interacts_with DB00082?
P35354 [ corrected ] activation by endotoxin mediates the decrease in IGF1 , but not in P17936 , [ corrected ] gene expression in the liver . The aim of this work was to analyse the role of cyclooxygenase-2 ( Ptgs2 ) in endotoxin-induced decrease in Igf1 and Igf binding protein-3 ( Igfbp3 ) . For this purpose , male Wistar rats were injected with lipolysaccharide ( LPS ) and/or the Ptgs2 inhibitor meloxicam . LPS induced a significant decrease ( P < 0.01 ) in serum concentrations of Igf1 and Igfbp3 and their mRNAs in the liver . Meloxicam administration prevented the inhibitory effect of LPS injection on serum Igf1 and its liver mRNA . By contrast , meloxicam administration was unable to modify the inhibitory effect of LPS on Igfbp3 . LPS injection also induced a decrease in P10912 ( Ghr ) mRNA in the liver , and meloxicam attenuated this effect . In order to elucidate a direct action of the Ptgs2 inhibitor on the liver cells , the effect of LPS and/or meloxicam was studied in primary cultures of hepatocytes with non-parenchymal cells . LPS decreased Igf1 and Ghr but not Igfbp3 gene expression in liver cells in culture . Meloxicam administration attenuated the inhibitory effect of LPS on Igf1 mRNA , whereas it did not modify the decrease in Ghr mRNA after LPS . The effect of meloxicam on the LPS response does not seem to be mediated by changes in nitric oxide or tumour necrosis factor ( Tnf ) production , since meloxicam did not modify the stimulatory effect of LPS on nitric oxide or Tnfalpha gene expression both in vivo and in vitro . All these data suggest that LPS-induced Ptgs2 activation decreases Igf1 gene expression in liver cells . DB00082 : a new treatment modality for acromegaly . Acromegaly , a multisystemic disease resulting from excessive growth hormone ( GH ) and insulin-like growth factor-I ( P05019 ) levels in adults , is associated with a two-to-threefold increase in mortality . The available treatment options ( surgery , radiotherapy and medical treatment with somatostatin analogues or dopamine agonists ) fail to achieve the currently accepted goals of therapy in a substantial number of patients . DB00082 , a newly developed P10912 antagonist , represents a novel treatment modality for this disease . It binds with the P10912 and induces internalization , but blocks receptor signaling events , thereby reducing P05019 production . The two main published studies suggest that it is the most potent medical therapy with greater specificity , without being dependent on the tumour characteristics . However , apart from its high cost and the dilemmas raised concerning the appropriateness of using serum P05019 concentrations as a marker of disease activity , it may also occasionally be associated with elevations in liver enzyme levels . Further studies are required to confirm its high success rates as well as to investigate the possibility of inducing an increase in the pituitary tumour size . Currently , pegvisomant is a second line treatment for acromegaly with an adjuvant role and possibly of greater value in cases of resistance to other therapeutic options . P10912 antagonists . Growth hormone ( GH ) has profound effects on vertebrate growth and cellular differentiation in diverse tissue types . Sexually dimorphic levels of circulating GH vary during development and throughout the lifespan . The synthesis and secretion of GH by the pituitary gland are precisely controlled . Abnormal levels are pathological ; hyposecretion in children results in dwarfism while hypersecretion results in acromegaly . This review provides an overview of GH and the GH/insulin-like growth factor ( DB01277 ) axis and highlights a P10912 antagonist ( i.e. Somavert(R) , pegvisomant ) . This antagonist competes with endogenous GH for the receptor and results in suppression of serum insulin-like growth factor ( DB01277 ) . DB00082 is important for the treatment of acromegaly and may have therapeutic implications for certain types of cancer and end organ damage due to diabetes . DB00082 treatment in a 4-year-old girl with neurofibromatosis type 1 . BACKGROUND/AIMS : Growth hormone ( GH ) excess in childhood is a rare disorder . Current treatment options such as somatostatin analogues , pituitary surgery or irradiation can have serious side effects . Recently , a P10912 antagonist , pegvisomant , was introduced for the treatment of adults with acromegaly . We wanted to investigate whether pegvisomant was effective in a child with octreotide-resistant GH excess . CASE : A 4-year-old girl with neurofibromatosis type 1 and GH excess associated with optic glioma received pegvisomant injections ( 10 mg subcutaneously ) with increasing intervals from daily to every 4th day . RESULTS : P05019 and P17936 decreased from +6.9 and 4.6 standard deviation scores ( SDS ) , respectively , to within normal range . Height velocity dropped from 12.4 SDS to mean -0.7 SDS ( range : -5.0 to 5.0 ) and height SDS decreased from +1.3 to +0.6 ( target height : +0.2 ) . Random non-fasting serum GH values were mean 5.0 mlU/l ( range : 1.6-9.5 ) . There was no change in fasting blood glucose ( 4.6-4.7 mmol/l ) or glycosylated haemoglobin ( 5.5 % ) and no subjective or biochemical side effects . Repeated tests of thyroid , adrenal and gonadal function showed no alterations during the treatment period . Intracranial tumours remained unchanged in size and visual impairment did not deteriorate . CONCLUSION : DB00082 normalized P05019 and P17936 levels . Growth velocity was normalized after initial catch-down growth , and it remains to be seen whether this result can be maintained during long-term treatment . Growth hormone and glucose metabolism : the model of the GH-receptor antagonists . DB00082 is a GH analogue that includes a single amino acid substitution at position 120 that generates the P10912 antagonist . Additional changes include amino acid substitutions within binding site 1 and a further modification by the addition of polyethylene glycol moieties that increase the half-life and reduce the immunogenicity of the molecule . In acromegalics , pegvisomant is the most effective treatment for normalizing the P05019 , and pegvisomant significantly improves insulin sensitivity in patients suffering from acromegaly . However , there are simply no data available that might support a role for pegvisomant treatment in disorders in which glucose metabolism is disturbed and in which reducing GH action would be theoretically beneficial . Management of endocrine disease : GH excess : diagnosis and medical therapy . Acromegaly is predominantly caused by a pituitary adenoma , which secretes an excess of GH resulting in increased IGF1 levels . Most of the GH assays used currently measure only the levels of the 22 kDa form of GH . In theory , the diagnostic sensitivity may be lower compared with the previous assays , which have used polyclonal antibodies . Many GH-secreting adenomas are plurihormonal and may co-secrete prolactin , DB00024 and α-subunit . Hyperprolactinaemia is found in 30-40 % of patients with acromegaly , and hyperprolactinaemia may occasionally be diagnosed before acromegaly is apparent . Although trans-sphenoidal surgery of a GH-secreting adenoma remains the first treatment at most centres , the role of somatostatin analogues , octreotide long-acting repeatable and lanreotide Autogel as primary therapy is still the subject of some debate . Although the normalisation of GH and IGF1 levels is the main objective in all patients with acromegaly , GH and IGF1 levels may be discordant , especially during somatostatin analogue therapy . This discordance usually takes the form of high GH levels and an IGF1 level towards the upper limit of the normal range . DB06663 , a new somatostatin analogue , may be more efficacious in some patients , but the drug has not yet been registered for acromegaly . Papers published on pasireotide have reported an increased risk of diabetes mellitus due to a reduction in insulin levels . DB00082 , the P10912 antagonist , is indicated - alone or in combination with a somatostatin analogue - in most patients who fail to enter remission on a somatostatin analogue . Dopamine-D2-agonists may be effective as monotherapy in a few patients , but it may prove necessary to apply combination therapy involving a somatostatin analogue and/or pegvisomant . Drug-induced activation of SREBP-controlled lipogenic gene expression in CNS-related cell lines : marked differences between various antipsychotic drugs . BACKGROUND : The etiology of schizophrenia is unknown , but neurodevelopmental disturbances , myelin- and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder . DB04540 is an essential component of myelin and has proved important for synapse formation . Recently , we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element-binding protein ( SREBP ) transcription factors . We here compare the action of chlorpromazine , haloperidol , clozapine , olanzapine , risperidone and ziprasidone on SREBP activation and SREBP-controlled gene expression ( ACAT2 , P04035 , Q01581 , P14324 , O75845 , Q9UBM7 , P01130 , P49327 and SCD1 ) in four CNS-relevant human cell lines . RESULTS : There were marked differences in the ability of the antipsychotic drugs to activate the expression of SREBP target genes , with clozapine and chlorpromazine as the most potent stimulators in a context of therapeutically relevant concentrations . Glial-like cells ( GaMg glioma and CCF-STTG1 astrocytoma cell lines ) displayed more pronounced drug-induced SREBP activation compared to the response in Q9UL51 human cortical neurons and SH-SY5Y neuroblastoma cells , indicating that antipsychotic-induced activation of lipogenesis is most prominent in glial cells . CONCLUSION : Our present data show a marked variation in the ability of different antipsychotics to induce SREBP-controlled transcriptional activation of lipogenesis in cultured human CNS-relevant cells . We propose that this effect could be relevant for the therapeutic efficacy of some antipsychotic drugs . Experience from the Argentine DB00082 Observational Study : preliminary data . The P10912 antagonist pegvisomant is an efficient agent to achieve biochemical control of acromegaly in those cases refractory to surgery and medical therapy with somatostatin analogs . We conducted an observational multicenter study consisting of data collection in accordance with the standard management of patients with acromegaly in everyday practice . We reviewed the medical records of 28 patients , 23 females , who were treated with pegvisomant due to the lack of biochemical response or intolerance to the somatostatin analogs . The objective was to monitor long-term safety and efficacy of the antagonist . 82 % of the patients had previous pituitary surgery , 53.6 % radiotherapy and 96.4 % received medical therapy for acromegaly . Only 19.2 % of the patients had pituitary residual tumor size larger than 1 cm , the remainder harbored a microadenoma or no visible tumor in the pituitary images . In terms of biochemical efficacy , P05019 levels decreased to normal ranges in 45 % and 58.8 % of patients after 3 and 6 months of treatment , respectively , the daily mean dose of pegvisomant being 9.6+/-1.1 mg . Adverse events , potentially related to pegvisomant were reported in 6 patients ( 21.4 % ) , local injection site reaction and elevated liver enzymes being the most frequent . Tumor size did not show enlargement in the evaluated population ( 15 patients ) during the period of the study . This paper presents preliminary data from a small observational study in Argentina which represents the first database in our country . Elevated retinol binding protein 4 induces apolipoprotein B production and associates with hypertriglyceridemia . CONTEXT AND OBJECTIVE : A high level of retinol binding protein 4 ( P02753 ) is reported to be associated with insulin resistance in humans . However , evidence from large-scale populations about the relationship between serum P02753 and metabolic phenotypes is scarce . In the present study , we aimed to evaluate serum P02753 distribution and its association with metabolic phenotypes among middle-aged and elderly Chinese . DESIGN AND PARTICIPANTS : Serum concentrations of P02753 in a cross-sectional sample of 2780 Chinese population aged 50-70 years old in Guangzhou were measured by ELISA . RESULTS : The mean of serum P02753 concentration was 28.04 μg/mL for male and 37.76 μg/mL for female ( P < .01 ) , respectively . Circulating P02753 was positively correlated with serum triglyceride and apolipoprotein B ( apoB ) concentrations . The odds ratio ( OR ) was substantially higher for hypertriglyceridemia ( OR , 3.26 ; 95 % confidence interval , 2.36-4.51 ) in the highest P02753 quartile compared with those in the lowest quartile after multiple adjustment for confounders . Furthermore , serum P02753 was significantly associated with fasting glucose , insulin levels , and homeostasis model assessment index-insulin resistance ( HOMA-IR ) . Moreover , we showed that P02753 enhanced microsomal triglyceride transfer protein ( P55157 ) expression and activity via up-regulation of protein disulfide isomerase ( P07237 ) , suppressed low-density lipoprotein receptor ( P01130 ) expression , and impaired insulin-signaling pathway , leading to inductions in apoB secretion both in vitro and in vivo . CONCLUSIONS : Elevated circulating P02753 concentrations were associated with higher risk of hypertriglyceridemia by inducing the secretion of triglyceride-rich apoB-containing lipoproteins . Bovine somatotropin attenuates phorbol ester-induced prostaglandin F2alpha production in bovine endometrial cells . The recent observation that bovine somatotropin ( bST ) treatment at a timed insemination improves pregnancy rates in lactating dairy cows raises the possibility that growth hormone ( GH ) may modulate the endocrine and biochemical cross talk between the conceptus and maternal uterus at the time of pregnancy establishment in cattle . The objective of this study was to characterize the cellular and molecular mechanisms by which exogenous GH affects phorbol ester-induced prostaglandin F2alpha ( PGF2alpha ) production in cultured bovine endometrial ( BEND ) cells . Serum-deprived BEND cells were incubated with or without recombinant bovine GH ( rbGH ) , insulin-like growth factor ( IGF ) -I , recombinant bovine interferon ( rbIFN ) -tau or a combination of rbGH + rbIFN-tau for 3 h and then treated with phorbol 12,13-dibutyrate ( PDBu ) for an additional 6 h . Exogenous PDBu increased PGF2alpha secretion and steady-state levels of P35354 mRNA within 3 h . Priming of BEND cells with rbGH reduced PGF2alpha response to PDBu , whereas cotreatment with P05019 amplified PDBu induction of PGF2alpha . Preincubation of cell monolayers with rbIFN-tau suppressed PGF2alpha and P35354 mRNA responses to PDBu . Inhibitory effects of rbGH and rbIFN-tau on PDBu-induced PGF2alpha production were additive . Results provide the first direct evidence that supplemental bST may interact with conceptus-secreted IFN-tau to modulate PGF2alpha secretion at the critical time of maternal recognition of pregnancy . A pegylated growth hormone receptor antagonist , pegvisomant , does not enter the brain in humans . BACKGROUND : GH receptors exist in the hippocampus , cerebral cortex , and hypothalamus , possibly influencing mood , cortical blood flow , and neuronal growth and mediating negative feedback . RATIONALE : DB00082 is a recombinant mutated GH molecule with high affinity , but little or no activating capability , for the P10912 . It is used clinically as a GH antagonist . HYPOTHESIS : Systemic pegvisomant enters brain interstitial fluid via putative choroid-plexus GH receptors , thereby allowing for antagonism of central actions of GH . SUBJECTS AND LOCATION : Six adults requiring a cerebrospinal fluid ( P04141 ) examination for nonneoplastic and noninflammatory syndromes participated at a tertiary medical center . METHODS : Direct assays were conducted of serum and P04141 pegvisomant concentrations 18-24 h after sc injection of pegvisomant ( 20 mg ) . OUTCOMES : Median ( range ) concentrations of pegvisomant in serum were 215 ( 74-539 ) microg/liter and in P04141 0.035 ( 0.010-0.28 ) microg/liter ( P=0.016 ) . P04141 drug levels were indistinguishable from assay threshold . Corresponding GH values were 0.29 ( 0.010-1.3 ) in serum and 0.075 microg/liter ( 0.01-0.13 ) in P04141 . The geometric mean ratios of serum/ P04141 pegvisomant and GH concentrations were 5116:1 and 3.5:1 , respectively , thus defining a more than 1400-fold difference between mutated and natural GH . CONCLUSIONS : Based upon P04141 measurements , a pegylated GH-receptor antagonist does not cross the human blood-brain barrier , thereby sparing inhibition of central nervous system GH actions . Thus , the capability of this antagonist to stimulate GH secretion predominantly reflects its actions outside the blood-brain barrier , such as via the median eminence and/or via suppression of P05019 concentrations . Global transcriptome analysis of formalin-fixed prostate cancer specimens identifies biomarkers of disease recurrence . Prostate cancer remains the second leading cause of cancer death in American men and there is an unmet need for biomarkers to identify patients with aggressive disease . In an effort to identify biomarkers of recurrence , we performed global RNA sequencing on 106 formalin-fixed , paraffin-embedded prostatectomy samples from 100 patients at three independent sites , defining a 24-gene signature panel . The 24 genes in this panel function in cell-cycle progression , angiogenesis , hypoxia , apoptosis , PI3K signaling , steroid metabolism , translation , chromatin modification , and transcription . Sixteen genes have been associated with cancer , with five specifically associated with prostate cancer ( P78543 , P17936 , Q96EB6 , P50539 , and P14324 ) . Validation was performed on an independent publicly available dataset of 140 patients , where the new signature panel outperformed markers published previously in terms of predicting biochemical recurrence . Our work also identified differences in gene expression between Gleason pattern 4 + 3 and 3 + 4 tumors , including several genes involved in the epithelial-to-mesenchymal transition and developmental pathways . Overall , this study defines a novel biomarker panel that has the potential to improve the clinical management of prostate cancer . An unusual somatotropin and thyreotropin secreting pituitary adenoma efficiently controlled by DB00104 and DB00082 . We describe the first case of a 36 year-old male patient with a somatotropin and thyreotropin secreting pituitary adenoma , co-treated by a long-acting releasing somatostatin analog ( DB00104 ) and a P10912 antagonist ( DB00082 ) . The patient normalized his biological disease activity reflected by hormone levels but his tumor size remained unchanged as measured by Q9BWK5 . The co-treatment was well tolerated and induced a synergic effect on IGF1 levels that allowed us to use low doses of both therapies . Chronic daily tadalafil prevents the corporal fibrosis and veno-occlusive dysfunction that occurs after cavernosal nerve resection . OBJECTIVES : To determine whether a long-term single daily oral dose of a longer half-life phosphodiesterase-5 ( O76074 ) inhibitor , tadalafil , has a similar effect to that of the shorter half-life O76074 inhibitors sildenafil and vardenafil , and can prevent the fibrosis and resultant corporal veno-occlusive dysfunction ( CVOD ) occurring after cavernosal nerve ( CN ) injury . MATERIALS AND METHODS : Male rats ( 10 per group ) had either a sham operation , unilateral CN resection ( P21554 ) or bilateral P21554 , and were left untreated or given retrolingually 5 mg/kg per day of tadalafil . After 45 days , CVOD was assessed via cavernosometry , and the underlying corporal tissue changes were examined by immunohistochemistry and histochemistry ( followed by quantitative image analysis ) , Western blots , and ad hoc methods . RESULTS : DB00820 treatment normalized the low response to papaverine and high drop rate in the intracavernosal pressure measured by cavernosometry after P21554 compared with sham-operated rats . DB00820 also normalized the increase in penile shaft collagen content , and the reduction in corporal smooth muscle cell ( SMC ) content , SMC/collagen , and replication index , and improved the lower collagen III/I ratio and the increase in apoptotic index , caused by P21554 , compared with sham operation . There were no effects of tadalafil on increased transforming growth factor beta1 , inducible nitric oxide synthase and xanthine oxidoreductase levels . CONCLUSIONS : A long-term single daily dose of tadalafil prevented CVOD and the underlying corporal fibrosis in the rat caused by CN damage , as effectively as the previously reported continuous treatment with vardenafil or sildenafil , through a cGMP-related mechanism that appears to be independent of inducible nitric oxide synthase induction . Ca2+-calmodulin and janus kinase 2 are required for activation of sodium-proton exchange by the Gi-coupled 5-hydroxytryptamine 1a receptor . The type 1 sodium-proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5-hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2+/calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist-induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G(i2)alpha and/or G(i3)alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton-sensing and/or proton-transporting region of P19634 --> activation of P19634 . The G(i/o)-coupled P08908 receptor now joins a handful of Gq-coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2+ . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process . Neuronal death by oxidative stress involves activation of O43524 through a two-arm pathway that activates stress kinases and attenuates insulin-like growth factor I signaling . Oxidative stress kills neurons by stimulating O43524 , a transcription factor whose activity is inhibited by insulin-like growth factor I ( P05019 ) , a wide-spectrum neurotrophic signal . Because recent evidence has shown that oxidative stress blocks neuroprotection by P05019 , we examined whether attenuation of P05019 signaling is linked to neuronal death by oxidative stress , as both events may contribute to neurodegeneration . We observed that in neurons , activation of O43524 by a burst of oxidative stress elicited by 50 muM hydrogen peroxide ( H(2)O(2) ) recruited a two-pronged pathway . A first , rapid arm attenuated AKT inhibition of O43524 through p38 MAPK-mediated blockade of P05019 stimulation of AKT . A second delayed arm involved activation of O43524 by Jun-kinase 2 ( P45984 ) . Notably , blockade of P05019 signaling through p38 MAPK was necessary for P45984 to activate O43524 , unveiling a competitive regulatory interplay between the two arms onto O43524 activity . Therefore , an abrupt rise in oxidative stress activates p38 MAPK to tilt the balance in a competitive AKT/ P45984 regulation of O43524 toward its activation , eventually leading to neuronal death . In view of previous observations linking attenuation of P05019 signaling to other causes of neuronal death , these findings suggest that blockade of trophic input is a common step in neuronal death . Evaluation of growth hormone ( GH ) action in mice : discovery of P10912 antagonists and clinical indications . The discovery of a growth hormone receptor antagonist ( GHA ) was initially established via expression of mutated GH genes in transgenic mice . Following this discovery , development of the compound resulted in a drug termed pegvisomant , which has been approved for use in patients with acromegaly . DB00082 treatment in a dose dependent manner results in normalization of DB01277 levels in most patients . Thus , it is a very efficacious and safe drug . Since the GH/ DB01277 axis has been implicated in the progression of several types of cancers , many have suggested the use of pegvisomant as an anti-cancer therapeutic . In this manuscript , we will review the use of mouse strains that possess elevated or depressed levels of GH action for unraveling many of GH actions . Additionally , we will describe experiments in which the GHA was discovered , review results of pegvisomant 's preclinical and clinical trials , and provide data suggesting pegvisomant 's therapeutic value in selected types of cancer . Beyond statins : new lipid lowering strategies to reduce cardiovascular risk . Statins are the first-line therapy in LDL- DB04540 ( LDL-C ) reduction and its clinical use has contributed to significant prevention and treatment of atherosclerotic vascular disease . Yet , a significant proportion of patients remain at high risk . Recently , a number of new therapies have been developed to further lower LDL-C . These agents may provide clinical benefit on top of statin therapy in patients with high residual risk , severe hypercholesterolemia or as an alternative for patients who are intolerant to statins . We review four novel approaches based on the inhibition of proprotein convertase subtilisin/kexin type 9 ( Q8NBP7 ) , apolipoprotein-B100 ( apoB ) , Cholesteryl ester transport protein ( P11597 ) and microsomal triglyceride transfer protein ( P55157 ) . ApoB and P55157 inhibitors ( DB05528 and DB08827 ) are indicated only for homozygous familial hypercholesterolemia patients . The results of ongoing trials with P11597 and Q8NBP7 inhibitors may warrant a wider employment in different categories of patients at high risk for cardiovascular disease . [ P10912 antagonist in the treatment of acromegaly ] . Exploration of construction , function and interaction of human growth hormone and growth hormone receptor in details resulted in the innovation of the new growth hormone receptor antagonist , pegvisomant . DB00082 with different mechanism of action extended the tools of medical management of acromegaly . Importance of the novel treatment modality is high . In one hand the necessity of the strict control of growth hormone/insulin-like growth factor-I axis has been proven regarding the mortality of the disease . On the other hand , despite the use of all current modes of treatment ( surgery , radiotherapy , dopamine agonists , somatostatin analogs ) , a significant cohort of patients with acromegaly remains inadequately controlled . DB00082 has been registered in 2004 . Since 2006 , it has been used in Hungary for the treatment of acromegaly in patients who have had an inadequate response to surgery and/or radiation therapy and/or other medical therapies , or for whom these therapies are not appropriate . Clinical use of pegvisomant in the treatment of acromegaly is effective , well tolerated , and safe , based on international Acrostudy database . In order to improve the efficacy of therapy clinical trials started with pegvisomant and somatostatin analog combination treatment . Evidence of several further effects of the growth hormone/insulin-like growth factor-I axis suggests other potential uses of growth hormone receptor antagonists . Q9H244 receptor signalling towards P31749 proceeds through P08069 cross-talk and requires activation of Src , Pyk2 and Rap1 . Previously it was shown that stimulation of the Q9H244 receptor activates P31749 signalling in P13671 glioma cells [ K. Van Kolen and H. Slegers , J. Neurochem. 89 , 442. ] . In the present study , the mechanisms involved in this response were further elucidated . In cells transfected with the Gbetagamma-scavenger beta- O14965 / P25098 or Rap1GAPII , stimulation with 2MeSADP failed to enhance P31749 phosphorylation demonstrating that the signalling proceeds through Gbetagamma-subunits and Rap1 . Moreover , Rap1-GTP pull-down assays revealed that Q9H244 receptor stimulation induced a rapid activation of Rap1 . Treatment of cells with the Ca2+ chelator BAPTA-AM and inhibition of Src and O14939 with Q99463 or 1-butanol , respectively , abrogated Q9H244 receptor-mediated activation of Rap1 and P31749 . In addition inhibition of PKCzeta decreased basal and 2MeSADP-stimulated phosphorylation of P31749 indicating a role for this PKC isoform in P31749 signalling . Although the increased P31749 phosphorylation was abolished in the presence of the P08069 tyrosine kinase inhibitor AG 1024 , 2MeSADP did not significantly increase receptor phosphorylation . Nevertheless , phosphorylation of a 120 kDa P08069 -associated protein was observed . The latter protein was identified by MALDI-TOF/TOF-MS as the proline-rich tyrosine kinase 2 ( Pyk2 ) that co-operates with Src in a O14939 -dependent manner . Consistent with the signalling towards Rap1 and P31749 , activation of Pyk2 was abrogated by Ca2+ chelation , inhibition of O14939 and P08069 tyrosine kinase activity . In conclusion , the data reveal a novel type of cross-talk between Q9H244 and P05019 receptors that proceeds through Gbetagamma- , Ca2+-and O14939 -dependent activation of the Pyk2/Src pathway resulting in GTP-loading of Rap1 required for an increased P31749 phosphorylation . P21554 regulates P29323 and GSK-3β-dependent glucocorticoid inhibition of osteoblast differentiation in murine MC3T3-E1 cells . Supraphysiological glucocorticoid administration accelerates loss of survival and differentiation in osteoblastic cells , thereby increasing the risks of osteopenic or osteonecrotic disorders . Neuroendocrine component type 1 cannabinoid receptor ( P21554 ) is found to regulate bone mass . This study characterized the biological role of P21554 in glucocorticoid-induced suppression of osteoblast differentiation . Murine MC3T3-E1 osteoblasts were incubated under osteogenic conditions in the presence or absence of 1 μM glucocorticoid , RNA interference , P21554 antagonist AM251 , and agonist WIN55212-2 . Cell survival was detected by formazan synthesis and TUNEL staining . Osteoblast differentiation was quantified by mineralized matrix accumulation and expression of the osteogenic factors Runx2 and osteocalcin . Expression of signaling molecules was assessed by immunoblotting . Glucocorticoid increased P21554 expression in association with decreased osteocalcin expression and mineralized nodule deposition . P21554 RNA interference and AM251 attenuated the deleterious actions of glucocorticoid treatment on survival and osteogenic activities , whereas activating P21554 by WIN55212-2 impaired osteoblast differentiation . P21554 signaling regulated JNK , P29323 , GSK-3β , and Akt activation as well as Runx2 and P05019 expression . Inhibition of GSK-3β by the kinase-inactive GSK-3β mutant or activation of P29323 by the active MEK-1 mutant abrogated glucocorticoid-induced inhibition of osteoblast differentiation . Glucocorticoid-induced P21554 expression occurred via glucocorticoid receptor-dependent transcriptional and translational regulation . Gain of Runx2 function and loss of P28562 action attenuated glucocorticoid-induced enhancement of P21554 expression . Taken together , P21554 regulation of P29323 and GSK-3β-dependent pathways participates in glucocorticoid inhibition of Runx2 signaling and osteoblast differentiation . Runx2 reciprocally regulates glucocorticoid-induced promotion of P21554 signaling . Our findings provide new insights into the role of the neuroendocrine component P21554 in glucocorticoid-induced osteoblast dysfunction . DB00820 , a further innovation in the treatment of sexual dysfunction . In recognition of the large number of sufferers of sexual dysfunction worldwide , and the variety of etiologies of the condition , investigation into effective pharmacological agents has been expanded . One method of intervention is inhibition of the phosphodiesterase type 5 ( O76074 ) enzyme , which has already been exploited with a considerable degree -- though not complete -- success . A number of new agents that inhibit O76074 are under development . Notable among these is tadalafil , which has demonstrated a high level of selectivity for O76074 over the other phosphodiesterases and has shown efficacy in improving erectile function and sexual satisfaction in phase III trials . Throughout the clinical development program for tadalafil , the drug has been well tolerated and without serious side effects . The manufacturer , Lilly Q9Y6W8 , received an approvable letter from the US Food and Drug Administration for use of the drug as a treatment for erectile dysfunction on April 30 , 2002 . Lilly Q9Y6W8 hopes to market tadalafil , with the trade name DB00820 , in the USA in 2003 . Inhibition of serotonergic neurons in the nucleus paragigantocellularis lateralis fragments sleep and decreases rapid eye movement sleep in the piglet : implications for sudden infant death syndrome . Serotonergic receptor binding is altered in the medullary serotonergic nuclei , including the paragigantocellularis lateralis ( PGCL ) , in many infants who die of sudden infant death syndrome ( P22304 ) . The PGCL receives inputs from many sites in the caudal brainstem and projects to the spinal cord and to more rostral areas important for arousal and vigilance . We have shown previously that local unilateral nonspecific neuronal inhibition in this region with GABA(A) agonists disrupts sleep architecture . We hypothesized that specifically inhibiting serotonergic activity in the PGCL would result in less sleep and heightened vigilance . We analyzed sleep before and after unilaterally dialyzing the P08908 agonist (+/-)-8-hydroxy-2-(dipropylamino)-tetralin ( 8-OH-DPAT ) into the juxtafacial PGCL in conscious newborn piglets . 8-OH-DPAT dialysis resulted in fragmented sleep with an increase in the number and a decrease in the duration of bouts of nonrapid eye movement ( NREM ) sleep and a marked decrease in amount of rapid eye movement ( O75628 ) sleep . After 8-OH-DPAT dialysis , there were decreases in body movements , including shivering , during NREM sleep ; body temperature and heart rate also decreased . The effects of 8-OH-DPAT were blocked by local pretreatment with N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexane-carboxamide , a selective P08908 antagonist . Destruction of serotonergic neurons with 5,7- DB02901 resulted in fragmented sleep and eliminated the effects of subsequent 8-OH-DPAT dialysis on O75628 but not the effects on body temperature or heart rate . We conclude that neurons expressing P08908 autoreceptors in the juxtafacial PGCL are involved in regulating or modulating sleep . Abnormalities in the function of these neurons may alter sleep homeostasis and contribute to the etiology of P22304 . DB00082 Pfizer/Sensus . Pfizer ( formerly Pharmacia ) , in collaboration with its wholly owned subsidiary Sensus , has developed and launched pegvisomant , a pegylated , genetically modified human growth hormone ( hGH ) , for the treatment of acromegaly . DB00082 , in contrast to classical somatostatin analogs which lower hGH synthesis , exerts its anti-hGH action by preventing P10912 activation . This drug is now available in the US and Europe for the treatment of acromegaly . DB01016 exerts an antitumor activity through reactive oxygen species-c-jun NH2-terminal kinase pathway in human gastric cancer cell line MGC-803 . DB01016 , a blocker of DB00171 -sensitive potassium ( K( DB00171 ) ) channels , can suppress progression of many cancers , but the involved mechanism is unclear . Herein we reported that MGC-803 cells expressed the K( DB00171 ) channels composed of Kir6.2 and Q09428 subunits . DB01016 induced cellular viability decline , coupled with cell apoptosis and reactive oxygen species ( ROS ) generation in MGC-803 cells . Meanwhile , glibenclamide increased NADPH oxidase catalytic subunit gp91(phox) expression and superoxide anion ( O2- ) generation , and caused mitochondrial respiration dysfunction in MGC-803 cells , suggesting that glibenclamide induced an increase of ROS derived from NADPH oxidase and mitochondria . DB01016 could also lead to loss of mitochondrial membrane potential , release of cytochrome c and apoptosis-inducing factor ( O95831 ) , and activation of c-jun NH2-terminal kinase ( JNK ) in MGC-803 cells . Pretreatment with antioxidant N-acetyl-l-cysteine ( Q9C000 ) prevented glibenclamide-induced JNK activation , apoptosis and cellular viability decline . Furthermore , glibenclamide greatly decreased the cellular viability , induced apoptosis and inhibited Akt activation in wild-type mouse embryonic fibroblast ( MEF ) cells but not in P45983 -/- or P45984 -/- MEF cells . Taken together , our study reveals that glibenclamide exerts an antitumor activity in MGC-803 cells by activating ROS-dependent , JNK-driven cell apoptosis . These findings provide insights into the use of glibenclamide in the treatment of human gastric cancer . Insights from growth hormone receptor blockade . DB00082 is a genetically manipulated growth hormone ( GH ) that disables signal transduction through the P10912 and thus functions as a P10912 antagonist . In a series of studies of the metabolic effects of GH in healthy male individuals , pegvisomant has been used to create a model of acute GH deficiency but without the typical alterations in body composition . This review summarizes studies of the effects of P10912 blockade and fasting , either alone or in combination , on determinants of GH release . Based on these and other data we present a model to explain the somatotroph hyperactivity of fasting P10912 targeting to lipid rafts requires extracellular subdomain 2 . P10912 ( P10912 ) is a single membrane-spanning glycoprotein dimer that binds GH in its extracellular domain ( O95905 ) . GH activates the P10912 intracellular domain ( ICD ) -associated tyrosine kinase , O60674 , which causes intracellular signaling . We previously found that plasma membrane ( PM ) -associated P10912 was dramatically enriched in the lipid raft ( LR ) component of the membrane and that localization of P10912 within PM regions may regulate GH signaling by influencing the profile of pathway activation . In this study , we examined determinants of LR localization of the P10912 using a reconstitution system which lacks endogenous O60674 and P10912 . By non-detergent extraction and multistep fractionation , we found that P10912 was highly enriched in the LR fraction independent of O60674 expression . Various P10912 mutants were examined in transfectants harboring O60674 . LR concentration was observed for a P10912 in which the native transmembrane domain ( TMD ) is replaced by that of the unrelated P01130 and for a P10912 that lacks its ICD . Thus , LR association requires neither the TMD nor the ICD . Similarly , a P10912 that lacks the O95905 , except for the membrane-proximal O95905 stem region , was only minimally LR-concentrated . Mutants with internal stem deletions in the context of the full-length receptor were LR-concentrated similar to the wild-type . A P10912 lacking O95905 subdomain 1 reached the PM and was LR-concentrated , while one lacking O95905 subdomain 2 , also reached the PM , but was not LR-concentrated . These data suggest LR targeting resides in O95905 subdomain 2 , a region relatively uninvolved in GH binding . Management of acromegaly : is there a role for primary medical therapy ? Acromegaly is a chronic , debilitating disease caused by chronic growth hormone ( GH ) hypersecretion which results in chronic medical comorbidities , poor quality of life and high mortality rates . Successful treatment can improve clinical signs and symptoms and normalize mortality rates . Over 95 % of acromegaly is caused by a somatotroph adenoma of the pituitary , and the first-line treatment is generally transsphenoidal surgery , which can be curative in 50-60 % of patients . Nonetheless , high rates of persistent acromegaly following surgery and the limited efficacy of radiation therapy necessitate chronic medical treatment for many patients . Somatostatin analogues have become the preferred first-line medical therapy for many practitioners , as they achieve better biochemical and direct tumor control than the dopamine agonists , and long-acting preparations make once monthly administration possible . Cabergoline , a dopamine agonist , offers a lower-cost option and may be effective in patients with a pituitary tumor that co-secretes GH and prolactin . DB00082 is a P10912 antagonist that produces exceptional biochemical response rates but lacks any direct effects on the tumor , which may limit its effectiveness as life-long monotherapy . Combinations of these three drug classes have not been rigorously studied , and preliminary trials do not suggest improved clinical outcomes . While medical treatment options for acromegaly have significantly improved over the last 30 years , limitations remain , and a multi-specialty team approach is necessary for the effective long-term management of patients with acromegaly . P10912 blocker administration and muscle-tendon collagen synthesis in humans . CONTEXT : The growth hormone ( GH ) /insulin-like growth factor-I ( P05019 ) axis stimulates collagen synthesis in tendon and skeletal muscle , but no studies have investigated the effect of reducing P05019 on collagen synthesis in healthy humans . OBJECTIVE : We hypothesised , that a GH blockade would decrease P05019 and collagen synthesis in the connective tissue of skeletal muscle and tendon . DESIGN : The study was randomised and double blinded . PARTICIPANTS : 20 healthy young males completed the study . INTERVENTION : The participants were randomised to 2 weeks of P10912 blocker supplementation ( pegvisomant , 5 mg/day , n=9 ) or placebo ( n=11 ) . MAIN OUTCOME MEASURES : Serum levels of GH , P05019 and P17936 ( P17936 ) were measured before and after pegvisomant/placebo supplementation . Fractional synthesis rates ( FSR ) for collagen and myofibrillar protein were determined with stable isotopes in tendon and muscle , and mRNA for collagen ( P02452 and P02461 ) as well as P05019 isoforms ( Ea and Ec ) were measured in skeletal muscle . RESULTS : DB00082 decreased serum P05019 by 20 % ( p < 0.01 ) and serum P17936 by 10 % ( p < 0.05 ) . DB00082 supplementation had no effect on collagen synthesis in tendon and skeletal muscle , nor was muscle myofibrillar protein synthesis affected . Similarly , pegvisomant supplementation had no effect on mRNA expression of P05019 and collagen in skeletal muscle . CONCLUSION : P10912 blocker administration in healthy humans resulted in a moderate decrease in serum P05019 . Collagen synthesis in tendon and skeletal muscle , as well as skeletal muscle P05019 and collagen mRNA expression , was unaffected by P10912 blocker supplementation . Kinetic studies of the pharmacologic response to captopril in rats . I . Role of the renin-angiotensin system . Pressor response to exogenous angiotensins was investigated in rats . Two-kidney Goldblatt hypertensive rats ( P10912 ) and sodium-deficient normotensive rats ( SDR ) , as well as normal rats , ( NR ) were used . Various amounts of angiotensin I ( Ang I ) or angiotensin ( Ang II ) were administered intravenously by constant infusion , with or without pretreatment with angiotensin converting enzyme ( P12821 ) inhibitor , and the pressor response was determined . DB01197 was used as the P12821 inhibitor . From the data obtained , a simple kinetic model for the renin-angiotensin system was constructed . The model was based on a linear compartment model with the following assumptions ; ( a ) there are compartments in respect to Ang I and II in the body ; ( b ) in the steady-state condition , Ang I is produced at a constant rate ; ( c ) a part of Ang I is converted to Ang II by a first-order rate process ; ( d ) Ang I and II are eliminated from the respective compartments by first-order rate processes and ( e ) the relationship between mean arterial blood pressure and the amount of Ang II in the body can be described by Hill 's equation with a baseline effect . Then the pressor response to angiotensins in P10912 , SDR or NR was fitted to the model . The result indicated that the pressor response to Ang I or Ang II can be described by the present model . The model parameters obtained were consistent with the actual physiological parameters of rats . Association of sixty-one non-synonymous polymorphisms in forty-one hypertension candidate genes with blood pressure variation and hypertension . We previously selected a group of hypertension candidate genes by a key word search using the OMIM database of NCBI and validated 525 coding single nucleotide polymorphisms ( SNPs ) in 179 hypertension candidate genes by DNA sequencing in a Japanese population . In the present study , we examined the association between 61 non-synonymous SNPs and blood pressure variations and hypertension . We used DNA samples taken from 1,880 subjects in the Suita study , a population-based study using randomly selected subjects . Analyses of covariance adjusting for age , body mass index , hyperlipidemia , diabetes , smoking , drinking , and antihypertensive medication revealed that 17 polymorphisms in 16 genes ( P04114 , CAST , P51801 , O60931 , P10912 , P13807 , P08603 , O95163 , Q14654 , P11150 , P06858 , P41231 , Q15165 , P02730 , TRH , P04275 ) were significantly associated with blood pressure variations . Multivariate logistic regression analysis with adjustment for the same factors revealed that 11 polymorphisms in 11 genes ( CAST , P16410 , P12259 , GC , P10912 , P11150 , Q13093 , P02730 , SLCI8A1 , TRH , P04275 ) showed significant associations with hypertension . Five polymorphisms in five genes , CAST(calpastatin) , P11150 ( hepatic lipase ) , P02730 ( band 3 anion transporter ) , TRH ( thyrotropin-releasing hormone ) , and P04275 ( P04275 ) , were significantly associated with both blood pressure variation and hypertension . Thus , our study suggests that these five genes were susceptibility genes for essential hypertension in this Japanese population . Long-term treatment of acromegalic patients resistant to somatostatin analogues with the P10912 antagonist pegvisomant : its efficacy in relation to gender and previous radiotherapy . CONTEXT : DB00082 is an effective treatment for somatostatin analogue-resistant acromegaly , but the determinants defining the response to this treatment are largely unknown . OBJECTIVE : To investigate the efficacy of pegvisomant treatment in resistant acromegalic patients ( e.g. serum IGF1 at least 1.25 x upper normal limit ) in a clinical setting and the factors conditioning this response . DESIGN AND SETTING : A retrospective cross-sectional study performed in six Spanish University hospitals from 2004 to 2007 . Patients Forty-four acromegalic patients ( 61.4 % female , mean age : 49+/-14 ) , 95 % of whom had undergone pituitary surgery and 61 % having received pituitary radiotherapy . The mean follow-up was 22.7+/-11.2 months . Main outcome measures IGF1 levels reflected treatment efficacy , and the influence of gender , age , weight , previous radiotherapy and duration of treatment was assessed . RESULTS : IGF1 normalisation was achieved in 84 % of the patients . Male gender ( P < 0.05 ) , previous irradiation ( P < 0.05 ) and the treatment duration ( r=0.364 , P < 0.02 ) were associated with a better response to pegvisomant therapy . There was a significant decrease in HbA1c ( P < 0.001 ) and in the mean insulin dose ( P < 0.01 ) in acromegalic diabetic patients . Although 25 % of patients experienced mild adverse events , pegvisomant was only withdrawn in four patients due to side effects ( two cases of tumour growth , one liver dysfunction and one headache ) . CONCLUSIONS : Long-term pegvisomant is a very effective therapy in resistant acromegaly . Male gender and prior radiotherapy influence the therapeutic response rate . Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA-approved nitrogen-containing bisphosphonate ( N-BP ) drug , at the molecular level . DB00630 not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell-induced osteoclasts and the preosteoblast MC3T3-E1 cell line were used to assess effects of anti-FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum-based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast-mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways . Induction , binding specificity and function of human Q9Y6W8 . Recently , we have identified the inducible co-stimulator ( Q9Y6W8 ) , an activation-dependent , T cell-specific cell surface molecule related to P10747 and P16410 . Detailed analysis of human Q9Y6W8 presented here shows that it is a 55-60-kDa homodimer with differently N-glycosylated subunits of 27 and 29 kDa . Q9Y6W8 requires both phorbol 12-myristate 13-acetate and ionomycin for full induction , and is sensitive to DB00091 . Q9Y6W8 is up-regulated early on all T cells , including the P10747 - subset , and continues to be expressed into later phases of T cell activation . On stimulation of T cells by antigen-presenting cells , the P10747 / P33681 , but not the P29965 / P25942 pathway is critically involved in the induction of Q9Y6W8 . Q9Y6W8 does not bind to P33681 -1 or P33681 -2 , and P10747 does not bind to O75144 ; thus the P10747 and Q9Y6W8 pathways do not cross-interact on the cell surface . In vivo , Q9Y6W8 is expressed in the medulla of the fetal and newborn thymus , in the T cell zones of tonsils and lymph nodes , and in the apical light zones of germinal centers ( predominant expression ) . Functionally , Q9Y6W8 co-induces a variety of cytokines including P05112 , P05113 , P05231 , P01579 , P01375 , GM- P04141 , but not P60568 , and superinduces P22301 . Furthermore , Q9Y6W8 co-stimulation prevents the apoptosis of pre-activated T cells . The human Q9Y6W8 gene maps to chromosome 2q33 - 34 . Successful treatment of resistant acromegaly with a growth hormone receptor antagonist . BACKGROUND/OBJECTIVE : DB00082 is a pegylated analogue of human GH and functions as a potent P10912 antagonist . This novel mode of action gives it the potential to achieve biochemical control in patients with acromegaly whose disease activity can not be satisfactorily controlled by conventional therapy . We have documented the clinical details of seven patients with residual active acromegaly after surgery and/or radiation therapy successfully treated with pegvisomant . PATIENTS/METHODS : Seven patients ( four male , mean age 47 years , range 34-67 years ) who participated in two separate clinical trials of pegvisomant have completed 2 years ( four patients ) or 1 year ( three patients ) of treatment . All had active acromegaly ( mean serum GH level > 5 mU/l ; serum P05019 elevated for age ) that could not be controlled with standard medical therapy ( dopamine agonist and/or a somatostatin analogue ) following appropriate primary treatment with surgery and/or radiotherapy . RESULTS : On a median dose of 20 mg/day ( range 15-40 ) pegvisomant , serum P05019 fell from a mean of 920+/-351 ng/ml ( s.d. ) to 258+/-91 ng/ml and was normalised in all seven patients . These changes were associated with improvements in soft tissue enlargement and general well being . Treatment was well tolerated and no change in pituitary tumour size was evident on Q9BWK5 scans performed every 6 months . CONCLUSIONS : Treatment with pegvisomant is safe and efficacy is maintained after 2 years . Serum P05019 may be normalised in patients who are refractory to conventional therapy . THow diet interacts with longevity genes . In laboratory mice , suppression of growth hormone ( GH ) signaling by spontaneous mutations or targeted disruption of GH- or IGF1-related genes can lead to an impressive increase of longevity . Hypopituitary Ames dwarf ( Prop1 df ) and P10912 knockout ( GHRKO ) mice live 35-70 % longer than their normal littermates . Many phenotypic characteristics of these long-lived mutants resemble findings in genetically normal animals subjected to calorie restriction ( CR ) . Microarray and RT-PCR studies of gene expression suggest that effects of the " longevity assurance genes " ( Prop1 df or Ghr-/- ) and CR are overlapping but not identical . Subjecting Ames dwarf mice to 30 % CR starting at 2 months of age leads to a further significant extension of their average and maximal lifespans . In contrast , identical CR regimen has either no or very little effect ( depending on gender ) on longevity of GHRKO mice . We suspect that this difference in response is related to the fact that CR improves insulin sensitivity in Ames dwarfs but does not further increase the extreme insulin sensitivity of GHRKO mice . To search for effects of CR associated with extension of longevity , we are studying expression of insulin and IGF1-related genes in the liver , skeletal muscle and heart of normal and GHRKO mice . Results obtained to date suggest that reduced Akt phosphorylation and Q07869 beta/delta expression in the liver , reduced P45983 phosphorylation and increased PGC1alpha expression in the muscle , and increased expression of IGF1 and insulin receptor in the heart are either related to mechanisms of CR action on longevity or represent potential biomarkers of delayed aging . The place of pegvisomant in the management of acromegaly . Conventional treatments for acromegaly include surgery , radiotherapy , dopamine agonists and somatostatin ( P52788 ) analogues , which effect disease control by lowering circulating growth hormone ( GH ) . Due to variability in tumour characteristics , combinations of these treatment modalities leave a significant number of patients with sub-optimal serum GH and insulin-like growth factor-I ( P05019 ) levels , which have been linked to increased morbidity and mortality . The P10912 antagonist pegvisomant is a genetically engineered analogue of GH that prevents functional dimerisation of the growth hormone receptor ( P10912 ) ; a process that is critical to GH action at the cellular level . A crucial amino acid substitution at DB00145 (120) to DB00125 (120) within the third alpha helix of the antagonist prevents functional P10912 dimerisation . DB00082 represents a novel treatment for acromegaly as , unlike existing treatment modalities , the effectiveness of pegvisomant is independent of pituitary tumour characteristics . Initial clinical studies in patients with active acromegaly have demonstrated serum P05019 normalisation in over 90 % of patients receiving 20 mg per day , such that , in terms of serum P05019 normalisation , pegvisomant now represents the most effective medical treatment for acromegaly . Although there are limited long-term data on the use of pegvisomant and questions regarding pituitary tumour growth and altered liver function remain , this therapy offers the prospect of serum P05019 normalisation in the vast majority of patients with active acromegaly . DB00082 treatment in gigantism caused by a growth hormone-secreting giant pituitary adenoma . BACKGROUND : Gigantism is rare with the majority of cases caused by a growth hormone ( GH ) -secreting pituitary adenoma . Treatment options for GH-secreting pituitary adenomas have been widened with the availability of long-acting dopamine agonists , depot preparations of somatostatin analogues , and recently the P10912 antagonist pegvisomant . CASE REPORT : A 23-year-old male patient presented with continuous increase in height during the past 6 years due to a GH-secreting giant pituitary adenoma . Because of major intracranial extension and failure of octreotide treatment to shrink the tumour , the tumour was partially resected by a trans-frontal surgical approach . At immunohistochemistry , the tumour showed a marked expression of GH and a sparsely focal expression of prolactin . Somatostatin receptors ( sst ) 1-5 were not detected . Tumour tissue weakly expressed dopamine receptor type 2 . The Gs alpha subunit was intact . Conversion from somatostatin analogue to pegvisomant normalized insulin-like-growth-factor-I ( P05019 ) levels and markedly improved glucose tolerance . CONCLUSION : DB00082 is a potent treatment option in patients with pituitary gigantism . In patients who do not respond to somatostatin analogues , knowledge of the P61278 receptor status may shorten the time to initiation of pegvisomant treatment . Optimizing control of acromegaly : integrating a growth hormone receptor antagonist into the treatment algorithm . Acromegaly is associated with significant morbidities and a 2- to 3-fold increase in mortality because of the excessive metabolic action of GH and P05019 , a marker of GH output . Reductions in morbidity correspond with decreases in P05019 , and mortality is lowered following normalization of P05019 or GH levels . Therefore , this has become an important end point . Current guidelines for the treatment of acromegaly have not considered recent advances in medical therapy , in particular , the place of pegvisomant , a P10912 antagonist . Treatment goals include normalizing biochemical markers , controlling tumor mass , preserving pituitary function , and relieving signs and symptoms . Surgery reduces tumor volume and is considered first-line therapy . Radiation reduces tumor volume and GH and P05019 levels , but the onset of action is slow and hypopituitarism typically develops . Therefore , pharmacotherapy is often used following surgery or as first-line therapy for nonresectable tumors . Dopamine agonists can be considered in patients exhibiting minimal disease or those with GH-prolactin-cosecreting tumors but will not achieve hormone normalization in most patients . Somatostatin analogs effectively suppress GH and P05019 in most patients , but intolerance ( e.g. diarrhea , cramping , gallstones ) can occur . DB00082 , the newest therapeutic option , blocks GH action at peripheral receptors , normalizes P05019 levels , reduces signs and symptoms , and corrects metabolic defects . DB00082 does not appear to affect tumor size and has few adverse effects . DB00082 is the most effective drug treatment for acromegaly in normalizing P05019 and producing a clinical response ; it is the preferred agent in patients resistant to or intolerant of somatostatin analogs . Pharmacological therapy for acromegaly : a critical review . The treatment of acromegaly has changed considerably over the last few decades . In the late 1970s , the introduction of the dopamine receptor agonists made it possible to reduce growth hormone ( GH ) secretion by somatotropinomas for the first time . Thereafter , the introduction of the somatostatin analogues in the early 1980s had major implications . Recently , the first data on the use of genetically engineered human P10912 ( P10912 ) antagonists that block GH actions have become available . These P10912 antagonists reduce both the biochemical abnormalities of acromegaly , as well as improve clinical signs and symptomatology . In this article we firstly review available data on dopamine agonists . Currently these compounds should be considered in patients with a mixed GH-prolactin secreting pituitary adenoma and/or those in whom pre-treatment insulin-like growth factor ( IGF ) -I concentrations are below 750 microg/L . We then discuss the somatostatin analogues . These compounds are capable of achieving biochemical control of GH and P05019 in 50-60 % of patients and tumour shrinkage in some 30 % . In particular , candidates for treatment with these compounds are those patients who have undergone an unsuccessful transsphenoidal operation or who await the therapeutic effect of external pituitary irradiation . In selected patients primary medical therapy with somatostatin analogues is certainly a feasible option . To date , pegvisomant is the only available member of a new class of drugs that was especially designed to block the P10912 . DB00082 is the most effective treatment for normalising P05019 concentrations and appears to have a good safety profile . However , liver function tests should be regularly monitored and tumour size should be closely followed . Finally , we propose a treatment algorithm for acromegaly . The challenges of reliance on insulin-like growth factor I in monitoring disease activity in patients with acromegaly . Serum insulin-like growth factor I ( P05019 ) is an important marker of disease activity in patients with acromegaly , and epidemiological data indicate control of circulating P05019 in patients with acromegaly restores life expectancy to normal . Improvements in the quality of , and access to , P05019 assays has encouraged monitoring of acromegaly with P05019 , although circulating growth hormone ( GH ) and P05019 values provide different information , so ideally both should be monitored . However , the introduction of the P10912 antagonist pegvisomant poses new challenges . DB00082 binds with high affinity to GH receptors , thereby blocking the action of GH at the tissue level and rendering the hormone biologically inactive . This leaves P05019 as the principal marker of disease activity . It is conceptually possible to induce a state of functional GH deficiency ( GHD ) with pegvisomant with P05019 values within the normal range . With the goal of minimizing the risk of over-treatment and GHD , we have provided preliminary guidance on the target range for P05019 in patients receiving pegvisomant based on the gender- and decade-based percentile ranges for P05019 of adult patients with untreated GHD enrolled in the Pfizer International Metabolic Database ( KIMS ) . DB00082 : a growth hormone receptor antagonist for the treatment of acromegaly . P10912 ( P10912 ) dimerization is a prerequisite to the generation of growth hormone ( GH ) action . DB00082 is a P10912 antagonist that has been designed to bind to the P10912 at the cell surface and hence block this process . Initial studies suggest that pegvisomant is a highly effective antagonist of GH action in patients with acromegaly . The blockade of GH action , rather than the inhibition of pituitary GH secretion , represents a novel concept in the medical management of acromegaly . In this review , the design , efficacy , challenges and future role of pegvisomant are discussed . P01308 reverses growth hormone-induced homologous desensitization . Growth hormone ( GH ) is secreted in a pulsatile pattern to promote body growth and metabolism . GH exerts its function by activating several signaling pathways , including O60674 / P35610 and MEK/ P29323 . P27361 /2 activation by GH plays important roles in gene expression , cell proliferation , and growth . We previously reported that in rat H4IIE hepatoma cells after an initial GH exposure , a second GH exposure induces P42229 phosphorylation but not P27361 /2 phosphorylation ( Ji , S. , Frank , S. J. , and Messina , J. L. ( 2002 ) J. Biol. Chem. 277 , 28384-28393 ) . In this study the mechanisms underlying GH-induced homologous desensitization were investigated . A second GH exposure activated the signaling intermediates upstream of MEK/ P29323 , including O60674 , Ras , and P04049 . This correlated with recovery of P10912 levels , but was insufficient for GH-induced phosphorylation of Q02750 /2 and P27361 /2 . P01308 restored the ability of a second GH exposure to induce phosphorylation of Q02750 /2 and P27361 /2 without altering P10912 levels or GH-induced phosphorylation/activation of O60674 and P04049 . GH and insulin synergized in promoting cell proliferation . Further investigation suggested that insulin increased the amount of MEK bound to Q8IVT5 ( kinase suppressor of Ras ) and restored GH-induced tyrosine phosphorylation of Q8IVT5 . Previous GH exposure also induced desensitization of P42224 and P40763 phosphorylation , but this desensitization was not reversed by insulin . Thus , insulin-regulated resensitization of GH signaling may be necessary to reset the complete response to GH after a normal , physiologic pulse of GH . DB01259 induces apoptosis in trastuzumab-resistant breast cancer cells : effects on insulin-like growth factor I signaling . The majority of breast cancer patients who achieve an initial therapeutic response to the P04626 -targeted antibody trastuzumab will show disease progression within 1 year . Thus , the identification of novel agents that effectively inhibit survival of cancer cells that have progressed on trastuzumab is critical . In the current study , we show that the dual epidermal growth factor receptor ( P00533 ) /human P00533 -2 ( P04626 ) kinase inhibitor lapatinib induces apoptosis in trastuzumab-resistant cells derived from the P04626 -overexpressing SKBR3 breast cancer line . DB01259 inhibited P00533 and P04626 signaling in resistant cells , blocking activation of downstream Akt , mitogen-activated protein kinase [ corrected ] Importantly , lapatinib also inhibited insulin-like growth factor I ( P05019 ) signaling and growth-promoting effects in parental and resistant cells , and the cytotoxic effects of lapatinib were further enhanced by the P08069 -blocking antibody alphaIR3 . As increased P08069 signaling has been implicated in trastuzumab resistance , our data strongly support further study of lapatinib as a potential therapeutic in breast cancers that have progressed on trastuzumab . Lessons from 6 years of P10912 antagonist therapy for acromegaly . DB00082 is a P10912 antagonist and a new agent for the medical management of acromegaly . The clinical efficacy and safety of pegvisomant in the treatment of active acromegaly were demonstrated in a 12-week , placebo-controlled trial of 112 patients . After a washout period , patients were randomized to a fixed dose of pegvisomant ( 10 , 15 or 20 mg/day ) or placebo given by sc injection . Serum P05019 levels were within the normal age-adjusted reference range in 54 , 81 and 89 % of patients in the 10- , 15- and 20-mg/day groups , respectively . The decrease in serum P05019 levels was accompanied by considerable improvement in the signs and symptoms of active acromegaly . This efficacy profile was maintained in a long-term continuation trial , with normalization of serum P05019 at 12 months occurring in 97 % of patients . DB00082 has been well tolerated with an adverse event profile similar to placebo . Two patients had elevations in liver function tests that resolved after discontinuing treatment with pegvisomant . During treatment with pegvisomant , liver function tests should be monitored on a regular basis . Two patients had an increase in pituitary tumor volume during pegvisomant therapy ; however , the relationship to pegvisomant therapy was not clear . In 131 patients treated for at least 6 months , there was no increase in mean tumor volume , regardless of whether they underwent previous radiotherapy . DB00082 is an effective new treatment for the management of patients with acromegaly . Longer-term data are needed to confirm the safety profile that has been demonstrated in studies up to 18 months . DB08827 : A novel agent for the treatment of homozygous familial hypercholesterolemia . PURPOSE : The pharmacology , pharmacokinetics , and clinical efficacy and safety of lomitapide in the management of homozygous familial hypercholesterolemia ( HoFH ) are reviewed . SUMMARY : DB08827 ( Juxtapid , Aegerion Pharmaceuticals ) is an oral microsomal triglyceride transfer protein ( P55157 ) inhibitor indicated for the treatment of patients with HoFH , a rare form of hypercholesterolemia that can lead to premature atherosclerotic disease . In clinical trials , the use of lomitapide alone or in combination with other lipid-lowering modalities reduced plasma concentrations of low-density lipoprotein cholesterol ( LDL-C ) by a mean of more than 50 % . DB08827 is associated with significant gastrointestinal adverse effects and increases in hepatic fat levels . DB08827 undergoes hepatic metabolism via cytochrome P-450 ( CYP ) isoenzyme 3A4 and interacts with P08684 substrates including atorvastatin and simvastatin ; dose adjustment is recommended when lomitapide is used concurrently with these agents . In patients receiving concomitant warfarin , the International Normalized Ratio ( INR ) should be closely monitored , as lomitapide use may increase INR values . The recommended initial dosage of lomitapide is 5 mg once daily , with subsequent upward dose adjustment at specified intervals according to tolerability . DB08827 is contraindicated in patients with moderate-to-severe liver disease , patients with sustained abnormal liver function tests , patients taking strong or moderate P08684 inhibitors , and pregnant patients . CONCLUSION : DB08827 is an oral P55157 inhibitor approved for the treatment of HoFH . This agent appears to be a realistic option for patients with HoFH who are unable to attain their LDL-C goal or can not tolerate statin therapy . Automated 22-kD growth hormone-specific assay without interference from DB00082 . BACKGROUND : Large variability exists among different growth hormone ( GH ) assays owing to differences in calibration , antibody specificity , isoform recognition , and interference from GH binding protein ( P30043 ) . The P10912 antagonist DB00082 presents a new challenge because DB00082 interferes with many GH assays . A recent consensus conference established criteria for standardization and evaluation of GH assays . Following consensus recommendations , we developed a new GH assay on an automated analyzer ( P22304 -iSYS , Immunodiagnostic Systems ) . METHODS : A monoclonal antibody not cross-reacting with DB00082 was combined with a monoclonal antibody specific for 22-kD GH . Isoform specificity and interference from P30043 was tested and compared to that seen in 2 existing automated GH assays ( Siemens Immulite , Diasorin Liaison ) . We also compared GH concentrations measured by the 3 assays for healthy volunteers and patients with acromegaly receiving different treatments . Using the iSYS assay , we also established nadir GH values during oral glucose load and analyzed changes in endogenous GH during DB00082 treatment . RESULTS : Analytical and functional sensitivities were 0.01 μg/L and 0.04 μg/L , with a dynamic range from 0.04 to 100 μg/L . Intraassay CVs were 2 % -4 % , whereas interassay CVs were 5 % -7 % at GH concentrations between 1.7 and 27.5 μg/L . The assay was specific for 22-kD GH and not affected by P30043 . The presence of DB00082 , which leads to a negative bias on the Immulite and dramatic overestimation of GH on the Liaison , had no impact on the iSYS GH assay . CONCLUSIONS : The new assay fulfils recent consensus recommendations and presents a useful new tool for reliable measurement of GH . Expression of DB00171 receptors in the rat dorsal root ganglion and spinal cord . Extracellular purine nucleotides and nucleosides play important roles in the nervous system , e.g. , neurotransmission , neuromodulation , chemoattraction and acute inflammation . Extracellular nucleotides act through DB00171 receptors ( P2 receptors ) . P2 receptors are classified into two families : the P2X receptors are ionotropic ligand-gated ion channels and the P2Y receptors are metabotropic G-protein-coupled receptors . Currently , seven P2X receptors ( P51575 -7 ) and eight P2Y receptors ( P47900 , P41231 , P51582 , Q15077 , Q96G91 , Q9H244 , Q9BPV8 and Q15391 ) are recognized . In the sensory nervous system , DB00171 is suggested to be one of first mediators of tissue damage , which activates primary afferents . Nerve injury often leads to neuropathic pain , such as mechanical allodynia and painful responses to normally innocuous stimuli . Peripheral nerve injury induces the upregulation of molecules in activated microglia in the spinal cord . Microglia in the spinal cord may play an important role in the development and maintenance of neuropathic pain . A prominent signaling pathway in the development of neuropathic pain involves DB00171 acting on microglial purinergic receptors . This review focuses on the expression of P2X and P2Y receptors mRNAs in the pain transmission pathway , i.e. , in the dorsal root ganglion ( Q86YR7 ) and spinal cord . Furthermore , we suggest that the multiple microglial P2Y receptors activated by peripheral nerve injury may play a key role in the development of neuropathic pain . LDL subfractions in acromegaly : relation to growth hormone and insulin-like growth factor-I . Acromegaly is associated with changes in lipoprotein metabolism and an excess in cardiovascular mortality . We have examined low density lipoprotein ( LDL ) subfraction distribution in 24 patients with active acromegaly and in controls matched for age , sex and body mass index . LDL was subfractionated by density gradient ultracentrifugation . The concentration of small dense LDL-III was significantly higher in the acromegalic patients compared to the controls ( 94.2 +/- 44.9 versus 67.2 +/- 30.4 mg/dl , P < 0.05 ) and there was a concomitant reduction in the intermediate subfraction LDL-II ( 124.8 +/- 31.3 versus 149.9 +/- 30.0 mg/dl , P < 0.05 ) . Univariate analysis showed that both growth hormone ( GH ) and insulin-like growth factor ( IGF ) -I correlated with LDL-III and inversely with LDL-II . Acromegalic patients were found to have lower hepatic lipase ( HL ) and lipoprotein lipase ( P06858 ) activities than controls ( HL : 13.29 +/- 6.56 versus 21.58 +/- 7.27 micromol FFA released/ml/h , P < 0.001 : P06858 : 7.22 +/- 3.04 versus 11.53 +/- 7.85 micromol FFA released/ml/h , P < 0.05 ) whereas plasma cholesteryl ester transfer protein ( P11597 ) activity was significantly increased ( 8.15 +/- 1.81 versus 5.54 +/- 1.86 pmol/microl/h , P < 0.001 ) . Both GH and P05019 were significantly associated with HL , P06858 and P11597 activities . Multivariate analysis on this relatively small sample size showed that in normal subjects , triglyceride and HL activity were the major determinants of LDL-III . In contrast , GH and HDL were the main determinants in acromegaly , accounting for 32 and 24 % in the variability of LDL-III respectively . In conclusion , GH excess has a direct effect on LDL subfraction distribution . Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( DB01238 ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G-protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5- Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short-term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long-term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time-to-relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug . DB00082 in the treatment of acromegaly . Epidemiological studies have highlighted the need for tight control of growth hormone ( GH ) and insulin-like growth factor I ( P05019 ) in patients with acromegaly . Studies highlighting the events involved in P10912 signaling have allowed the development of a pegylated P10912 antagonist ( pegvisomant ) for use in humans , which has been designed to outcompete GH for the P10912 , but which contains a position 120 amino acid substitution that prevents recruitment of a second P10912 . This process of receptor dimerisation is crucial for signal transduction and P05019 generation . Clinical trials of pegvisomant suggest it is the most effective treatment for acromegaly to date , as this therapy is capable of normalising serum P05019 in up to 97 % of patients when doses of 40 mg per day are used . This paper reviews the development of pegvisomant and the clinical experience in patients with acromegaly to date . The growth hormone receptor antagonist pegvisomant blocks both mammary gland development and MCF-7 breast cancer xenograft growth . Mammary gland development is dependent upon the growth hormone ( GH ) /insulin-like growth factor-I ( P05019 ) axis , this same axis has also been implicated in breast cancer progression . In this study we investigated the effect of a GH antagonist , pegvisomant ( Somavert , Pfizer ) , on normal mammary gland development and breast cancer xenograft growth . Intraperitoneal administration of pegvisomant resulted in a 60 % suppression of hepatic P05019 mRNA levels and upto a 70-80 % reduction of serum P05019 levels . DB00082 administration to virgin female mice caused a significant delay of mammary ductal outgrowth that was associated with a decrease in the number of terminal end buds and reduced branching and complexity of the gland . This effect of pegvisomant was mediated by a complete inhibition of both GH and IGF-IR-mediated signaling within the gland . In breast cancer xenograft studies , pegvisomant caused shrinkage of MCF-7 xenografts , with an initial 30 % reduction in tumor volume , which was associated with a 2-fold reduction in proliferation and a 2-fold induction of apoptosis . Long-term growth inhibition of MCF-7 xenografts was noted . In contrast , pegvisomant had no effect on MDA-231 or MDA-435 xenografts , consistent with primary growth of these xenografts being unresponsive to P05019 both in vitro and in vivo . In MCF-7 xenografts that regressed , pegvisomant had only minor effects upon P10912 and IGF-IR signaling . This data supports previous studies indicating a role for GH/IGF in mammary gland development , and suggests that pegvisomant maybe useful for the prevention and/or treatment of estrogen receptor positive breast cancer . [ P10912 antagonists : potential indications ] . DB00082 is a mutated human growth hormone molecule , which binds to the growth hormone receptor . This binding , however , does not lead to signal transduction . Therefore , in high concentrations pegvisomant acts as a growth hormone receptor antagonist . In a short term study ( 3 months ) pegvisomant was shown to be an effective treatment for acromegaly . On theoretical grounds decreasing the biological effects of growth hormone in patients with diabetes mellitus could have a favourable impact on the severity of the secondary complications associated with this disease . Animal models for diabetic retino- and nephropathy are in accordance with this concept . Human data are lacking but clinical studies investigating the effect of pegvisomant in diabetes mellitus are in preparation . Growth hormone , either directly or via its downstream effector insulin-like growth factor-I ( P05019 ) has been implicated as an important factor in the growth of malignant tumours . Animal studies in which human colon and breast cancer models were used showed that pegvisomant can powerfully decrease tumour growth . Studies in cancer patients have not yet started . Additional metabolic effects of adding P10912 antagonist to long-acting somatostatin analog in patients with active acromegaly . OBJECTIVE : Somatostatin analogs , dopamine agonists and GH-receptor antagonist -- pegvisomant are used in medical therapy of acromegaly . Since pegvisomant has not antitumor effect , the combination of pegvisomant and somatostatin analog could be an attractive option . Aim of study was to assess the effects of pegvisomant and octreotide P10586 treatment on GH and DB01277 levels , and glucose tolerance in acromegaly , and to assess efficacy and tolerability of rapid ( after 7 days ) pegvisomant dose titration . MATERIAL AND METHODS : Six patients ( 4 men , 2 women ) aged 47.5 years ( median ) with active acromegaly , after neurosurgery failed , resistant to maximal doses of octreotide , received daily 10-20 mg pegvisomant throughout 2 weeks . They were given octreotide P10586 30 mg monthly for at least 6 months before pegvisomant therapy . Clinical symptoms , GH , DB01277 , fasting glucose and insulin levels were measured on the 0 , 8th and 15th day of pegvisomant therapy . On the 8th day pegvisomant dose was titrated based on serum DB01277 level . RESULTS : DB01277 levels reduced from 739 at the beginning to 418 ng/ml ( medians ) on the 15th day of treatment and normalized in one patient . These changes were associated with improvement of glucose metabolism . One diabetic patient could even stop insulin therapy . CONCLUSIONS : DB00082 is an attractive adjuvant therapy for controlling acromegaly . DB00082 improves insulin sensitivity as well as glucose tolerance . The P10912 antagonist is good option for patients with active acromegaly coexistent with disturbances of glucose metabolism , especially with diabetes mellitus . Rapid pegvisomant dose increasing to efficient or maximal is well tolerated and effective . Novel use of endogenous GH-measurement directly after transsphenoidal microsurgery in acromegaly treated with pegvisomant . OBJECTIVE : The P10912 antagonist pegvisomant is increasingly used as therapy in acromegaly . Pituitary surgery might be indicated on pegvisomant treatment , due to side effects , adenoma growth or intention to cure after primary treatment . This study was initiated to clarify if , and when , GH measurement could be useful postoperatively with an assay specific for endogenous GH that does not cross-react with pegvisomant . METHODS : This study was designed as a prospective study in 2006 with the German Pituitary Working Group . Only 2 cases with potentially resectable adenomas from the German DB00082 Observational Study ( GPOS ) had been operated . Now with a post-operative follow-up of more than 5 years in these 2 cases , the usefulness of immediate pre-operative GH measurement shortly after pegvisomant treatment was evaluated . RESULTS : In both patients a steep decline of endogenous GH after transnasal microsurgery could be proven by using the special GH assay after near radical or radical removal , of the GH secreting adenomas respectively . Conventional GH assays showed no effect . GH half-life was more than 20 min in the patient with a small invasive residual adenoma and less than 20 min in the cured patient . Endogenous GH-levels declined to less than 1 ng/ml in the days after surgery in the patient with long-term cure . CONCLUSION : Measurement of endogenous GH in this special subgroup of patients under pegvisomant therapy can be used to decide upon early reoperation . Thus the beneficial effect of pegvisomant on acromegalic symptoms can be kept without interfering with post-operative monitoring of GH levels . [ P35354 inhibitor non-steroidal anti-inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox-1 constitutive and Cox-2 inducible , has prompted the development of new molecules with high Cox-2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12.5 to 25 mg/d ) and celecoxib is indicated in osteoarthritis ( 200 mg/d ) and in rheumatoid arthritis ( 200 to 400 mg/d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( DB01050 ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg/d but not investigated for rofecoxib . The selective inhibition of Cox-2 with no effect on Cox-1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox-2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis . Colocalization of cannabinoid receptor 1 with somatostatin and neuronal nitric oxide synthase in rat brain hypothalamus . Despite several overlapping functions of cannabinoid receptor 1 ( P21554 receptor ) , somatostatin ( P61278 ) , and neuronal nitric oxide synthase ( P29475 ) in the hypothalamus , nothing is currently known whether P21554 receptor-positive neurons coexpress P61278 and P29475 . In the present study , we describe the colocalization of P21554 receptor with P61278 and P29475 in the rat brain hypothalamus . In the hypothalamus , the distributional patterns and colocalization of P21554 receptor with P61278 and P29475 were selective and region specific . P21554 receptor and P61278 exhibited comparable colocalization ( < 60 % ) in paraventricular nucleus ( PVN ) and periventricular nucleus ( PeVN ) , followed by 20 % colocalization in ventromedial hypothalamic nucleus ( VMH ) . Neurons showing colocalization between P21554 receptor and P29475 in PeVN constituted > 80 % , followed by 60 and 30 % in PVN and VMH , respectively . In contrast , P61278 - and P29475 -positive neurons displayed comparable colocalization ( > 55 % ) in PeVN and VMH , followed by PVN ( ~20 % ) . In the median eminence , P21554 receptor- , P61278 - , and P29475 -like immunoreactivity was mostly confined to the nerve fibers . The morphological colocalization of P21554 receptor with P61278 and P29475 shed new light on the understanding of their roles in regulation of physiological and pharmacological response to certain stimuli in hypothalamic nuclei specifically in food intake and energy balance . A comparison of the effects of pegvisomant and octreotide on glucose , insulin , gastrin , cholecystokinin , and pancreatic polypeptide responses to oral glucose and a standard mixed meal . Standard medical therapy for patients with acromegaly includes somatostatin analogs . Owing to the widespread expression of somatostatin receptors , these may be associated with unwanted effects , such as altered glucose tolerance and impaired gut hormone release . DB00082 is a novel pegylated GH analog that competes with wild-type GH for GH-receptor binding sites but contains a position 120 , amino acid substitution that prevents functional P10912 dimerization , a known prerequisite for GH signal transduction and generation of P05019 . We have studied the short-term effects of these two therapies ( pegvisomant 20 mg/d for 7 d and octreotide 50 microg thrice daily for 7 d ) on glucose tolerance and stimulated gut hormone release in six healthy male volunteers in an open-label , random-order , cross-over study . Subjects were assessed at baseline ( oral glucose tolerance test and standard mixed meal ) and on d 6 and 7 of each therapy with a minimum washout of 2 wk between treatments . Area under the curve and peak responses were analyzed using one-way repeated-measures Q9UNW9 ( on ranks where appropriate ) . DB00082 had no effect on glucose tolerance or stimulated gut hormone response during an oral glucose tolerance test and a standard meal . In contrast , octreotide significantly increased fasting plasma glucose , lowered fasting plasma insulin , and led to deterioration in glucose tolerance ; three subjects developed impaired glucose tolerance and one diabetes mellitus by World Health Organization criteria . DB00104 significantly impaired stimulated release of cholecystokinin , gastrin , insulin , and pancreatic polypeptide . In conclusion , pegvisomant , unlike octreotide , is not associated with deterioration in glucose tolerance and impairment of stimulated gut hormone release in normal males . Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name DB06209 , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON-TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk:benefit ratio will likely play a major role in directing the best place for therapy with this new agent . DB00082 : current and potential novel therapeutic applications . BACKGROUND : DB00082 is a genetically engineered molecule , which exhibits specific growth hormone ( GH ) antagonism by directly interacting with the P10912 . It is currently licensed for the treatment of acromegaly where surgery and medical therapy with somatostatin analogues have failed . OBJECTIVE : To delineate the role of pegvisomant in the treatment of acromegaly and its novel application in other areas of clinical medicine where suppression of GH action may be of therapeutic benefit . METHODS : A literature review from PubMed- and EMBASE-listed publications and the web-sites of licensing organisations for medicinal products . CONCLUSION : DB00082 is currently used as a second line therapy in the management of acromegaly . It is highly effective in suppressing the metabolic effects of elevated GH levels when used alone or in combination with somatostatin analogues . However , its long term efficacy and safety for this indication has yet to be established . Preliminary data indicate that pegvisomant may have a role in management of type 1 diabetes with beneficial effects on insulin sensitivity and in preventing the progression of microvascular complications . Additional roles as an adjunct to cancer chemotherapy regimens and for the diagnosis of GH deficiency have been proposed , but have yet to be confirmed . Anxiolytic and antidepressant effects of intracerebroventricularly administered somatostatin : behavioral and neurophysiological evidence . Somatostatin ( P61278 ) is a cyclic polypeptide that inhibits the release of a variety of regulatory hormones ( e.g. growth hormone , insulin , glucagon , thyrotropin ) . Moreover , P61278 is widely distributed within the CNS , acting both as a neurotransmitter and as a neuromodulator of other neurotransmitter systems . However , despite its extensive expression in limbic areas , and its co-localization with GABA , a neurotransmitter previously implicated in emotion , the effects of P61278 on anxiety and depression have not been investigated . By performing intraventricular infusions in rats we demonstrate , for the first time , that P61278 has anxiolytic- and antidepressant-like effects in the elevated plus-maze and forced swim test , respectively . In addition , by performing local field potential recordings of hippocampal theta activity evoked by reticular stimulation in urethane-anesthetized rats we also show that P61278 application suppresses the frequency of theta in a similar fashion to diazepam . This neurophysiological signature , common to all classes of anxiolytic drugs ( i.e. benzodiazepines , selective 5-HT reuptake inhibitors , P08908 agonists ) provides strong converging evidence for the anxiolytic-like characteristics of P61278 . Our pharmacological antagonism experiments with bicuculline further suggest that the anxiolytic effect of P61278 may be attributable to the interaction of P61278 with GABA , whereas the antidepressant-like effect of P61278 may be GABA-independent . In addition to contributing to the current understanding of the role of neuropeptides in mood and emotion , these findings support a clinical role for P61278 ( or its analogues ) in the treatment of anxiety and depression .