Telmisartan as an add-on treatment for dogs with refractory idiopathic epilepsy: a nonrandomized, uncontrolled, open-label clinical trial

Erez HanaelVeterinary Teaching Hospital, Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel

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Orit ChaiVeterinary Teaching Hospital, Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel

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Lilach KonstanitinVeterinary Teaching Hospital, Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel

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Laura GibeonBlue Pearl Veterinary Partners, New York, NY

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Kira RapaportVeterinary Teaching Hospital, Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel

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Marco RuggeriVeterinary Teaching Hospital, Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel

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Alon FriedmanZlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, Israel
Department of Medical Neuroscience, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada

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Merav H. ShamirVeterinary Teaching Hospital, Koret School of Veterinary Medicine, Hebrew University of Jerusalem, Rehovot, Israel

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Abstract

OBJECTIVE

To evaluate the effect on seizure frequency of add-on telmisartan treatment in dogs with refractory idiopathic epilepsy.

ANIMALS

11 client-owned dogs with idiopathic epilepsy and ≥ 2 generalized seizures/mon that were currently being treated with ≥ 2 antiepileptic drugs.

PROCEDURES

Telmisartan was administered at a dosage of 0.25 to 1 mg/kg, PO, every 12 hours for 4 to 16 months. Seizure frequencies before and during telmisartan treatment were recorded.

RESULTS

10 dogs completed the 4-month treatment protocol. One dog was excluded owing to a transient increase in serum creatinine concentration; no adverse effects of telmisartan were observed in the remaining 10 dogs. A reduction in seizure frequency greater than an estimated expected placebo effect of 30% was evident in 7 of the 10 dogs. Long-term (12 to 16 months) follow-up information was available for 6 dogs, of which 4 had a further reduction in seizure frequency. Differences in seizure frequency were not statistically significant. No significant difference was found in serum phenobarbital concentration throughout the treatment period in the 7 dogs that were tested.

CLINICAL RELEVANCE

Telmisartan has the potential to reduce seizure frequency when administered as an add-on antiepileptic drug in dogs with refractory idiopathic epilepsy. A randomized, double-blind, placebo-controlled trial is needed to determine the true efficacy of telmisartan. On the basis of our results, a sample size of 54 dogs with refractory idiopathic epilepsy would be needed.

Abstract

OBJECTIVE

To evaluate the effect on seizure frequency of add-on telmisartan treatment in dogs with refractory idiopathic epilepsy.

ANIMALS

11 client-owned dogs with idiopathic epilepsy and ≥ 2 generalized seizures/mon that were currently being treated with ≥ 2 antiepileptic drugs.

PROCEDURES

Telmisartan was administered at a dosage of 0.25 to 1 mg/kg, PO, every 12 hours for 4 to 16 months. Seizure frequencies before and during telmisartan treatment were recorded.

RESULTS

10 dogs completed the 4-month treatment protocol. One dog was excluded owing to a transient increase in serum creatinine concentration; no adverse effects of telmisartan were observed in the remaining 10 dogs. A reduction in seizure frequency greater than an estimated expected placebo effect of 30% was evident in 7 of the 10 dogs. Long-term (12 to 16 months) follow-up information was available for 6 dogs, of which 4 had a further reduction in seizure frequency. Differences in seizure frequency were not statistically significant. No significant difference was found in serum phenobarbital concentration throughout the treatment period in the 7 dogs that were tested.

CLINICAL RELEVANCE

Telmisartan has the potential to reduce seizure frequency when administered as an add-on antiepileptic drug in dogs with refractory idiopathic epilepsy. A randomized, double-blind, placebo-controlled trial is needed to determine the true efficacy of telmisartan. On the basis of our results, a sample size of 54 dogs with refractory idiopathic epilepsy would be needed.

Supplementary Materials

    • Supplementary Table S1 (PDF 84 KB)

Contributor Notes

Corresponding author: Dr. Shamir (merav.shamir@mail.huji.ac.il)
  • 1.

    Jacobs MP, Leblanc GG, Brooks-Kayal A, et al. Curing epilepsy: progress and future directions. Epilepsy Behav. 2009;14(3):438445. doi:10.1016/j.yebeh.2009.02.036

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Hesdorffer DC, Beck V, Begley CE, et al. Research implications of the Institute of Medicine Report, Epilepsy Across the Spectrum: Promoting Health and Understanding. Epilepsia. 2013;54(2):207216. doi:10.1111/epi.12056

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Knake S, Hamer HM, Rosenow F. Status epilepticus: a critical review. Epilepsy Behav. 2009;15(1):1014. doi:10.1016/j.yebeh.2009.02.027

  • 4.

    Löscher W, Potschka H, Rieck S, Tipold A, Rundfeldt C. Anticonvulsant efficacy of the low-affinity partial benzodiazepine receptor agonist ELB 138 in a dog seizure model and in epileptic dogs with spontaneously recurrent seizures. Epilepsia. 2004;45(10):12281239. doi:10.1111/j.0013-9580.2004.21204.x

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Ehrlich P. Das Sauerstoffbedürfnis Des Organismus. August Hirschwald; 1885.

  • 6.

    Ivens S, Kaufer D, Flores LP, et al. TGF-beta receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis. Brain. 2007;130(pt 2):535547. doi:10.1093/brain/awl317

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Friedman A, Kaufer D, Heinemann U. Blood-brain barrier breakdown-inducing astrocytic transformation: novel targets for the prevention of epilepsy. Epilepsy Res. 2009;85(2-3):142149. doi:10.1016/j.eplepsyres.2009.03.005

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Shlosberg D, Benifla M, Kaufer D, Friedman A. Blood-brain barrier breakdown as a therapeutic target in traumatic brain injury. Nat Rev Neurol. 2010;6(7):393403. doi:10.1038/nrneurol.2010.74

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Abbott NJ, Friedman A. Overview and introduction: the blood-brain barrier in health and disease. Epilepsia. 2012;53(suppl 6):16. doi:10.1111/j.1528-1167.2012.03696.x

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Raabe A, Schmitz AK, Pernhorst K, et al. Cliniconeuropathologic correlations show astroglial albumin storage as a common factor in epileptogenic vascular lesions. Epilepsia. 2012;53(3):539548. doi:10.1111/j.1528-1167.2012.03405.x

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    David Y, Cacheaux LP, Ivens S, et al. Astrocytic dysfunction in epileptogenesis: consequence of altered potassium and glutamate homeostasis? J Neurosci. 2009;29(34):1058810599. doi:10.1523/JNEUROSCI.2323-09.2009

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Lapilover EG, Lippmann K, Salar S, et al. Peri-infarct blood-brain barrier dysfunction facilitates induction of spreading depolarization associated with epileptiform discharges. Neurobiol Dis. 2012;48(3):495506. doi:10.1016/j.nbd.2012.06.024

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Bar-Klein G, Cacheaux LP, Kamintsky L, et al. Losartan prevents acquired epilepsy via TGF-β signaling suppression. Ann Neurol. 2014;75(6):864875. doi:10.1002/ana.24147

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Cacheaux LP, Ivens S, David Y, et al. Transcriptome profiling reveals TGF-beta signaling involvement in epileptogenesis. J Neurosci. 2009;29(28):89278935. doi:10.1523/JNEUROSCI.0430-09.2009

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Kim SY, Porter BE, Friedman A, Kaufer D. A potential role for glia-derived extracellular matrix remodeling in postinjury epilepsy. J Neurosci Res. 2016;94(9):794803. doi:10.1002/jnr.23758

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Weissberg I, Wood L, Kamintsky L, et al. Albumin induces excitatory synaptogenesis through astrocytic TGF-β/ALK5 signaling in a model of acquired epilepsy following blood-brain barrier dysfunction. Neurobiol Dis. 2015;78:115125. doi:10.1016/j.nbd.2015.02.029

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Hanael E, Veksler R, Friedman A, et al. Blood-brain barrier dysfunction in canine epileptic seizures detected by dynamic contrast-enhanced magnetic resonance imaging. Epilepsia. 2019;60(5):10051016. doi:10.1111/epi.14739

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Israeli D, Tanne D, Daniels D, et al. The application of MRI for depiction of subtle blood brain barrier disruption in stroke. Int J Biol Sci. 2010;7(1):18. doi:10.7150/ijbs.7.1

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Bar-Klein G, Lublinsky S, Kamintsky L, et al. Imaging blood-brain barrier dysfunction as a biomarker for epileptogenesis. Brain. 2017;140(6):16921705. doi:10.1093/brain/awx073

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Füchtbauer L, Groth-Rasmussen M, Holm TH, et al. Angiotensin II type 1 receptor (AT1) signaling in astrocytes regulates synaptic degeneration-induced leukocyte entry to the central nervous system. Brain Behav Immun. 2011;25(5):897904. doi:10.1016/j.bbi.2010.09.015

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Łukawski K, Janowska A, Jakubus T, Tochman-Gawda A, Czuczwar SJ. Angiotensin AT1 receptor antagonists enhance the anticonvulsant action of valproate in the mouse model of maximal electroshock. Eur J Pharmacol. 2010;640(1–3):172177. doi:10.1016/j.ejphar.2010.04.053

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Yao Y, Zou R, Liu X, et al. Telmisartan but not valsartan inhibits TGF-beta-mediated accumulation of extracellular matrix via activation of PPARgamma. J Huazhong Univ Sci Technolog Med Sci. 2008;28(5):543548. doi:10.1007/s11596-008-0512-z

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Schierok H, Pairet M, Hauel N, Wienen W. Effects of telmisartan on renal excretory function in conscious dogs. J Int Med Res. 2001;29(2):131139. doi:10.1177/147323000102900210

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24.

    De Risio L, Bhatti S, Muñana K, et al. International veterinary epilepsy task force consensus proposal: diagnostic approach to epilepsy in dogs. BMC Vet Res. 2015;11(1):148. doi:10.1186/s12917-015-0462-1

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Potschka H, Fischer A, Löscher W, et al. International veterinary epilepsy task force consensus proposal: outcome of therapeutic interventions in canine and feline epilepsy. BMC Vet Res. 2015;11(1):177. doi:10.1186/s12917-015-0465-y

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26.

    Muñana KR, Zhang D, Patterson EE. Placebo effect in canine epilepsy trials. J Vet Intern Med. 2010;24(1):166170. doi:10.1111/j.1939-1676.2009.0407.x

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    National Institute of Diabetes and Digestive and Kidney Diseases. Telmisartan. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases; 2012.

    • Search Google Scholar
    • Export Citation
  • 28.

    Bugbee AC, Coleman AE, Wang A, Woolcock AD, Brown SA. Telmisartan treatment of refractory proteinuria in a dog. J Vet Intern Med. 2014;28(6):18711874. doi:10.1111/jvim.12471

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29.

    Baek I-H, Lee B-Y, Lee E-S, Kwon K-I. Pharmacokinetics of angiotensin II receptor blockers in the dog following a single oral administration. Drug Res (Stuttg). 2013;63(7):357361. doi:10.1055/s-0033-1341424

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    van Vliet EA, Otte WM, Wadman WJ, et al. Blood-brain barrier leakage after status epilepticus in rapamycin-treated rats I: magnetic resonance imaging. Epilepsia. 2016;57(1):5969. doi:10.1111/epi.13246

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31.

    Caro-Vadillo A, Daza-González MA, Gonzalez-Alonso-Alegre E, Rodríguez A, Gómez-García J. Effect of a combination of telmisartan and amlodipine in hypertensive dogs. Vet Rec Case Rep. 2018;6(2):e000471. doi:10.1136/vetreccr-2017-000471

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32.

    Villapol S, Saavedra JM. Neuroprotective effects of angiotensin receptor blockers. Am J Hypertens. 2015;28(3):289299. doi:10.1093/ajh/hpu197

  • 33.

    Torika N, Asraf K, Danon A, Apte RN, Fleisher-Berkovich S. Telmisartan modulates glial activation: in vitro and in vivo studies. PLoS One. 2016;11(5):e0155823. doi: 10.1371/journal.pone.0155823

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34.

    Rodriguez-Perez AI, Sucunza D, Pedrosa MA, et al. Angiotensin type 1 receptor antagonists protect against alpha-synuclein-induced neuroinflammation and dopaminergic neuron death. Neurotherapeutics. 2018;15(4):10631081. doi:10.1007/s13311-018-0646-z

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35.

    Sekar S, Mani S, Rajamani B, et al. Telmisartan ameliorates astroglial and dopaminergic functions in a mouse model of chronic Parkinsonism. Neurotox Res. 2018;34(3):597612. doi:10.1007/s12640-018-9921-3

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36.

    Deguchi I, Furuya D, Fukuoka T, Tanahashi N. Effects of telmisartan on the cerebral circulation of hypertensive patients with chronic-stage stroke. Hypertens Res. 2012;35(12):11711175. doi:10.1038/hr.2012.105

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37.

    Pushpa VH, Padmaja Shetty K, Suresha RN, Jayanthi MK, Ashwini V, Vaibhavi PS. Evaluation and comparison of anticonvulsant activity of telmisartan and olmesartan in experimentally induced animal models of epilepsy. J Clin Diagn Res. 2014;8(10):HC08HC11. doi:10.7860/JCDR/2014/9455.5061

    • Search Google Scholar
    • Export Citation
  • 38.

    Pereira MGAG, Becari C, Oliveira JAC, Salgado MCO, Garcia-Cairasco N, Costa-Neto CM. Inhibition of the renin–angiotensin system prevents seizures in a rat model of epilepsy. Clin Sci (Lond). 2010;119(11):477482. doi:10.1042/CS20100053

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39.

    Penix LP, Davis W, Subramaniam S. Inhibition of NO synthase increases the severity of kainic acid-induced seizures in rodents. Epilepsy Res. 1994;18(3):177184. doi:10.1016/0920-1211(94)90038-8

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40.

    Moezi L, Shafaroodi H, Hassanipour M, Fakhrzad A, Hassanpour S, Dehpour AR. Chronic administration of atorvastatin induced anti-convulsant effects in mice: the role of nitric oxide. Epilepsy Behav. 2012;23(4):399404. doi:10.1016/j.yebeh.2012.02.001

    • Crossref
    • Search Google Scholar
    • Export Citation

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