interacts_with DB00549?
Pharmacological investigation of the role of leukotrienes in the pathogenesis of experimental NSAID gastropathy . The role of leukotrienes in the pathogenesis of acute gastric ulceration induced by nonsteroidal antiinflammatory drugs was investigated using a rat model . One part of the study involved oral pretreatment with a leukotriene synthesis inhibitor 1 h prior to administration of indomethacin ( 20 mg/kg per os ) . Three hours after indomethacin , the extent of macroscopically visible gastric damage was determined , and gastric LTB4 synthesis was determined . The compounds tested were PF-5901 , A-64077 , nordihydroguaiaretic acid , and L-698,037 . Each compound produced dose-related inhibition of gastric LTB4 synthesis and a parallel reduction in the severity of indomethacin-induced damage . The antioxidant properties of these compounds was assessed using an in vitro assay . There was no correlation between the antioxidant properties of the compounds and their ability to reduce the severity of indomethacin-induced gastric damage . In the second part of the study , the effects of intravenous , administration of LTD4 and LTB4 receptor antagonists on indomethacin-induced gastric epithelial damage ( measured by permeability to [51Cr] DB00974 ) were assessed . The two Q9Y271 antagonists ( MK-571 and DB00549 ) significantly reduced the permeability changes induced by indomethacin , while the two LTB4 antagonists ( SC-41930 and LY-255,283 ) were without significant effect . Despite the reduction of gastric epithelial injury , blockade of LTD4 receptors did not markedly affect the extent of macroscopically visible injury . These data are consistent with the hypothesis that leukotrienes contribute to the epithelial injury and macroscopically visible damage induced by NSAIDs . However , it remains unclear to what extent leukotrienes are involved in the initiation of the injury , as opposed to its amplification . No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( DB00422 ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to DB00422 in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between DB00422 responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of DB00422 among adults with ADHD . Brain 5-HT and inhibition of aggressive behavior in animals : 5-HIAA and receptor subtypes . Evolutionary constant serotonin ( 5-HT ) neuronal systems evolved along medial brain structures ; yet , wide variations in functionality characterize serotonergic systems in mediating aggressive responses in species ranging from lobsters , ants , electric fish , and rodents to primates . So far , the attempts to correlate cerebrospinal fluid ( P04141 ) 5-hydroxyindoleacetic acid ( 5-HIAA ) levels with measures of aggression have revealed inverse , direct , or no correlations in different nonhuman primate species . It is difficult to harmonize the occasional correlations between P04141 5-HIAA and adaptive aggressive acts in nonhuman primates ( a ) with clinically diagnosed suicidal or impulsive individuals , and ( b ) with the biochemical , anatomical , and presumably functional differentiation of 5-HT pathways and receptor subtypes . Eltoprazine , a mixed P08908 /B agonist , and meta-trifluoro-methylphenyl-piperazine HCl ( TFMPP ) , a more selective P28222 agonist , specifically decrease aggressive behavior in several animal species and situations in both sexes without detriment to other social , exploratory , or motoric activities . A definite role for P08908 , 5-HT2 , and 5- Q9H205 receptor subtypes in the mechanisms mediating aggressive behaviors has to await the development of selective agonists and antagonists , respectively . Interaction of murine peritoneal leukocytes and mesothelial cells : in vitro model system to survey cellular events on serosal membranes during inflammation . All serosal cavities including peritoneum are lined with a simple squamous mesothelium . Primary culture of murine mesothelial cells has been established to study their cellular interactions with peritoneal leukocytes . The mesothelial character was determined by the cytokeratin and vimentin expression . The mesothelial cells expressed P05362 and P16070 molecules . The expression of P05362 , but not P16070 , was significantly enhanced by the treatment with P01375 ( 100 U/ml ) . We have also investigated possible influence of transforming growth factors , TGF-alpha ( 20 ng/ml ) and TGF-beta ( 2 ng/ml ) , and epidermal growth factor ( 20 ng/ml ) . These factors were not found to modulate P05362 or P16070 expression in vitro . During coculture experiments unstimulated mesothelial cells were almost nonadherent for both resident and elicited peritoneal mononuclear leukocytes for several hours . P01375 or P01133 pretreatment of mesothelial cells greatly enhanced their adhesive affinity to peritoneal mononuclear leukocytes , while TGF-beta pretreatment even reduced the low basal adhesion . Prolonged coculture for 3 weeks resulted in remarkable proliferation and differentiation of both resident and elicited monocytes/macrophages on the mesothelial surface . The stimulation of mesothelial cell culture with P01133 resulted in the macrophage colony-stimulating activity ( M- Q13216 ) production . M- Q13216 was mainly due to P09603 as confirmed with anti P09603 monoclonal antibody ; the residual M- Q13216 was not formed by GM- P04141 . After several passages the mesothelial cells started to produce M- Q13216 spontaneously . Plasma levels of DB02527 , cGMP and P80511 in sildenafil-induced headache . DB00203 , a selective inhibitor of the cyclic guanosine monophosphate ( cGMP ) degrading phosphodiestrase 5 ( O76074 ) , induced migraine without aura in 10 of 12 migraine patients and in healthy subjects it induced significantly more headache than placebo . The aim of the present study was to determine whether the pain-inducing effects of sildenafil would be reflected in plasma levels of important signalling molecules in migraine : cGMP , cyclic adenosine monophosphate ( DB02527 ) and calcitonin gene-related peptide ( P80511 ) . Ten healthy subjects ( four women , six men ) and 12 patients ( 12 women ) suffering from migraine without aura were included in two separate double-blind , placebo-controlled , cross-over studies in which placebo or sildenafil 100 mg was administered orally . Plasma levels of P80511 , DB02527 and cGMP were determined in blood from the antecubital vein . Despite the ability of sildenafil to induce headache and migraine , no significant differences in plasma levels of P80511 , cGMP and DB02527 were detected after sildenafil compared with placebo . In conclusion , plasma levels of P80511 , cGMP and DB02527 remain normal during sildenafil-induced headache or migraine . However , since previous studies indicate an important role of these signalling molecules , the present study questions whether DB02527 and cGMP in peripheral blood can be used for monitoring pathophysiological events in headache and migraine mechanisms . Influence of a 3-day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug-drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . DB00207 was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg/day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C(max) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5/day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98,116 ) and 119 ( 104,136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg/dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together . Roles of calcitonin gene-related peptide ( P80511 ) in hyperpnea-induced constriction in guinea pigs . It has been reported that hyperpnea-induced bronchoconstriction in guinea pigs is a potential model for exercise-induced asthma in humans . We hypothesized that calcitonin gene-related peptide ( P80511 ) could modulate leukotriene D4 ( LTD4 ) -induced responses and be involved in the pathophysiology in this asthma model . We measured tracheal ( Ptr ) and alveolar pressure ( PA ) using alveolar capsules in open-chested , mechanically ventilated ( f = 1 Hz , VT = 9 ml/kg , PEEP = 4 cm H2O ) guinea pigs . Animals were intravenously pretreated with saline ( SAL ) , P80511 (8-37) ( P80511 receptor antagonist ) , P80511 , MK-571 ( Q9Y271 antagonist ) , MK-886 ( P09917 inhibitor ) , or P80511 (8-37) + MK-571 , and then underwent dry gas hyperpnea challenge ( HC , 95 % 02-5 % CO2 , 150 breaths/min , 7 min ) . We calculated resistance of lung ( RL ) , tissue ( Rti ) , and airway ( Raw ) . HC increased RL , Rti , and Raw in SAL controls ( 322 +/- 27 , 430 +/- 59 , 299 +/- 23 % baseline , respectively ) . MK-571 , MK-886 , and P80511 significantly reduced the responses to HC , while P80511 (8-37) enhanced HC-induced responses . Pretreatment with P80511 (8-37) and MK-571 in combination attenuated HC-induced constriction . In addition , pretreatment with P80511 reduced responses induced by intravenous administration of LTD4 . These observations suggest that P80511 might be involved in the pathophysiology of hyperpnea-induced constriction in guinea pigs via modulation of LTD4-elicited responses . Induction of granulocytic differentiation in myeloblasts by hydroquinone , a metabolite of benzene , involves the leukotriene D4 receptor . Chronic exposure of humans to benzene ( BZ ) , a Class I carcinogen , causes acute myelogenous leukemia , possibly via its bone marrow metabolite , hydroquinone ( HQ ) . The ability to alter cytokine-dependent growth and differentiation in hematopoietic stem or progenitor cells appears to be a property of agents with leukemogenic potential . We have previously reported that BZ and HQ specifically stimulate granulopoiesis in mice and cause granulocytic differentiation in normal murine interleukin ( IL ) -3-dependent , granulocyte colony-stimulating factor ( DB00099 ) -inducible 32D myeloblasts . BZ induces granulocytic differentiation by upregulating the production of leukotriene D4 ( LTD4 ) , an essential intracellular mediator of G- P04141 signaling . We report here that HQ ( 0.5-4.0 microM ) , as well as LTD4 ( 1 nM-10 microM ) , causes a concentration-dependent induction of granulocytic differentiation in 32D myeloblasts . Unlike LTD4 , which induces terminal granulocytic differentiation , HQ undergoes a myeloperoxidase-dependent oxidation to bioreactive p-benzoquinone ( BQ ) , which induces differentiation predominantly to the myelocyte stage . Studies with the highly specific Q9Y271 antagonist , MK-571 , suggest that BQ induces granulocytic differentiation in myeloblasts by activating the Q9Y271 , thus obviating the requirement for LTD4 . This was confirmed by the demonstration that HQ , in the presence of LTD4 , shifts the stage-specific pattern of terminal differentiation induced by LTD4 to the incomplete ( myelocyte ) profile induced by HQ . The inability of HQ to induce a complete program of terminal granulocytic differentiation in myeloblasts , as well as its ability to compete with induction by LTD4 , may have a bearing on the leukemogenic potential of BZ . Leukotriene D4-induced increases in cytosolic calcium in THP-1 cells : dependence on extracellular calcium and inhibition with selective leukotriene D4 receptor antagonists . Agonist-induced changes in intracellular calcium ion concentration ( [Ca++]i ) were examined in human monocytic leukemia THP-1 cells loaded with fura 2/acetoxymethyl ester ( fura 2/AM ) . Leukotriene (LT)D4 induced a concentration-dependent biphasic response consisting of a transient phase ( up to 5-fold peak increase ) followed by a sustained phase , showing characteristics of a receptor-operated calcium channel . Homologous desensitization to LTD4 was observed . The responses to LTD4 were reduced by 80 to 90 % in calcium-free buffer . The responses to LTD4 in a calcium-free buffer were dependent upon the duration of prior exposure of the cells to a calcium-free environment . The response at 30 or 60 min after exposure to calcium-free buffer was greater than that at earlier time points ( time-dependent sensitization ) . Similar responses were obtained with THP-1 cells exposed to DB00974 -containing buffer . It is speculated that such time-dependent sensitization is a result of changes at the receptor level . The responses to LTD4 were blocked by two specific LTD4 antagonists , MK-0571 and DB00549 , in a concentration-dependent manner . When given after addition of LTD4 , MK-0571 or DB00549 reversed the sustained phase of the LTD4-induced response , suggesting that maintenance of the response requires persistent activation of the Q9Y271 . DB00549 was 5 to 10 times more potent than MK-0571 ( IC50 values of 1.1 and 9.3 nM , respectively ) , in agreement with results from radioligand binding studies reported separately .