MH_dev_122

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 LTB 4 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 LTB 4 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 LTD 4 and LTB 4 receptor antagonists on indomethacin-induced gastric epithelial damage ( measured by permeability to [ 51Cr ] DB00974 ) were assessed . The two Q9Y271 REA antagonists ( MK - 571 and DB00549 SUB ) significantly reduced the permeability changes induced by indomethacin , while the two LTB 4 antagonists ( SC - 41930 and LY -255,283 ) were without significant effect . Despite the reduction of gastric epithelial injury , blockade of LTD 4 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 MEN ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 REA , P28222 REA , Q8IWU9 , P09172 REA , P21917 REA , P21964 REA , and P60880 REA ) in the response to DB00422 MEN 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 MEN responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of DB00422 MEN 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 REA ) 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 REA 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 REA / B agonist , and meta-trifluoro-methylphenyl-piperazine HCl ( TFMPP ) , a more selective P28222 REA 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 REA , 5 - HT2 , and 5 - Q9H205 REA 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 REA and P16070 REA molecules . The expression of P05362 REA , but not P16070 REA , was significantly enhanced by the treatment with P01375 REA ( 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 REA or P16070 REA expression in vitro . During coculture experiments unstimulated mesothelial cells were almost nonadherent for both resident and elicited peritoneal mononuclear leukocytes for several hours . P01375 REA or P01133 REA 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 REA resulted in the macrophage colony-stimulating activity ( M - Q13216 REA ) production . M - Q13216 REA was mainly due to P09603 REA as confirmed with anti P09603 REA monoclonal antibody ; the residual M - Q13216 REA was not formed by GM - P04141 REA . After several passages the mesothelial cells started to produce M - Q13216 REA spontaneously .

Plasma levels of DB02527 , cGMP and P8 0511 in sildenafil-induced headache . DB00203 MENMAX DB00203 MEN , a selective inhibitor of the cyclic guanosine monophosphate ( cGMP ) degrading phosphodiestrase 5 ( O76074 REA ) , 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 ( P8 0511 ) . 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 P8 0511 , 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 P8 0511 , cGMP and DB02527 were detected after sildenafil compared with placebo . In conclusion , plasma levels of P8 0511 , 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 REA ) , a substrate of P08684 REA . The effects of azithromycin on Q13216 REA disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 REA which remained unchanged throughout the study . DB00207 MEN was administered for 3 days . Baseline measurements of Q13216 REA 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 REA blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 REA on both days 2 and 5 , and the C ( max ) values of Q13216 REA . 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 / dayx 3 days ) does not alter the disposition kinetics of Q13216 REA in a clinically significant way , and that Q13216 REA dosage adjustments are not warranted in renal transplant patients taking these two drugs together .

Roles of calcitonin gene-related peptide ( P8 0511 ) 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 ( P8 0511 ) could modulate leukotriene D4 ( LTD 4 ) - 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 ) , P8 0511 (8 - 37 ) ( P8 0511 receptor antagonist ) , P8 0511 , MK - 571 ( Q9Y271 REA antagonist ) , MK - 886 ( P09917 REA inhibitor ) , or P8 0511 (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 P8 0511 significantly reduced the responses to HC , while P8 0511 (8 - 37 ) enhanced HC-induced responses . Pretreatment with P8 0511 (8 - 37 ) and MK - 571 in combination attenuated HC-induced constriction . In addition , pretreatment with P8 0511 reduced responses induced by intravenous administration of LTD 4 . These observations suggest that P8 0511 might be involved in the pathophysiology of hyperpnea-induced constriction in guinea pigs via modulation of LTD 4 - 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 ( LTD 4 ) , an essential intracellular mediator of G - P04141 REA signaling . We report here that HQ ( 0.5- 4.0 microM ) , as well as LTD 4 ( 1 nM - 10 microM ) , causes a concentration-dependent induction of granulocytic differentiation in 32D myeloblasts . Unlike LTD 4 , 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 REA antagonist , MK - 571 , suggest that BQ induces granulocytic differentiation in myeloblasts by activating the Q9Y271 REA , thus obviating the requirement for LTD 4 . This was confirmed by the demonstration that HQ , in the presence of LTD 4 , shifts the stage-specific pattern of terminal differentiation induced by LTD 4 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 LTD 4 , 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 LTD 4 was observed . The responses to LTD 4 were reduced by 80 to 90 % in calcium-free buffer . The responses to LTD 4 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 LTD 4 were blocked by two specific LTD 4 antagonists , MK - 0571 and DB00549 SUB , in a concentration-dependent manner . When given after addition of LTD 4 , MK - 0571 or DB00549 SUB reversed the sustained phase of the LTD 4 - induced response , suggesting that maintenance of the response requires persistent activation of the Q9Y271 REA . DB00549 SUB 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 .