Efficacy of tamoxifen for the treatment of severe equine asthma

Mainguy-Seers, Sophie; Picotte, Khristine; Lavoie, Jean‐Pierre

doi:10.1111/jvim.15289

Cited by 14 publications

(16 citation statements)

References 36 publications

(48 reference statements)

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“…These differences might make the clinical effect of TX on respiratory burst questionable and warrants further testing in order to determine the actual clinical applicability of these results. A recent, independent study evaluated the clinical effect of orally dosed TX in horses with severe equine asthma and could not demonstrate clinical improvement; although airway resistance was reduced, there was no significant improvement in BALF neutrophil counts (Mainguy‐Seers, Picotte, & Lavoie, ). Thus, no conclusions should be made regarding clinical applicability of TX until further data are available.…”

Section: Discussionmentioning

confidence: 99%

Tamoxifen induces apoptosis and inhibits respiratory burst in equine neutrophils independently of estrogen receptors

Olave

Alvarez

Uberti

et al. 2018

Vet Pharm & Therapeutics

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Neutrophils play an important role in the exacerbation and maintenance of severe equine asthma; persistent neutrophil activity and delayed apoptosis can be harmful to surrounding tissues. Tamoxifen (TX) is a nonsteroidal estrogen receptor modulator with immunomodulatory effects and induces early apoptosis of blood and bronchoalveolar lavage neutrophils from horses with acute lung inflammation. This study investigated if the in vitro effects of tamoxifen are produced by its action on nuclear (α and β) and membrane (GPR30) estrogen receptors in healthy equine neutrophils. Results showed that TX inhibits neutrophil respiratory burst induced by opsonized zymosan in a dose‐dependent manner. Nuclear (17‐β‐Estradiol) and GPR30 cell membrane (G1) estrogen receptor agonists and their antagonists (ICI 182,780 and G15, respectively) do not block or reproduce the effect of TX. Therefore, TX does not inhibit respiratory burst through estrogen receptors. TX (8.5 μM) also increased phosphatidylserine translocation, a marker of early apoptosis, which did not occur with any of the estrogen receptor agonists or antagonists. Thus, tamoxifen generates dose‐dependent inhibition of respiratory burst and increased early apoptosis in healthy equine neutrophils, independently of nuclear or membrane estrogen receptors. Further studies are necessary to explore the signaling pathways of tamoxifen‐induced ROS inhibition and phosphatidylserine translocation.

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Section: Discussionmentioning

confidence: 99%

Tamoxifen induces apoptosis and inhibits respiratory burst in equine neutrophils independently of estrogen receptors

Olave

Alvarez

Uberti

et al. 2018

Vet Pharm & Therapeutics

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“…In addition, our data also showed that TX has the ability to induce in vivo apoptosis of granulocytic cells in a model of induced acute lung inflammation in horses, with concomitant clinical improvement (Perez et al., 2016). An independent group also found that TX produces an improvement in airway resistance in horses with exacerbated severe equine asthma, although no significant improvement in BALF neutrophil counts was observed in that study (Mainguy‐Seers, Picotte, & Lavoie, 2018). Thus, no conclusions should be made regarding the clinical applicability of TX until further data are available.…”

Section: Introductionmentioning

confidence: 90%

Tamoxifen and its metabolites induce mitochondrial membrane depolarization and caspase‐3 activation in equine neutrophils

Albornoz

Morales

Uberti

et al. 2020

Veterinary Medicine & Sci

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Neutrophils participate in innate immunity as the first line of host defence against microorganisms. However, persistent neutrophil activity and delayed apoptosis can be harmful to surrounding tissues; this problem occurs in diverse inflammatory diseases, including asthma‐affected horses. Previous studies in horses with acute lung inflammation indicated that treatment with tamoxifen (TX), a selective oestrogen receptor modulator, produces a significant decrease in bronchoalveolar lavage fluid (BALF) neutrophil content. The aim of this study was to investigate the effect of tamoxifen and its metabolites (N‐desmethyltamoxifen and endoxifen) on the mitochondrial membrane potential assay by flow cytometry, and the activation of effector caspase‐3 through immunoblotting, in peripheral blood neutrophils obtained from healthy horses (n = 5). Results show that tamoxifen, N‐desmethyltamoxifen and endoxifen depolarize the mitochondrial membrane and activate caspase‐3 in healthy equine neutrophils in vitro. These findings suggest that tamoxifen and its metabolites may activate the intrinsic apoptotic pathway in equine neutrophils. However, more studies are necessary to further explore the signalling pathways of these drugs in the induction of apoptosis.

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“…In this study, we determined pharmacokinetic parameters of TAM in adult horses. The few clinical studies that have looked into the potential use of TAM for equine airway inflammation have been based on a single dosage (approximately 0,25 mg/kg) extrapolated from human medicine, with conflicting results regarding clinical efficacy based on that single empirical dose [15,16]. However, there is robust pre-clinical information on modulation of inflammation, which warrants the pharmacokinetic and safety data presented here [17][18][19][20][21].…”

Section: Discussionmentioning

confidence: 95%

“…In the present study, a single administration of 0.25 mg/kg of TAM was used. This dose was originally extrapolated from standard human dosages [48], and was the same dose used in previous equine clinical studies [15,16]. The drug was administered after 8 h of overnight fasting.…”

Section: Tam Administrationmentioning

confidence: 99%

Tamoxifen in horses: pharmacokinetics and safety study

et al. 2019

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Background Tamoxifen (TAM), a selective modulator of estrogen receptors (SERMs) has been recently explored as a therapeutic option for the oral treatment of airway inflammation in the horse. The objective of this work was to establish pharmacokinetic parameters of TAM and its main metabolites in equines, as well as to determine its clinical safety in short-term treatments. Results We determined TAM and its three main metabolites (4-OH tamoxifen, endoxifen, and N-desmethyl tamoxifen) in plasma after single administration of 0.25 mg/kg in healthy adult horses ( n = 12). A maximum concentration of TAM was achieved 3 h after the oral administration (4.65 pg/mL ± 1.69); 4-OH tamoxifen was the metabolite that reached the highest concentration (78 pg/mL ± 70), followed by N-desmethyl tamoxifen (0.43 pg / mL ± 0.48), and finally endoxifen (0.17 pg/mL ± 0.17). All metabolites showed peak concentration 2 h after oral administration of the drug. Oral TAM bioavailability was 13,15% ± 4,18, with a steady state volume of distribution of 7831 ± 2922 (L/kg). Elimination half-life was 15.40 ± 5.80 h, and clearance was 5876 ± 699 (mL/kg/min). Clinical safety of TAM was determined over a 7-day course of treatment (0.25 mg/kg, orally q 24 h, n = 20). No adverse effects were observed through clinical examination, blood hematology, serum biochemistry, ophthalmological and reproductive examinations. Endometrial edema observed in some mares was attributed to normal cyclic activity. Conclusions Tamoxifen has moderate oral bioavailability and a large volume of distribution, with three main metabolites in horses. Additionally, oral TAM administration over a 7-day treatment period demonstrated to be clinically safe, without adverse effects on clinical, hematological or serum biochemical parameters. These data could contribute to the continued research into this drug’s potential for the treatment of different inflammatory conditions in equine species. Electronic supplementary material The online version of this article (10.1186/s13620-019-0143-7) contains supplementary material, which is available to authorized users.

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Efficacy of tamoxifen for the treatment of severe equine asthma

Cited by 14 publications

References 36 publications

Tamoxifen induces apoptosis and inhibits respiratory burst in equine neutrophils independently of estrogen receptors

Tamoxifen induces apoptosis and inhibits respiratory burst in equine neutrophils independently of estrogen receptors

Tamoxifen and its metabolites induce mitochondrial membrane depolarization and caspase‐3 activation in equine neutrophils

Tamoxifen in horses: pharmacokinetics and safety study

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