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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Following the review article by Gon&#231;alves et al&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> on the potential use of renin&#8211;angiotensin&#8211;aldosterone system inhibitors to reduce the severity of COVID-19&#44; Kow et al&#46; published a comment on it in a Letter to the Editor&#44; stating their general agreement but with some specific critical considerations&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> Among these&#44; they suggest that the partial peroxisome proliferator-activated receptor-gamma &#40;PPAR-&#947;&#41; agonist action of telmisartan could be the cause of the therapeutic benefit observed in patients with COVID-19&#46; Gon&#231;alves et al&#46; subsequently replied&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a> The interesting debate that ensued stimulated our interest in highlighting some pharmacological properties of telmisartan&#46; To our knowledge&#44; these properties enable it to be considered the best agent among the available angiotensin receptor blockers &#40;ARBs&#41; to reach peripheral tissues in effective concentrations to antagonize the inflammatory process triggered by the SARS-CoV-2 virus&#44; after its administration in high therapeutic doses&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">4&#44;5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Telmisartan is the most lipophilic ARB &#40;its partition coefficient is approximately 100 times higher than that of losartan and more than 10<span class="elsevierStyleHsp" style=""></span>000 times higher than that of EXP3174&#44; the active metabolite of losartan&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> Telmisartan is the ARB with the highest volume of distribution &#40;500 l&#41;&#44; which enables its extensive binding to peripheral tissues&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> and with the longest plasma half-life &#40;24 h&#44; as opposed to 2 h for losartan&#41;&#44; undergoing accumulation in peripheral tissues until it reaches a steady state at 4&#8211;5 days&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">4</span></a> Seven days after daily administration of 160 mg orally in hypertensive patients&#44; telmisartan reaches a maximum plasma concentration of 2871 ng&#47;ml&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a> Bearing in mind that the molecular weight of telmisartan is 514&#46;61&#44; these values correspond to 5&#46;58 &#956;M&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Telmisartan is a more potent ARB than losartan&#58; affinity estimates &#40;pKi or pIC50&#41; at mammalian AT1 receptors are 8&#46;33 and 7&#46;71&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> In addition&#44; telmisartan dissociates from the AT1 receptor in an apparently irreversible manner &#40;AT1 receptor dissociation half-life&#58; 213 min&#59; AT1 receptor dissociation half-life of losartan&#58; 67 min and EXP3174&#58; 81 min&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a> Based on its long plasma half-life and its slow dissociation of the AT1 receptor&#44; telmisartan behaves in clinical practice as an irreversible antagonist&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Telmisartan is a partial agonist at PPAR-&#947; receptors with a 10-fold greater potency than losartan &#40;telmisartan EC50&#58; 5 &#956;M&#59; losartan EC50&#58; 50 &#956;M&#41;&#46; After administration of telmisartan at a daily dose of 160 mg&#44; it reaches a maximum plasma concentration of 5&#46;58 &#956;M at seven days&#46; Based on its high lipophilicity and high volume of distribution&#44; it is reasonable to assume that telmisartan concentrations in peripheral tissues will be higher than those in plasma&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">In summary&#44; it is considered that telmisartan at therapeutic doses&#44; in addition to blocking AT1 receptors&#44; stimulates PPAR-&#947; causing additional anti-inflammatory effects&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">8&#8211;10</span></a></p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0030" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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Vol. 43. Núm. 4.
Páginas 219-220 (abril 2024)
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Vol. 43. Núm. 4.
Páginas 219-220 (abril 2024)
Letter to the Editor
Acesso de texto completo
RAAS inhibitors in COVID-19: Not all are created equal. Telmisartan is the one
Inibidores de RAAS em COVID-19: nem todos são criados iguais!: Telmisartan é o único
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Rodolfo P. Rothlina,
Autor para correspondência
safc@ama-med.org.ar

Corresponding author.
, Facundo Pelorossob, Mariano Duartec,d, Liliana Nicolosie, Ignacio Fernandez Criadof, María Victoria Salgadog,h, Héctor Vetullii
a Sociedad Argentina de Farmacología Clínica, Asociación Médica Argentina, Argentina
b Servicio de Anatomía Patológica, Hospital de Alta Complejidad El Calafate SAMIC, Argentina
c Laboratorio de Hipertensión, División de Cardiología, Hospital de Clínicas «José de San Martín», Facultad de Medicina, Universidad de Buenos Aires, Argentina
d Segunda Cátedra de Fisiología, Facultad de Medicina, Universidad de Buenos Aires, Argentina
e División de Cardiología, Hospital Español de Buenos Aires, Argentina
f Sección de Tecnología Educativa e Informática Médica, Hospital de Clínicas «José de San Martín», Facultad de Medicina, Universidad de Buenos Aires, Argentina
g Centro de Estudios de Estado y Sociedad, Ciudad Autónoma de Buenos Aires, Argentina
h Servicio de Medicina Familiar, Hospital de Alta Complejidad El Calafate SAMIC, Argentina
i Servicio de Electrofisiología Cardíaca, Arritmias y Marcapasos, Sanatorio Otamendi y Miroli, Ciudad Autónoma de Buenos Aires, Argentina
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Jorge Gonçalves, Catarina D. Santos, Paula Fresco, Fernando Fernandez-Llimos
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Following the review article by Gonçalves et al.1 on the potential use of renin–angiotensin–aldosterone system inhibitors to reduce the severity of COVID-19, Kow et al. published a comment on it in a Letter to the Editor, stating their general agreement but with some specific critical considerations.2 Among these, they suggest that the partial peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist action of telmisartan could be the cause of the therapeutic benefit observed in patients with COVID-19. Gonçalves et al. subsequently replied.3 The interesting debate that ensued stimulated our interest in highlighting some pharmacological properties of telmisartan. To our knowledge, these properties enable it to be considered the best agent among the available angiotensin receptor blockers (ARBs) to reach peripheral tissues in effective concentrations to antagonize the inflammatory process triggered by the SARS-CoV-2 virus, after its administration in high therapeutic doses.4,5

Telmisartan is the most lipophilic ARB (its partition coefficient is approximately 100 times higher than that of losartan and more than 10000 times higher than that of EXP3174, the active metabolite of losartan).4 Telmisartan is the ARB with the highest volume of distribution (500 l), which enables its extensive binding to peripheral tissues,4 and with the longest plasma half-life (24 h, as opposed to 2 h for losartan), undergoing accumulation in peripheral tissues until it reaches a steady state at 4–5 days.4 Seven days after daily administration of 160 mg orally in hypertensive patients, telmisartan reaches a maximum plasma concentration of 2871 ng/ml.6 Bearing in mind that the molecular weight of telmisartan is 514.61, these values correspond to 5.58 μM.

Telmisartan is a more potent ARB than losartan: affinity estimates (pKi or pIC50) at mammalian AT1 receptors are 8.33 and 7.71, respectively.7 In addition, telmisartan dissociates from the AT1 receptor in an apparently irreversible manner (AT1 receptor dissociation half-life: 213 min; AT1 receptor dissociation half-life of losartan: 67 min and EXP3174: 81 min).7 Based on its long plasma half-life and its slow dissociation of the AT1 receptor, telmisartan behaves in clinical practice as an irreversible antagonist.

Telmisartan is a partial agonist at PPAR-γ receptors with a 10-fold greater potency than losartan (telmisartan EC50: 5 μM; losartan EC50: 50 μM). After administration of telmisartan at a daily dose of 160 mg, it reaches a maximum plasma concentration of 5.58 μM at seven days. Based on its high lipophilicity and high volume of distribution, it is reasonable to assume that telmisartan concentrations in peripheral tissues will be higher than those in plasma.

In summary, it is considered that telmisartan at therapeutic doses, in addition to blocking AT1 receptors, stimulates PPAR-γ causing additional anti-inflammatory effects.8–10

Conflicts of interest

The authors have no conflicts of interest to declare.

References
[1]
J. Gonçalves, C.D. Santos, P. Fresco, et al.
Potential use of renin–angiotensin–aldosterone system inhibitors to reduce COVID-19 severity.
Rev Port Cardiol, 42 (2023 Sep), pp. 817-818
[2]
C.S. Kow, D.S. Ramachandram, S.S. Hasan.
RAAS inhibitors in COVID-19: they are not all the same!.
Rev Port Cardiol, 42 (2023), pp. 815-816
[3]
J. Gonçalves, C.D. Santos, P. Fresco, et al.
Reply to: RAAS inhibitors in COVID-19: not all are created equal!.
Rev Port Cardiol, 42 (2023 Sep), pp. 817-818
[4]
R.P. Rothlin, F.G. Pelorosso, M. Duarte, et al.
Telmisartan and losartan: the marked differences between their chemical and pharmacological properties may explain the difference in therapeutic efficacy in hospitalized patients with COVID-19.
Pharmacol Res Perspect, 11 (2023), pp. e01083
[5]
M. Duarte, F. Pelorosso, L.N. Nicolosi, et al.
Telmisartan for treatment of Covid-19 patients: an open multicenter randomized clinical trial.
EClinicalMedicine, 18 (2021), pp. 100962
[6]
J. Stangier, C.A.P.F. Su, W. Roth.
Pharmacokinetics of orally and intravenously administered telmisartan in healthy young and elderly volunteers and in hypertensive patients.
J Int Med Res, 28 (2000), pp. 149-167
[7]
M.C. Michel, C. Foster, H.R. Brunner, et al.
A systematic comparison of the properties of clinically used angiotensin II type 1 receptor antagonists.
Pharmacol Rev, 13 (2013), pp. 809-848
[8]
P. Zhang, Y. Hou, W. Tu, et al.
Population-based discovery and Mendelian randomization analysis identify telmisartan as a candidate medicine for Alzheimer's disease in African Americans.
Alzheimers Dement, 19 (2023), pp. 1876-1887
[9]
Y. Wang, J. Xue, Y. Li, et al.
Telmisartan protects against high glucose/high lipid-induced apoptosis and insulin secretion by reducing the oxidative and ER stress.
Cell Biochem Funct, 37 (2019), pp. 161-168
[10]
M.A. Ayza, K.A. Zewdie, B.A. Tesfaye, et al.
Anti-diabetic effect of telmisartan through its partial PPARγ-agonistic activity.
Diabetes Metab Syndr Obes, 12 (2020), pp. 3627-3635
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