Recent letters
Displaying 1-10 letters out of 15 published
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Management of hypertension induced by VEGF signalling inhibition
Submit responseComments on “Effect of the multi-targeted receptor tyrosine kinase inhibitor, ABT-869, on blood pressure in conscious rats and mice: reversal with anti-hypertensive agents and effect on tumor growth inhibition”
This letter is in response to the report by Franklin et al. (2009). The authors describe preclinical data from a series of well-designed experiments that address a relevant clinical issue: the control of mechanism-related hypertension induced by inhibitors of VEGF signalling. Such inhibitors are being examined widely in advanced cancer patients as monotherapy, or in combination with established or novel therapeutic approaches.
Franklin et al. (2009) studied hypertensive responses to a mixed VEGF/PDGF receptor tyrosine kinase inhibitor, ABT-869, in rat and mouse, and demonstrated prevention or reversal of blood pressure increases by treatment with a variety of anti-hypertensive agents. The authors concluded that only modest differences exist between use of an angiotensin converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB) or a calcium channel blocker (CCB) to control a hypertension induced by ABT-869. These findings are said to be consistent with the recommendations of Dincer et al. (2006) who suggested that ACE-inhibitors be considered as the anti-hypertensive medication of choice to control hypertension produced by bevacizumab, a monoclonal antibody to VEGF-A. Furthermore, the data are said to be in contrast to our own results which showed that nifedipine, a dihydropyridine CCB, was more effective than the ACE inhibitor captopril in controlling hypertension induced by the pan-VEGFR tyrosine kinase inhibitor cediranib (Curwen et al. 2008).
Given these conclusions, we wish to clarify the interpretation of our preclinical data and the implications for selecting anti-hypertensive medication when treating blood pressure increases induced by VEGF signalling inhibitors in patients. Our data are fully concordant with the results of Franklin et al. (2009): diastolic blood pressure increases of 10 to 14 mmHg induced by either ABT-869 or cediranib in rat can be reversed effectively by treatment with an ACE inhibitor. The studies differ only in that we believe that we are the first to also examine reversal of a more severe hypertension in rats (a diastolic blood pressure increase of 35 to 50 mm Hg), induced by even greater VEGF signalling inhibition. Under these circumstances, the hypertensive change remained refractory to treatment with an ACE inhibitor and nifedipine, a direct vasodilator, was required.
Although the majority of cancer patients who receive VEGF signalling inhibitors and require anti-hypertensive treatment will respond well to many standard drugs such as ACE inhibitors, our preclinical data suggest that there may be circumstances where use of a direct vasodilator is warranted, especially in patients where homeostatic mechanisms are compromised. Indeed, variability in both the magnitude of blood pressure increase induced by VEGF signalling inhibition, and an individual’s response to anti-hypertensive medication, is observed clinically. For example, from a clinical study involving the pan-VEGF receptor tyrosine kinase inhibitor axitinib, Rixe et al. (2007) documented anything between one and greater than three anti-hypertensive therapies being used in patients, in an attempt to reduce treatment-related hypertension.
In summary, whilst the use of ACE inhibitors may be an appropriate first choice for treating moderate hypertension induced by VEGF signalling inhibitors, it is unlikely that a single class of anti-hypertensive agent will be effective in all cases. Alternative anti-hypertensives will be required for a cohort of patients and under these circumstances the use of direct vasodilators should be considered. The use of dihydropyridine CCBs has been recommended to treat hypertension induced by sunitinib or sorafenib (small molecule kinase inhibitors with activity against VEGF receptors) when blood pressure becomes difficult to control with other standard approaches such as ACE inhibitors (Bhojani et al. 2008). An alternative strategy could be to select dihydropyridine CCBs in the first instance to control blood pressure increases that result from VEGF signalling inhibition, thereby helping to protect patients from encountering further hypertensive episodes.
J.O. CURWEN and S.R. WEDGE
Cancer Bioscience, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, UK.
References
Bhojani N, Jeldres C, Patard JJ, Perrotte P, Suardi N, Hutterer G, Patenaude F, Oudard S and Karakiewicz PI (2008) Toxicities associated with the administration of sorafenib, sunitinib, and temsirolimus and their management in patients with metastatic renal cell carcinoma. Eur Urol 53:917-930.
Curwen JO, Musgrove HL, Kendrew J, Richmond GH, Ogilvie DJ and Wedge SR (2008) Inhibition of vascular endothelial growth factor-A signaling induces hypertension: examining the effect of cediranib (Recentin; AZD2171) treatment on blood pressure in rat and the use of concomitant antihypertensive therapy. Clin Cancer Res 14:3124-3131.
Dincer M and Altundag K (2006) Angiotensin-converting enzyme inhibitors for bevacizumab-induced hypertension. Ann Pharmacother 40:2278- 2279.
Franklin PH, Banfor PN, Tapang P, Segreti JA, Widomski DL, Larson KJ, Noonan WT, Gintant GA, Davidsen SK, Albert DH, Fryer RM and Cox BF (2009) Effect of the multi-targeted receptor tyrosine kinase inhibitor, ABT-869, on blood pressure in conscious rats and mice: reversal with anti- hypertensive agents and effect on tumor growth inhibition. J Pharmacol Exp Ther 329:928-937.
Rixe O, Bukowski RM, Michaelson MD, Wilding G, Hudes GR, Bolte O, Motzer RJ, Bycott P, Liau KF, Freddo J, Trask PC, Kim S and Rini BI (2007) Axitinib treatment in patients with cytokine-refractory metastatic renal- cell cancer: a phase II study. Lancet Oncol 8:975-984.
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Complex toxicity of valproate
Submit responseThis interesting study shows the effects of vaproate on the mitochondrial metabolism. As to the mechanisms the reactive metabolites certainly play a role while the parent drug is also an inhibitor of the histone deacetylase (1).
A close congener of valproate, the ethylhexanoic acid is an inbibitor of the carbamoyl phosphate synthase (2) which impairs the urea cycle function. A similar effect by valproate would explain the hyperammonemic complication associated with its use. This could contribute also to the liver damage as the complete urea cycle exists only in hepatocytes.
1 Kopelovich L, Crowell JA, Fay JR. The epigenome as a target for cancer chemoprevention. JNCI 2003; 95: 1747-57
2 Manninen A, Kröger S, Liesivuori J, Savolainen H. 2-ethylhexanoic acid inhibits urea synthesis and stimulates carnitine acetyltransferase activity in rat liver mitochondria. Arch Toxicol 1989; 63: 160-1.
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Response to Letter from H. Namazi
Submit responseResponses to comments on “Atrial natriuretic peptide reduces ischemia/reperfusion-induced spinal cord injury: A novel molecular mechanism”
Naoaki Harada1, Takuya Nakayama2, Miki Asano2, Norikazu Nomura2, Takayuki Saito2, Akira Mishima2, Kenji Okajima1
Departments of 1Translational Medical Science Research and 2Cardiovascular Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
We previously reported that activated neutrophils play a central role in the development of the ischemia/reperfusion (I/R)-induced spinal cord injury (SCI) in rats by inducing endothelial cell damage (Hirose et al., 2000). Activated neutrophils damage endothelial cells by releasing a wide variety of inflammatory mediators including neutrophil proteases and oxygen free radicals (Taoka and Okajima, 2000). Since the intercellular clefts between tightly adherent, activated neutrophils and the endothelium form a microenvironment protected from circulating antiproeases and antioxidant, the neutrophil-endothelial cell interaction is a critical event in the development of activated neutrophil-induced endothelial cell injury (Taoka et al., 1997). Prostacyclin (PGI2) reduces endothelial cell injury by inhibiting neutrophil activation or by down-regulating the endothelial expression of E-selectin and ICAM-1 (Della Bella et al., 2001). We previously demonstrated that calcitonin gene-related peptide released from sensory neurons reduces SCI in rats by inhibiting neutrophil activation through an increase in endothelial production of PGI2 (Kitamura et al., 2007). We recently showed that atrial natriuretic peptide (ANP) reduces I/R-induced SCI in rats by inhibiting neutrophil activation through enhancement of sensory neuron activation (Nakayama et al., 2007).
The commentators suggested that, since ANP is capable of inhibiting the tumor necrosis factor (TNF)-induced increase in expression of neutrophil adhesion molecules E-selectin and ICAM-1 in human umbilical vein endothelial cells in vitro (Kiemer et al., 2002), inhibition of neutrophil adhesion to the endothelium might be a major mechanism by which ANP reduces I/R-induced SCI in rats. However, our in vivo study demonstrated that both reduction of I/R-induced SCI and increases in tissue levels of TNF and neutrophils in rats administered ANP were completely abrogated by pretreatment with SB366791, a selective inhibitor of vanilloid receptor-1 on sensory neurons, and indomethacin (Nakayama et al., 2007). Thus, we concluded that enhancement of sensory neuron activation by ANP might play the most important role in reduction of I/R- induced SCI in rats by inhibiting neutrophil activation.
References
Della Bella S, Molteni M, Mocellin C, Fumagalli S, Bonara P and Scorza R (2001) Novel mode of action of iloprost: in vitro down-regulation of endothelial cell adhesion molecules. Prostaglandins Other Lipid Mediat 65:73-83.
Hirose K, Okajima K, Taoka Y, Uchiba M, Tagami H, Nakano K, Utoh J, Okabe H and Kitamura N (2000) Activated protein C reduces the ischemia/reperfusion-induced spinal cord injury in rats by inhibiting neutrophil activation. Ann Surg 232:272-280.
Kiemer AK, Weber NC and Vollmar AM (2002) Induction of IkappaB: atrial natriuretic peptide as a regulator of the NF-kappaB pathway. Biochem Biophys Res Commun 295:1068-1076.
Kitamura T, Harada N, Goto E, Tanaka K, Arai M, Shimada S and Okajima K (2007) Activation of sensory neurons contributes to reduce spinal cord injury in rats. Neuropharmacology 52:506-514.
Nakayama T, Harada N, Asano M, Nomura N, Saito T, Mishima A and Okajima K (2007) Atrial natriuretic peptide reduces ischemia/reperfusion- induced spinal cord injury in rats by enhancing sensory neuron activation. J Pharmacol Exp Ther 322:582-590.
Taoka Y and Okajima K (2000) Role of leukocytes in spinal cord injury in rats. J Neurotrauma 17:219-229.
Taoka Y, Okajima K, Uchiba M, Murakami K, Kushimoto S, Johno M, Naruo M, Okabe H and Takatsuki K (1997) Role of neutrophils in spinal cord injury in the rat. Neuroscience 79:1177-1182.
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Atrial natriuretic peptide reduces ischemia/reperfusion-induced spinal
Submit responseI read with great interest the article by Nakayama and colleagues (1).
This work shows that melatonin and atrial natriuretic peptide (ANP) markedly suppresses the functional activity of neutrophils, which is underscored by reduced myeloperoxidase activity compared with a placebo. I would like to complete the discussion of Nakayama and coworkers (1) by introducing a major route through which ANP could suppress the activity of neutrophils.
The recent focus on ischemia-reperfusion injury has been on interaction between neutrophils and endothelial cells. The injury attributed to plugging of the microvasculature by neutrophils may initiate the cascade of injury by releasing free radicals, enzymes, and cytokines and physically injuring the endothelium and obstructing the capillaries, thus impairing oxygen supply to the tissue. Also transendothelial migration of neutrophils, with release of reactive oxygen species and cytokines, causes further damage to the injured tissue (2, 3). However, a key component in the pathogenesis of reperfusion syndrome is the upregulation of surface adhesion molecules on the vascular endothelium and their subsequent interaction with the activated neutrophils (4). The most important adhesion protein identified on neutrophils is the integrin lymphocyte function-associated antigen-1 (LFA-1; CD11a/CD18), which is the ligand for intercellular adhesion molecule-1 (ICAM-1) expressed on the endothelium. The LFA-1/ICAM-1 interaction is crucial for the ingress of neutrophils into the inflammatory sites (5, 6). ANP down regulate the expression of ICAM-1 and LFA-1, and through binding to LFA-1, they interfere with ICAM-1–LFA-1 interaction (7, 8). This important mechanism should be borne in mind as the major mechanism for ANP-induced inhibition of neutrophil activity.
Reference
1-Nakayama T, Harada N, Asano M, etal. Atrial natriuretic peptide reduces ischemia/reperfusion-induced spinal cord injury in rats by enhancing sensory neuron activation. J Pharmacol Exp Ther 2007; 322(2):582 -90.
2 - Svensson LG, Crawford ES, Hess KR, et al. Experience with 1509 patients undergoing thoracoabdominal aortic operation. J Vasc Surg 1993; 17: 357–370.
3- Bednar MM, Gross CE, Balazy M, Falck JR. Antineutrophil strategies. Neurology 1997; 49 (suppl 4): 20–22.
4- Boyle EM, Pohlman TH, Cornejo CJ, Verrier ED. Ischemia-reperfusion injury. Ann Thorac Surg 1997; 64: S24–30.
5- Haskard DO and Lee TH. The role of leukocyte-endotheial interactions in the accumulation of leukocytes in allergic inflammation. Am Rev Respir Dis 1992; 145: 10–13.
6- Chen PL, Easton A. Apoptotic Phenotype Alters the Capacity of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand to Induce Human Vascular Endothelial Activation. J Vasc Res 2007; 45(2):111-122.
7- Kiemer AK, Weber NC, Vollmar AM. Induction of IkappaB: atrial natriuretic peptide as a regulator of the NF-kappaB pathway. Biochem Biophys Res Commun 2002; 295(5):1068-76.
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Author's Response
Submit responseDear Dr. Lange,
We thank you for your interest in our work and we are very appreciative of your feedback on the discussion of our published results. We encourage the readers to refer to Dr. Lange’s comments and our responses below for a complete addendum to the discussion section.
Responses:
One question that was asked in your letter was whether the liver and muscle isoforms have the same phosphorylation sites. As per Rider et al., Biochem J. 381:561-79, 2004, the liver isoenzyme is phosphorylated at the N-terminus, adjacent to the PFK-2 domain, by PKA (cAMP-dependent protein kinase), leading to PFK-2 inactivation and FBPase-2 activation. In contrast, the heart isoenzyme (representative of muscle) is phosphorylated at the C-terminus by several protein kinases in different signaling pathways, resulting in PFK-2 activation. There are several references that dive deeply into organ specifc isoforms, but in the interest of being concise in our discussion, we did not seek to review the breath of literature on this enzyme in our paper.
The point of nomenclature for the enzyme is well taken and we ask that this letter serve as a correction in all places where we refer to fructose 2, 6-bisphosphate we would like the readers to be aware of the more recent nomenclature which describes the increased understanding of the structure-function relationship of the enzyme as a homodimeric bifunctional enzyme thus the term 6-phosphofructo-2-kinase)/FBPase-2 (fructose-2, 6-bisphosphatase). Your reference to the Bensaad paper is of interest, but we did not find this enzyme in our study. You also mentioned the specific location of the phosphorylated amino acid. As you stated, since distant phosphorylation events can influence activity, we are interested in treatment-related alteration at any site.
Your comment about the means by which fructose 2, 6 bisphosphate was increased serves to clarify that the bi-functional enzyme was actually over expressed. Thank you for this more specific reference to the experiment, however we are aligned in that the over expression of the bi- functional enzyme did result in increased amounts of fructose 2, 6, bisphosphate which was ultimately responsible for the observed effect on blood glucose. This was the major point to be conveyed by the sentence.
Finally, thank you for the additional references. Your overall perspective on the bi-functional enzyme is appreciated.
Respectfully,
Myrtle Davis
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Metabolic details
Submit responseDear Authors,
We read with great interest your paper on the use of H89 in a proteomic study to identify changes in phosphorylation states of liver proteins. We had some problems related to the metabolism, which you discuss. These are outlined below.
From the discussion in your paper……………
We identified distinct modifications of protein phosphorylation in protein extracts derived from livers of rats treated with H89. Fructose 1,6-bisphosphatase is of primary interest and is one of the rate-limiting enzymes of gluconeogenesis in liver, and its phosphorylation state was potentially altered in H89-treated animals. Fructose 1,6-bisphosphatase (FBPase) has been reported as a substrate for cAMP/PKA (Murray et al., 1984; Rakus et al., 2003) and Rakus et al. (2003) proposed that phosphorylation of FBPase may regulate its activity. PKA phosphorylation of the liver isoform of fructose 2,6- bisphosphatase (an inhibitor of fructose 1,6-bisphosphatase) at serine 32 has been reported (Kurland et al., 2000). Serines 388, 341, and 356 of FBPase have also been reported to be phosphorylation sites for PKA (Ekman and Dahlqvist-Edberg, 1981; Ekdahl, 1987). These data are consistent with the fact that cAMP plays a major, if not primary, role in the regulation of hepatic gluconeogenesis. The relationship between the observed difference in fructose 2,6-bisphosphatase phosphorylation and hepatic metabolism was not determined in this study, but increased expression of hepatic fructose 2,6-bisphosphate resulted in lowered blood glucose levels in normal mice accompanied by increased plasma lactate, triglycerides, and free fatty acids (Wu et al., 2001). Fructose 1,6-bisphosphatase was also found to be very sensitive for assessing cadmium-induced nephrotoxicity (Rajanna et al., 1984). Additional work is underway to determine whether the phosphorylation state of this protein family can serve as a specific biomarker of cAMP/PKA pathway modulation in liver and the relationship to hepatic glucose metabolism.
Line 8, Rakus et al. 2003, is cited twice. This is a reference to the rabbit muscle isoform and the described work is all in liver. The liver and muscle isoforms are not the same. Do they have the same phosphorylation sites?
Lines 10-15 It is stated that the liver isoform of fructose-2,6- bisphosphatase is an inhibitor of fructose-1,6-bisphosphatase (FDPase). The liver isoform referred to above is the c-terminal half of the bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. There is no separate stand alone fructose-2,6-bisphosphatase. Also, one of the products of the bifunctional enzyme (through its kinase activity) is fructose-2,6-bisphosphate, and this small molecular weight regulator is an inhibitor of FDPase, not the fructose-2,6-bisphosphatase enzyme. Recently, an apparently stand-alone bisphosphatase has been discovered, TIGAR (Bensaad, et al. – CELL 126, 107 July 14, 2006), that is p53 inducible.
The PKA phosphorylation of the liver bifunctional enzyme (Kurland) occurs in the n-terminal domain, which is where the kinase activity, not the bisphosphatase activity is. It is true, however that the phosphorylation of the kinase domain at Ser-32 can influence (activate) the bisphosphatase activity.
Line 20, you state that; increased expression of fructose-2,6- bisphosphate resulted in lowered blood glucose levels in normal mice. This is incorrect. The overexpression of the bifunctional enzyme engineered to produce fructose-2,6-bisphosphate led to a higher level of this regulator, which gave the observed effects.
See also; Niswender, C.M., Willis, B.S. Wallen, A., Sweet, I. R., Jetton, T.L., Thompson, B.R., Wu, C., Lange, A.J., and McKnight, G. S. (2005) Cre Recombinase-Dependent Expression of a Constitutively Active Mutant Allele of the Catalytic Subunit of Protein Kinase A. Genesis, 43: 108-118. This paper identifies the bifunctional enzyme as a PKA target.
Respectfully,
Alex J. Lange
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Authors' Response
Submit responseWe have been given the opportunity to provide a brief response to the letter by Drs. Carillo, Nicholls and Young and are grateful for the opportunity. The main point of their letter relates to our claim that indacaterol has a better cardiac safety profile than formoterol in the rhesus monkey. It is important to emphasise that their argument is based on comparisons of potency determined at an early time point with no account being taken of the duration of action of the observed effects. This is an important point, since as we show in our in vivo guinea-pig model (Fig. 5), although the acute bronchoprotective response to formoterol is poorly dose-related, its duration of action is clearly dependant on the dose. Therefore a fair comparison of the two compounds should not only consider the magnitude of the response at an early time point but also take into account the duration of action. This is true for the bronchoprotective effect and for the associated tachycardia. Indeed, from a safety standpoint, it may be imagined that the body would more easily cope with an acute short-lived increase in heart rate than with a tachycardia of long duration.
We agree that if one focuses exclusively on the magnitude of the acute response, doses of 0.3µg/kg formoterol and 12.5µg/kg indacaterol, are equieffective with respect to their bronchorelaxant effects and give similar increases in heart rate (11 ± 1.7% and 13 ± 1.2% for formoterol and indacaterol, respectively). However, for indacaterol the tachycardia is short lasting and not significantly different from control values 90 minutes following drug administration. We have previously published the dose-response curves for the time course of the bronchoprotective effects and tachycardia in response to formoterol in the rhesus monkey (Figure 1 in Fozard and Buescher, 2001). With respect to tachycardia, formoterol at 0.14 and 0.34µg/kg induced significant, dose-related increases in heart rate that outlasted the duration of the experiment (270 min). [Please note that the symbols designating the tachycardia at these doses were unfortunately reversed]. At the 0.34µg/kg dose, the bronchoprotective effect of formoterol, although initially attaining close to 80% inhibition, was short lasting and was not significantly different from the control value 155 min after drug administration. This contrasts with 215 minutes for a dose of 1.2µg/kg of formoterol and > 275 minutes for the 12.5µg/kg dose of indacaterol. Thus, although it can be argued that for a similar degree of bronchoprotection observed at the early time point the peak effect on heart rate is similar for formoterol and indacaterol, our data clearly indicate that the tachycardia is short lasting for indacaterol but not for formoterol. In contrast, as Dr. Carillo and his colleagues point out, the duration of the bronchoprotective effect of indacaterol is longer than that of formoterol. On the basis of the above we stand by our conclusion that, in the rhesus monkey, indacaterol has an improved cardiac safety profile over formoterol.
Alexandre Trifilieff and John R. Fozard Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland
Reference Fozard JR and Buescher H (2001) Comparison of the anti-bronchoconstrictor activities of inhaled formoterol, its (R,R)- and (S,S)-enantiomers and salmeterol in the rhesus monkey. Pulm Pharmacol Ther 14:289-295.
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Comments on “In-vitro and in-vivo pharmacological characterisation of indacaterol"
Submit responseWe read with great interest the paper by Battram et al. (2006) describing the pharmacological properties of indacaterol, a new long acting β agonist (LABA) that is currently in development. The authors compare the safety profiles of indacaterol and the most widely used LABA compounds for the treatment of asthma and COPD, formoterol and salmeterol. It is stated in this article that indacaterol shows an improved cardiovascular safety profile in comparison with formoterol. However, because of deficiencies in design and data analysis, in our judgement this is an unsafe conclusion.
In their article, Battram et al. (2006) make the following statement: “we have demonstrated in the rhesus monkey that, for an equivalent degree of bronchoprotection, indacaterol has a better cardiac safety profile than formoterol”. However, the data show that for an equivalent degree of bronchoprotection, indacaterol & formoterol have equivalent, very small, effects on heart rate. The statement by Battram et al was made on the basis of a comparison between a sub-maximal dose of indacaterol with a supra-maximal dose of formoterol. According to their data (see Fig.7A from Battram et al., 2006), a dose of formoterol of 1.2 µg/kg elicits a 76% inhibition of bronchoconstriction and 26% increase in heart rate, whereas indacaterol at 12.5 µg/kg provides a 75% inhibition of bronchoconstriction and 13% increase in heart rate. However, a lower dose of formoterol, 0.3 µg/kg, provides an equivalent degree of bronchoprotection (73%) and a much lower increase in heart rate (11%). Thus at an equi-effective dose, the effect of formoterol on heart rate is almost identical to that observed with indacaterol at 12.5 µg/kg. This shows clearly that indacaterol and formoterol, in the rhesus monkey, have equivalent cardiac safety profiles.
this sentence doesn’t quite work for me, why also? And following with However makes it worse, could you try something likeThe ED50 values for formoterol & indacaterol as calculated by the authors are 0.14 and 1.7µg/kg respectively. However, in these experiments only three doses of indacaterol were tested and the magnitude of the maximal response was not determined. In our view, it is not possible to accurately calculate the ED50 value for indacaterol under these experimental conditions. Despite this limitation, at the calculated ED50 values for inhibition of bronchoconstriction the observed increases in heart rate elicited by both drugs are virtually identical (see Fig.7A from Battram et al., 2006).In a second set of experiments in the rhesus monkey, the time course of bronchoprotection and changes in heart rate for a single dose of compound were studied (Fig 7B from Battram et al., 2006). The authors selected the highest dose of formoterol used in the previous experiment (1.2 µg/kg) and 12.5 µg/kg for indacaterol. It can be argued that the selected doses are equivalent since they are approximately 8-fold higher than the corresponding ED50 values for inhibition of bronchoconstriction, but as discussed above, the ED50 value for indacaterol cannot be accurately calculated from the experimental data presented. Therefore, the most objective comparison would have been done selecting submaximal and equi-effective doses of both compounds. In this experiment indacaterol appears to show shorter lasting effects on heart rate. It is evident, however, that during the course of the experiment the effect of formoterol on heart-rate declined at least as fast as the effect of indacaterol, suggesting that if an equivalent dose of formoterol were chosen there would be no difference.
In Battram et al the data clearly show that the duration of action of indacaterol is longer than that of formoterol and salmeterol, however the non-equivalence of the doses selected to compare the cardiovascular safety profile of these compounds in rhesus monkey makes the conclusion regarding comparative cardiac profile unsafe. This study illustrates the ease with which a misleading interpretation can result when there is a failure to select equi-effective doses in safety studies. Indacaterol provides an interesting new development in long acting beta therapy but there are no data to support a better cardiac safety profile than formoterol.
Juan J. Carrillo, David J. Nicholls and Alan Young
Department of Discovery BioScience, AstraZeneca R&D Charnwood, Loughborough, LE11 5RH, UK
References
Battram C, Charlton SJ, Cuenoud B, Dowling MR, Fairhurst RA, Farr D, Fozard JR, Leighton-Davies JR, Lewis CA, McEvoy L, Turner RJ, and Trifilieff A (2006) In-vitro and in-vivo pharmacological characterisation of indacaterol (5-[(R)-2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one), a novel inhaled β2 adrenoceptor agonist with a 24-hour duration of action. J Pharmacol Exp Ther (JPET Fast Forward).
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Help..need some information on the association of terbutaline and its effects on infants
Submit responseHelp..need some info on the effects of terbutaline used to stop pre term labor and SVT in infant...my dauther had svt at birth and still has it at age 2...is it a result of the terbutaline I took??? she has no structural abnormalities with her heart..
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Submit responseasoto@canalejo.org
