment patients , 36 having an ADHD diagnosis , 176 adult patients with ADHD without SUDs , and 500 healthy controls were genotyped for variants in the P21917 ( exon 3 VNTR ) , P21918 ( upstream VNTR ) , P28222 ( rs6296 ) , P09172 ( rs2519152 ) , P21964 ( rs4680 ; Val158Met ) , and P35372 ( rs1799971 ; 118A > G ) genes . Association with disease was tested using logistic regression models . This pilot study was adequately powered to detect larger genetic effects ( OR≥2 ) of risk alleles with a low frequency . Compared to controls , ADHD patients ( with and without SUDs ) showed significantly increased frequency of the P09172 ( rs2519152 : OR 1.73 ; CI 1.15-2.59 ; P=0.008 ) and the P35372 risk genotypes ( rs1799971 : OR 1.71 ; CI 1.17-2.50 ; P=0.006 ) . The P09172 risk genotype was associated with ADHD diagnosis , with the association strongest in the pure ADHD group . The P35372 risk genotype increased the risk for the combined ADHD and SUD phenotype . The present study strengthens the evidence for a shared genetic basis for ADHD and addiction . The association of P35372 with the ADHD and SUD combination could help to explain the contradictory results of previous studies . The power limitations of the study restrict the significance of these findings : replication in larger samples is warranted . Fluorescence energy transfer analysis of calmodulin-peptide complexes . The interactions between calmodulin and the tryptophan residues of synthetic peptides corresponding to the calmodulin binding domains of skeletal muscle myosin light-chain kinase and the plasma membrane calcium pump were examined . The single tryptophan residue contained in each peptide became relatively immobilized and inaccessible to iodide ion upon binding to calmodulin , indicating that the indole side chain was inserted into a hydrophobic cleft in the surface of calmodulin . Fluorescence energy transfer from peptidyl tryptophan residues to an AEDANS moiety attached to cysteine-26 of spinach calmodulin was measured . Included in these analyses was a tryptophan-containing peptide analog of the calmodulin binding domain of neuromodulin . These data indicated that the indole ring of each peptide inserted 32-35 A away from cysteine-26 and may therefore interact with the carboxyl-terminal lobe of P62158 in its " bent " conformation [ Persechini & Kretsinger ( 1988a ) J. Cardiovasc. Pharmacol. 12 ( Suppl 5 ) , S1- P28222 ; Ikura et al. ( 1992 ) Science 256 , 632-638 ; Vorherr et al. ( 1992 ) Eur. J. Biochem. 204 , 931-937 ] . The interchange of tryptophan-3 and phenylalanine-21 of the calcium pump peptide increased the efficiency of energy transfer to the AEDANS-moiety approximately 12-fold , reducing the calculated distance to 20 A . These data suggest that phenylalanine-21 of the calcium pump peptide interacts with the hydrophobic cleft in the amino-terminal lobe of P62158 . Meta-analysis of oral DB00669 therapy for migraine : number needed to treat and relative cost to achieve relief within 2 hours . OBJECTIVE : To determine the cost-effectiveness of the P28222 /1D agonists , or triptans , in the acute treatment of migraine . METHODS : To determine the cost-effectiveness of the triptans , a meta-analysis was conducted of the efficacy data from 27 oral DB00669 trials , using the endpoint of " pain-free " status within 2 hours after initial dosing as the indicator of efficacy . Efficacy data were used to determine the number needed to treat ( Q13423 ) to achieve pain-free status in 1 patient within 2 hours postdose and then applied the per-dose costs for each DB00669 to the Q13423 values . RESULTS : Rizatriptan 10 mg and almotriptan 12.5 mg were the most cost-effective of the triptans , costing $ 48.34 and $ 48.57 US dollars , respectively , to achieve pain-free status in 1 patient within 2 hours postdose . DB00998 2.5 mg was the most costly , with a cost-effective ratio of $ 162.49 US dollars . All other triptans fell between these extremes : zolmitriptan 5 mg ( $ 65.18 US dollars ) , sumatriptan 100 mg ( $ 70.83 US dollars ) , sumatriptan 50 mg ( $ 75.67 US dollars ) , zolmitriptan 2.5 mg ( $ 78.74 US dollars ) , and naratriptan 2.5 mg ( $ 141.43 US dollars ) , in decreasing order of cost-effectiveness . CONCLUSION : Using an Q13423 analysis , the least-costly drugs to achieve migraine cure within 2 hours are rizatriptan 10 mg and almotriptan 12.5 mg . From a population health perspective , the lower acquisition cost of almotriptan 12.5 mg allows for effective treatment of more patients than rizatriptan 10 mg for no additional medication cost . Opposed effects of lithium on the MEK- P29323 pathway in neural cells : inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms . DB01356 is widely used in the treatment of bipolar disorder , but despite its proven therapeutic efficacy , the molecular mechanisms of action are not fully understood . The present study was undertaken to explore lithium effects of the MEK/ P29323 cascade of protein kinases in astrocytes and neurons . In asynchronously proliferating rat cortical astrocytes , lithium decreased time- and dose-dependently the phosphorylation of MEK and P29323 , with 1 mM concentrations achieving 60 and 50 % inhibition of P29323 and MEK , respectively , after a 7-day exposure . DB01356 also inhibited [3H]thymidine incorporation into DNA and induced a G2/M cell cycle arrest . In serum-deprived , quiescent astrocytes , pre-exposure to lithium resulted in the inhibition of cell cycle re-entry as stimulated by the mitogen endothelin-1 : under this experimental setting , lithium did not affect the rapid , peak phosphorylation of MEK taking place after 3-5 min , but was effective in inhibiting the long-term , sustained phosphorylation of MEK . DB01356 inhibition of the astrocyte MEK/ P29323 pathway was independent of inositol depletion . Further , compound SB216763 inhibited Tau phosphorylation at Ser396 and stabilized cytosolic beta-catenin , consistent with the inhibition of glycogen synthase kinase-3 beta ( P49841 ) , but failed to reproduce lithium effects on MEK and P29323 phosphorylation and cell cycle arrest . In cerebellar granule neurons , millimolar concentrations of lithium enhanced MEK and P29323 phosphorylation in a concentration-dependent manner , again through an inositol and P49841 independent mechanism . These opposing effects in astrocytes and neurons make lithium treatment a promising strategy to favour neural repair and reduce reactive gliosis after traumatic injury . The efficacy and tolerability of frovatriptan and dexketoprofen for the treatment of acute migraine attacks . DB00998 is a DB00669 characterized by a high affinity for P28222 /1D receptors and a long half-life contributing to a more sustained and prolonged action than other triptans . DB09214 is a nonsteroidal anti-inflammatory drug with a relatively short half-life and rapid onset of action , blocking the action of cyclo-oxygenase , which is involved in prostaglandins ' production , thus reducing inflammation and pain . Both drugs have been successfully employed as monotherapies for the treatment of acute migraine attacks . The combination of these two drugs ( frovatriptan 2.5 mg plus dexketoprofen 25 or 37.5 mg ) has been tested in migraine sufferers , showing a rapid and good initial efficacy , with 2-h pain free rates of 51 % , and a high persistence in the 48-h following the onset of pain : recurrence occurred in only 29 % of attacks and sustained pain free rates were 43 % at 24- and 33 % at 48-h . Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products : inhibitory effect of gliclazide . AIM : We have previously demonstrated that advanced glycation end products ( AGEs ) stimulate bovine retinal endothelial cell ( BREC ) proliferation through induction of vascular endothelial growth factor ( P15692 ) production by these cells . We have also shown that gliclazide , a sulfonylurea which decreases oxidative stress , inhibits this effect . The aim of the present study was to characterize the signalling pathways involved in P51606 -induced BREC proliferation and P15692 production and mediating the inhibitory effect of gliclazide on these biological events . METHODS : BRECs were treated or not treated with AGEs in the presence or absence of gliclazide , antioxidants , protein kinase C ( PKC ) , mitogen-activated protein kinase ( MAPK ) or nuclear factor-kappaB ( NF-kappaB ) inhibitors . BREC proliferation was assessed by measuring [ 3H ] -thymidine incorporation into DNA . Activation of PKC , MAPK and NF-kappaB signal transduction pathways and determination of P15692 expression were assessed by Western blot analysis using specific antibodies . MAPK activity was also determined by an in vitro kinase assay . RESULTS : Treatment of BRECs with AGEs significantly increased cell proliferation and P15692 expression . AGEs induced P05771 translocation , extracellular signal-regulated protein kinase 1/2 and NF-kappaB activation in these cells . Pharmacological inhibition of these signalling pathways abolished P51606 effects on cell proliferation and P15692 expression . Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N-acetyl-l-cysteine resulted in a significant decrease in P51606 -induced activation of PKC- , MAPK- and NF-kappaB-signalling pathways . CONCLUSIONS : Our results demonstrate the involvement of PKC , MAPK and NF-kappaB in P51606 -induced BREC proliferation and P15692 expression . DB01120 inhibits BREC proliferation by interfering with these intracellular signal transduction pathways . DB00998 , a P28222 /1D receptor agonist for migraine . DB00998 is one of the most recent serotonin receptor agonists to receive FDA , approved labelling for use in the acute management of migraine with or without aura in adults . The mechanism of action of frovatriptan is thought to be similar to that of a serotonin agonist . However , frovatriptan has distinctive pharmacokinetic and pharmacologic properties , chiefly , a high affinity for serotonin receptors 1B and 1D and a long elimination half-life ; frovatriptan was shown to be more selective for cerebral than coronary arteries , a property which makes frovatriptan more favourable in patients at risk of coronary artery disease . Additionally , frovatriptan has a half-life of approximately 25 h , substantially longer than that of any other agent within its class . This property makes frovatriptan suitable for patients who typically suffer migraines of long duration and/or those who suffer migraine recurrence . The efficacy of frovatriptan in the treatment of acute migraine was demonstrated in five double-blind , randomised , placebo-controlled trials . At 2h , headache response rates for frovatriptan 2.5 mg ranged from 38 to 40 % compared to 22-35 % for placebo . Headache recurrence for frovatriptan 2.5 mg at 24h ranged from 9 to 14 % compared with 18 % in placebo subjects . DB00998 has no clinically significant pharmacokinetic interactions with drugs used for migraine prophylaxis or with commonly prescribed medications . Adverse effects of frovatriptan including dizziness , paresthesia , dry mouth , fatigue and flushing were generally mild and well tolerated . Given the fact that patient response to serotonin agonists is individualised , and selecting an effective agent may involve trial and error , frovatriptan is a welcome alternative in the acute management of migraine . P35372 and P20813 gene variants as risk factors in methadone-related deaths . DB00333 is a medication valued for its effectiveness in the treatment of heroin addiction ; however , many fatal poisonings associated with its use have been reported over the years . We have examined the association between P20813 and micro-opioid receptor ( P35372 ) gene variations and apparent susceptibility to methadone poisoning . Genomic DNA was extracted from postmortem whole blood of 40 individuals whose deaths were attributed to methadone poisoning . The presence of P20813 *4,*9 , and *6 alleles and the P35372 A118G variant was determined by SNP genotyping . P20813 *4 , *9 , and *6 alleles were found to be associated with higher postmortem methadone concentrations in blood ( P < or = 0.05 ) . P35372 A118G was also associated with higher postmortem methadone concentrations in blood but not to a level of statistical significance ( P = 0.39 ) . In these methadone-related deaths , P35372 118GA was associated with higher postmortem benzodiazepine concentrations ( P = 0.04 ) , a finding not associated with morphine-related deaths . The risk of a methadone-related fatality during treatment may be evaluated in part by screening for P20813 *6 and A118G . Effects of external calcium on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229-7 . DB01373 is a known signalling molecule in eukaryotic cells and plays a central role in the regulation of many cellular processes . In the following study , we report on the effect of external calcium treatments on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229-7 . We observed that the intracellular calcium content of P. bainier 229-7 mycelia was increased in response to exposure to high external Ca(2+) concentrations . Both ginsenoside Rd biotransformation and β-glucosidase activity were both found to be dependent on the external calcium concentration . At an optimal Ca(2+) concentration of 45 mM , maximal ginsenoside Rd bioconversion rate of 92.44 % was observed and maximal β-glucosidase activity of 0.1778 U was reached in a 72-h biotransformation . The Ca(2+) channel blocker Verapamil blocked the trans-membrane influx of calcium and decreased ginsenoside Rd biotransformatiom . In addition , β-glucosidase activity and ginsenoside Rd content decreased by 36.0 and 29.2 % respectively after a 72-h incubation in the presence of 0.05 mM P62158 ( P62158 ) antagonist DB00850 . These results suggest that both Ca(2+) channels and P62158 are involved in ginsenoside Rd biotransformation via regulation of β-glucosidase activity . This is the first report regarding the effects of calcium signal transduction on biotransformation and enzyme activity in fungi . Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase-2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long-term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( DB00461 ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti-inflammatory drugs ( NSAIDs ) , and the meta-analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10-fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared . A new cell culture-based assay quantifies vitamin K 2,3-epoxide reductase complex subunit 1 function and reveals warfarin resistance phenotypes not shown by the dithiothreitol-driven Q9BQB6 assay . BACKGROUND : DB00682 directly inhibits the vitamin K 2,3-epoxide reductase complex subunit 1 ( Q9BQB6 ) enzyme to effect anticoagulation . Q9BQB6 function has historically been assessed in vitro using a dithiothreitol ( DTT ) -driven vitamin K 2,3-epoxide reductase ( Q9BQB6 ) assay . DB00682 inhibits wild-type Q9BQB6 function by the DTT- Q9BQB6 assay . However , Q9BQB6 variants with warfarin resistance-associated missense mutations often show low Q9BQB6 activities and warfarin sensitivity instead of resistance . OBJECTIVES : A cell culture-based , indirect Q9BQB6 assay was developed and characterized that accurately reports warfarin sensitivity or resistance for wild-type and variant Q9BQB6 proteins . METHODS : Human coagulation factor (F)IX and Q9BQB6 variants were coexpressed in P29320 293T cells under standardized conditions at various warfarin concentrations . Secreted FIX activity served as surrogate marker to report wild-type and variant Q9BQB6 inhibition by warfarin . RESULTS AND CONCLUSIONS : DB00682 dose-response curves fit to the secreted FIX activity data for coexpressed hVKORC1 wild-type , Val29Leu , Val45Ala and Leu128Arg variants . The corresponding calculated IC50 values were 24.7 , 136.4 , 152.0 and 1226.4 nm , respectively . Basal activities in the absence of warfarin for all Q9BQB6 variants were similar to that of wild-type Q9BQB6 . Ranked IC50 values from the cell culture-based assay accurately reflect elevated warfarin dosages for patients with Q9BQB6 missense mutation-associated warfarin resistance . Activation of Akt1 by human 5-hydroxytryptamine (serotonin)1B receptors is sensitive to inhibitors of MEK . Akt1/protein kinase B and the mitogen-activated protein ( Q96HU1 ) kinases extracellular signal-regulated kinase 1 ( P27361 ) and P28482 have been shown to promote cell survival in a cell-specific manner . Since many receptors activate both pathways , inhibitors are commonly used to study the relative role of each pathway . In the present study , we examined the effects of PD098059 and U0126 , two structurally dissimilar inhibitors of Q96HU1 kinase kinase ( Q02750 /2 ) , on the activation of P29323 and Akt stimulated by human 5-hydroxytryptamine(1B) ( serotonin ) ( P28222 ) receptors . Surprisingly , pathways for activation of both P29323 and Akt were found to be sensitive to the two MEK inhibitors at concentrations commonly used to selectively inhibit the activation of P29323 . Both compounds caused complete inhibition of phosphorylation of P29323 and a maximal 60 % inhibition of P28222 receptor-mediated phosphorylation of Akt . Inhibition of Akt activation required almost complete inhibition of P29323 . Transfection with cDNA for activated forms of Q02750 /2 caused increased phosphorylation of P29323 but not of Akt , demonstrating that independent activation of MEK/ P29323 was insufficient for activation of Akt . Therefore , it is not clear whether inhibition of activation of Akt resulted from selective inhibition of MEK or from additional actions on other unidentified common pathways . Nevertheless , our findings that PD098059 and U0126 inhibit activation of Akt at commonly used concentrations demonstrate that in at least some systems , these compounds inhibit activation of both P29323 and Akt , and can not be used to discern the relative roles of each pathway in mediating cellular responses . Pharmacokinetic evaluation of frovatriptan . INTRODUCTION : Migraine is the most common painful neurological disorder , affecting 13 % of the general population . Triptans represent a powerful pharmacological tool in acute migraine treatment , however , a significant portion of treated patients can not have access to this class due to possible adverse affects . Today , a total of seven DB00669 molecules are available , representing a commonly prescribed migraine treatment . Although there is a need of extensive use of triptans , only 25 % of migraine patients are using triptans . AREAS COVERED : This review includes triptans and evidence for the use of frovatriptan . A systematic approach is used to discuss the pharmacodynamic and pharmacokinetic aspects of frovatriptan , considering the emerging data on the clinical efficacy of frovatriptan in the treatment of migraine and cluster headaches . The data were obtained by searching the following key words in MEDLINE : pharmacokinetic , pharmacodynamic , triptans , frovatriptan , migraine , menstrual migraine , relatively to the period 1988 - 2011 . EXPERT OPINION : DB00998 has been developed in order to improve safety and efficacy of triptans . It shows a favorable tolerability and efficacy profile , limited to 24/48-h headache recurrence , when compared with other triptans . Preclinical data suggest that the pharmacokinetic profile of frovatriptan may differ from other available triptans . In fact , among triptans , frovatriptan showed the highest potency at the P28222 receptor ( 8.2 ) and the longer half-life ( 26 h ) . These parameters determine the clinical properties of frovatriptan ; in particular the lowest rate of headache recurrence in comparison with other triptans . Constitutive G(i2)-dependent activation of adenylyl cyclase type II by the P08908 receptor . Inhibition by anxiolytic partial agonists . The P08908 receptor is implicated in depression and anxiety . This receptor couples to G(i) proteins to inhibit adenylyl cyclase ( AC ) activity but can stimulate AC in tissues ( e.g. hippocampus ) that express ACII . The role of ACII in receptor-mediated stimulation of DB02527 formation was examined in P29320 -293 cells transfected with the P08908 receptor , which mediated inhibition of basal and G(s)-induced DB02527 formation in the absence of ACII . In cells cotransfected with P08908 receptor and ACII plasmids , P08908 agonists induced a 1 . 5-fold increase in DB02527 level . Cotransfection of P08908 receptor , ACII , and Galpha(i2) , but not Galpha(i1) , Galpha(i3) , or Galpha(o) , resulted in an agonist-independent 6-fold increase in the basal DB02527 level , suggesting that G(i2) preferentially coupled the receptor to ACII . The P28222 receptor also constitutively activated ACII . Constitutive activity of the P08908 receptor was blocked by pertussis toxin and the Gbetagamma antagonist , betaCT , suggesting an important role for Gbetagamma-mediated activation of ACII . The DB00156 -149 --> Ala mutation in the second intracellular domain of the P08908 receptor disrupted Gbetagamma-selective activation of ACII . Spontaneous P08908 receptor activity was partially attenuated by P08908 receptor partial agonists with anxiolytic activity ( e.g. buspirone and flesinoxan ) but was not altered by full agonists or antagonists . Thus , anxiolytic activity may involve inhibition of spontaneous P08908 receptor activity . Differential functional activity of 5-hydroxytryptamine receptor ligands and beta adrenergic receptor antagonists at 5-hydroxytryptamine1B receptor sites in Chinese hamster lung fibroblasts and opossum renal epithelial cells . Functional activity of 5-hydroxytryptamine ( 5-HT ) receptor ligands and beta adrenergic receptor antagonists was studied at P28222 receptor sites in Chinese hamster lung ( CHL ) fibroblasts by measuring two cellular responses : inhibition of forskolin-stimulated cyclic AMP formation and potentiation of basic fibroblast growth ( BFGF ) induced mitogenesis . A good correlation was found between the potency of agonists to inhibit forskolin-induced cyclic AMP formation and their potency to potentiate P09038 -induced thymidine incorporation in CHL fibroblasts . Potent agonist activity was measured with 5-methoxy-3,1,2,3,6-tetrahydro-4-pyidinyl- 1H-indole ( RU 24,969 ) , 5-carboxamidotryptamine ( 5-CT ) , 3-(1,2,5,6)-tetrahydro-4-pyridyl-5-pyrrolo(3,2-b)pyril-5-one ( CP 93,129 ) and 5-HT , whereas sumatriptan displayed weak agonist activity at concentrations different from its binding affinity for P28222 binding sites . In contrast to the observed P28222 receptor-mediated agonist activity in opossum kidney cells for metergoline and the beta adrenergic receptor antagonists : cyanopindolol , 4-(3-tert-butyl-amino-2-hydroxypropoxy)-indole-2 carbonic acid isopropyl ester ( SDZ 21,009 ) , isamoltane , (-)-propranolol and (-)-pindolol , antagonist activity at P28222 receptor sites was yielded in CHL fibroblasts in accordance with the reported observations at rat brain P28222 receptors . Methiothepin was the only compound that antagonized both the opossum kidney cell and CHL fibroblast P28222 receptor-mediated responses although the antagonist effect was more pronounced in CHL fibroblasts. ( ABSTRACT TRUNCATED AT 250 WORDS ) Involvement of P28222 receptors in DB00669 -induced contractile responses in guinea-pig isolated iliac artery . Using a series of triptans we characterized in vitro the 5-hydroxytryptamine ( 5-HT ) receptor that mediates the contraction in guinea-pig iliac arteries moderately precontracted by prostaglandin F2alpha ( PGF2alpha ) . Additionally , we investigated by reverse-transcriptase polymerase chain reaction ( RT-PCR ) which DB00669 -sensitive receptor is present in this tissue . DB00998 , zolmitriptan , rizatriptan , naratriptan , sumatriptan , and almotriptan contracted guinea-pig iliac arteries with pD2 values of 7.52+/-0.04 , 6.72+/-0.03 , 6.38+/-0.06 , 6.22+/-0.05 , 5.86+/-0.05 and 5.26+/-0.04 respectively . For comparison , the pD2 values for 5-HT and 5-carboxamidotryptamine ( 5-CT ) were 7.52+/-0.02 and 7.55+/-0.03 respectively . In contrast to all other triptans tested , the concentration-response curve for eletriptan was biphasic ( first phase : 0.01-3 microM , pD2 approximately 6.6 ; second phase : > or = 10 microM ) . Contractions to 5-HT , 5-CT , frovatriptan , zolmitriptan , rizatriptan , naratriptan , sumatriptan , almotriptan , and eletriptan ( first phase ) were antagonized by the P28222 /1D receptor antagonist GR127935 ( 10 nM ) and the P28222 receptor antagonist SB216641 ( 10 nM ) . RT-PCR studies in guinea-pig iliac arteries showed a strong signal for the P28222 receptor while expression of P28221 and P30939 receptors was not detected in any sample . The present results demonstrate that DB00669 -induced contraction in guinea-pig iliac arteries is mediated by the P28222 receptor . The guinea-pig iliac artery may be used as a convenient in vitro model to study the (cardio)vascular side-effect potential of anti-migraine drugs of the DB00669 family .