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BACKGROUND: Pimobendan, diuretics, and an angiotensin-converting enzyme inhibitor (ACEi) are widely used for the management of chronic valvular heart disease in dogs; however, the effects of that combination on heart rate variability (HRV) are unknown. The purpose of this study was to assess the HRV of symptomatic myxomatous mitral valve degeneration (MMVD) dogs in response to therapy with a combination of pimobendan, diuretics, and ACEi. RESULTS: MMVD stage C (n = 17) dogs were enrolled and a 1-hour Holter recording together with echocardiography, blood pressure measurement, and blood chemistry profiles were obtained before and 1, 3, and 6 months after oral treatment with pimobendan (0.25 mg/kg), enalapril (0.5 mg/kg), and furosemide (2 mg/kg) twice daily. The results revealed that MMVD stage C dogs at the baseline had lower values of time-domain indices, low frequency (LF), high frequency (HF), and total power, as well as higher value of LF/HF. Triple therapy significantly increases these parameters in MMVD stage C dogs (P < 0.05). A positive moderate correlation was observed between time domain parameters and a left ventricular internal diastole diameter normalized to body weight (P < 0.05). CONCLUSIONS: It can be concluded that MMVD stage C dogs possess low HRV due to either the withdrawal of parasympathetic tone or enhanced sympathetic activation, and a combination therapy was shown to enhance cardiac autonomic modulation inferred from the increased heart rate variability. Therefore, a combination therapy may be useful for restoring normal autonomic nervous system activity in dogs with MMVD stage C.
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Doenças do Cão , Prolapso da Valva Mitral , Cães , Animais , Furosemida/farmacologia , Furosemida/uso terapêutico , Enalapril/farmacologia , Enalapril/uso terapêutico , Frequência Cardíaca , Valva Mitral , Cardiotônicos/farmacologia , Prolapso da Valva Mitral/veterinária , Diuréticos , Doenças do Cão/tratamento farmacológicoRESUMO
BACKGROUND: Pimobendan has been proven to delay the onset of congestive heart failure (CHF) in dogs with mitral regurgitation (MR); however, molecular underlying mechanisms have not been fully elucidated. This study aimed to investigate (1) the effects of pimobendan on cardiac function, cardiac mitochondrial quality and morphology, and cardiac ultrastructure in a rat model of chronic MR and (2) the direct effect of pimobendan on intracellular reactive oxygen species (ROS) production in cardiac cells. MR was surgically induced in 20 Sprague-Dawley rats, and sham procedures were performed on 10 rats. Eight weeks post-surgery, the MR rats were randomly divided into two groups: the MR group and the MR + pimobendan group. Pimobendan (0.15 mg/kg) was administered twice a day via oral gavage for 4 weeks, whereas the sham and MR groups received equivalent volumes of drinking water. Echocardiography was performed at baseline (8 weeks post-surgery) and at the end of the study (4 weeks after treatment). At the end of the study protocol, all rats were euthanized, and their hearts were immediately collected, weighed, and used for transmission electron microscopy and mitochondrial quality assessments. To evaluate the role of pimobendan on intracellular ROS production, preventive or scavenging properties were tested with H2O2-induced ROS generation in rat cardiac myoblasts (H9c2). RESULTS: Pimobendan preserved cardiac functions and structure in MR rats. In addition, pimobendan significantly improved mitochondrial quality by attenuating ROS production and depolarization (P < 0.05). The cardiac ultrastructure and mitochondrial morphology were significantly preserved in the MR + pimobendan group. In addition, pimobendan appeared to play as a ROS scavenger, but not as a ROS preventer, in H2O2-induced ROS production in H9c2 cells. CONCLUSIONS: Pimobendan demonstrated cardioprotective effects on cardiac function and ultrastructure by preserving mitochondrial quality and acted as an ROS scavenger in a rat model of MR.
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Doenças do Cão , Insuficiência da Valva Mitral , Ratos , Animais , Cães , Insuficiência da Valva Mitral/tratamento farmacológico , Insuficiência da Valva Mitral/veterinária , Peróxido de Hidrogênio , Espécies Reativas de Oxigênio , Ratos Sprague-Dawley , Mitocôndrias , Células MuscularesRESUMO
CONTEXT: Attempts are ongoing to develop medications to fight against the COVID-19 pandemic. Our previous study revealed the in vitro anti-SARS-CoV-2 activity of fingerroot [Boesenbergia rotunda (L.) Mansf. (Zingiberaceae)] and its phytochemical, panduratin A. OBJECTIVE: To investigate the pharmacokinetic profiles of panduratin A as a pure compound and in a fingerroot extract formulation in beagle dogs. MATERIALS AND METHODS: A total of 12 healthy dogs were randomly divided into three groups, a single dose of 1 mg/kg panduratin A by intravenous and multiple doses of 5 and 10 mg/kg panduratin A fingerroot extract formulation by oral administration for seven consecutive days. The plasma concentration of panduratin A was determined by LCMS. RESULTS: The peak concentrations of a single dose of 5 and 10 mg/kg panduratin A fingerroot extract formulation were 12,416 ± 2,326 and 26,319 ± 8,221 µg/L, respectively. Increasing the oral dose of fingerroot extract formulation, equivalent to panduratin A 5-10 mg/kg, showed dose proportionality, with an approximately 2-fold increase in Cmax and AUC. The absolute oral bioavailability of panduratin A in the fingerroot extract formulation was approximately 7-9%. The majority of panduratin A was biotransformed into several products via oxidation and glucuronidation, and predominantly excreted via the faecal route. CONCLUSION: The oral formulation of fingerroot extract was safe in beagle dogs, and increasing dose showed dose proportionality in terms of the systemic exposure of panduratin A. This information will support the phytopharmaceutical product development of fingerroot extract against the COVID-19 pandemic.
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COVID-19 , Zingiberaceae , Cães , Animais , Humanos , Disponibilidade Biológica , Pandemias , Zingiberaceae/química , Administração Oral , Extratos Vegetais , Redes e Vias MetabólicasRESUMO
Cardiac inflammation has been proposed as one of the primary mechanisms of anthracycline-induced acute cardiotoxicity. A reduction in cardiac inflammation might also reduce cardiotoxicity. This study aimed to evaluate the potential of estrogen therapy and regular exercise on attenuating cardiac inflammation in the context of doxorubicin-induced cardiomyopathy. Ovariectomized rats were randomly allocated into estrogen supplementation, exercise training, and mast cell stabilizer treatment groups. Eight weeks after ovariectomy, rats received six cumulative doses of doxorubicin for two weeks. Echocardiography demonstrated a progressive decrease in ejection fraction in doxorubicin-treated rats without hypertrophic effect. This systolic defect was completely prevented by either estrogen supplementation or mast cell stabilizer treatment but not by regular exercise. As a heart disease indicator, increased ß-myosin heavy chain expression induced by doxorubicin could only be prevented by estrogen supplementation. Decrease in shortening and intracellular Ca2+ transients of cardiomyocytes were due to absence of female sex hormones without further effects of doxorubicin. Again, estrogen supplementation and mast cell stabilizer treatment prevented these changes but exercise training did not. Histological analysis indicated that the hyperactivation of cardiac mast cells in ovariectomized rats was augmented by doxorubicin. Estrogen supplementation and mast cell stabilizer treatment completely prevented both increases in mast cell density and degranulation, whereas exercise training partially attenuated the hyperactivation. Our results, therefore, suggest that estrogen supplementation acts similarly to mast cell stabilizers in attenuating the effects of doxorubicin. Ineffectiveness of regular exercise in preventing the acute cardiotoxicity of doxorubicin might be due to a lesser effect on preventing cardiac inflammation.
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Degranulação Celular/efeitos dos fármacos , Doxorrubicina , Estradiol/administração & dosagem , Terapia de Reposição de Estrogênios , Terapia por Exercício , Mastócitos/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Disfunção Ventricular Esquerda/prevenção & controle , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Sinalização do Cálcio/efeitos dos fármacos , Cardiotoxicidade , Modelos Animais de Doenças , Feminino , Mediadores da Inflamação/metabolismo , Mastócitos/metabolismo , Mastócitos/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Ovariectomia , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Disfunção Ventricular Esquerda/induzido quimicamente , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
The benefits of α-mangostin for various tissues have been reported, but its effect on the heart has not been clarified. This study aimed to evaluate the effects of α-mangostin on cardiac function. Using a cardiac sarcoplasmic reticulum (SR) membrane preparation, α-mangostin inhibited SR Ca2+ -ATPase activity in a dose-dependent manner (IC50 of 6.47 ± 0.7 µM). Its suppressive effect was specific to SR Ca2+ -ATPase but not to myofibrillar Ca2+ -ATPase. Using isolated cardiomyocytes, 50 µM of α-mangostin significantly increased the duration of cell relengthening and increased the duration of Ca2+ transient decay, suggesting altered myocyte relaxation. The relaxation effect of α-mangostin was also supported in vivo after intravenous infusion. A significant suppression of both peak pressure and rate of ventricular relaxation (-dP/dt) relative to DMSO infusion was observed. The results from the present study demonstrated that α-mangostin exerts specific inhibitory action on SR Ca2+ -ATPase activity, leading to myocardial relaxation dysfunction.
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Diástole/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/antagonistas & inibidores , Xantonas/toxicidade , Animais , Ventrículos do Coração/fisiopatologia , Masculino , Coelhos , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismoRESUMO
Pathogenic BAG5 variants recently linked to dilated cardiomyopathy (DCM) prompt further investigation into phenotypic, mutational, and pathomechanistic aspects. We explored the clinical and molecular characteristics of DCM associated with BAG5 variants, uncovering the consistently severe manifestations of the disease and its impact on the endoplasmic reticulum (ER) stress response. The analysis involved three siblings affected by DCM and arrhythmia, along with their four unaffected siblings, their unaffected father, and their mother who exhibited arrhythmia. The parents were consanguineous. Exome and Sanger sequencing identified a novel BAG5 variant, c.444_445delGA (p.Lys149AsnfsTer6), homozygous in affected siblings and heterozygous in parents and unaffected siblings. We generated heterozygous and homozygous Bag5 point mutant knock-in (KI) mice and evaluated cardiac pathophysiology under stress conditions, including tunicamycin (TN) administration. Bag5-/- mice displayed no abnormalities up to 12 months old and showed no anomalies during an exercise stress test. However, following TN injection, Bag5-/- mice exhibited significantly reduced left ventricular fractional shortening (LVFS) and ejection fraction (LVEF). Their cardiac tissues exhibited a notable increase in apoptotic cells, despite non-distinctive changes in CHOP and GRP78 levels. Interestingly, only Bag5 KI male mice demonstrated arrhythmia, which was more pronounced in Bag5-/- than in Bag5+/-males. Here, our study reveals a novel BAG5 mutation causing DCM by impairing the ER stress response, with observed sex-specific arrhythmia differences.
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Arritmias Cardíacas , Cardiomiopatia Dilatada , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático , Animais , Cardiomiopatia Dilatada/genética , Estresse do Retículo Endoplasmático/genética , Humanos , Arritmias Cardíacas/genética , Masculino , Feminino , Camundongos , Linhagem , Camundongos Knockout , Adulto , Apoptose/genética , MutaçãoRESUMO
Background: Tilapia lake virus (TiLV), also known as Tilapinevirus tilapiae, poses a significant threat to tilapia aquaculture, causing extensive mortality and economic losses. Understanding the mechanisms and pathogenesis of TiLV is crucial to mitigate its impact on this valuable fish species. Methodology: In this study, we utilized transmission electron microscopy to investigate the ultrastructural changes in E-11 cells following TiLV infection. We also examined the presence of TiLV particles within the cells. Cellular viability and mitochondrial functions were assessed using MTT and ATP measurement assays and mitochondrial probes including JC-1 staining and MitoTracker™ Red. Results: Our findings provide novel evidence demonstrating that TiLV causes cytotoxicity through the destruction of mitochondria. Transmission electron micrographs showed that TiLV particles were present in the cytoplasm of E-11 cells as early as 1 h after infection. Progressive swelling of mitochondria and ultrastructural damage to the cells were observed at 1, 3 and 6 days post-infection. Furthermore, losses of mitochondrial mass and membrane potential (MMP) were detected at 1 day after TiLV inoculation, as determined by mitochondrial probes. The results of the MTT assay also supported the hypothesis that the cell deaths in E-11 cells during TiLV infection may be caused by the disruption of mitochondrial structure and function. Conclusions: Our study reveals the significant role of mitochondrial disruption in contributing to cellular death during the early stages of TiLV infection. These findings advance the understanding of TiLV pathogenesis and further enhance our knowledge of viral diseases in fish.
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Doenças dos Peixes , Infecções por Orthomyxoviridae , Vírus de RNA , Tilápia , Vírus , Animais , Vírus de RNA/fisiologiaRESUMO
Sacubitril/valsartan (SAC/VAL), an angiotensin receptor blocker-neprilysin inhibitor, has been widely used to treat several types of heart failure. Nevertheless, the effects of drugs in mitral regurgitation patients, from the molecular level to therapeutic effects, remain unclear. This study investigates the roles of SAC/VAL on cardiac function, mitochondrial quality, autophagy, mitophagy, and natriuretic peptides in a rat model of chronic mitral regurgitation. Male Sprague-Dawley rats underwent MR induction (n = 16) and sham surgeries (n = 8). Four weeks post-surgery confirmed MR rats were randomly divided into MR (n = 8) and SAC/VAL (n = 8) groups. The SAC/VAL group was administered SAC/VAL, whereas the MR and the sham rats received vehicle via oral gavage daily for 8 weeks. Cardiac geometry, function, and myocardial fibrosis were assessed by echocardiography and histopathology. Spectrophotometry and real-time PCR were performed to assess the pharmacological effects on mitochondrial quality, autophagy, mitophagy, and natriuretic peptides. MR rats demonstrated significant left heart dilation and left ventricular systolic dysfunction compared with the sham group, which could be significantly improved by SAC/VAL. In addition, SAC/VAL significantly reduced myocardial cardiac remodeling and fibrosis in MR rats. SAC/VAL improved the mitochondrial quality by attenuating mitochondrial reactive oxygen species production and mitochondrial depolarization compared with the MR group. Also, the upregulation of autophagy-related, mitophagy-related, and natriuretic peptide system gene expression in MR rats was attenuated by SAC/VAL treatment. In conclusion, this study demonstrated that SAC/VAL treatment could provide numerous beneficial effects in MR conditions, suggesting that this drug may be an effective treatment for MR.
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Insuficiência Cardíaca , Insuficiência da Valva Mitral , Masculino , Ratos , Animais , Insuficiência da Valva Mitral/tratamento farmacológico , Remodelação Ventricular , Tetrazóis/farmacologia , Ratos Sprague-Dawley , Valsartana/farmacologia , Valsartana/uso terapêutico , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/tratamento farmacológico , Aminobutiratos/farmacologia , Aminobutiratos/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Antagonistas de Receptores de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Combinação de MedicamentosRESUMO
AIMS: New drugs for heart failure (HF) that target restoring the impaired NO-sGC-cGMP pathway are being developed. We aimed to investigate the effects of vericiguat, an sGC stimulator, on cardiac function, blood pressure (BP), cardiac mitochondrial quality, and cardiac fibrosis in rat models of chronic mitral regurgitation (MR). MATERIALS AND METHODS: We surgically induced MR in 20 Sprague-Dawley rats and performed sham procedures on 10 rats (negative control). Four weeks post-surgery, we randomly divided the MR rats into two groups: MR group and MR + vericiguat group. Vericiguat (0.5 mg/kg, PO) was administered once a day via oral gavage for 8 weeks, while the sham and MR groups received equivalent volumes of drinking water instead. We took echocardiography and BP measurements at baseline (4 weeks post-surgery) and at the end of study (8 weeks after treatment). At the study end, all rats were euthanized and their hearts were immediately collected, weighed, and used for histopathology and mitochondrial quality assessments. KEY FINDINGS: Vericiguat preserved cardiac functions and structural remodeling in the MR rats, with significantly lower systolic BPs than baseline values (P < 0.05). Additionally, vericiguat significantly improved the mitochondrial quality by attenuating ROS production, depolarization and swelling when comparing the values in both groups (P < 0.05). The fibrosis area also significantly decreased in the MR + vericiguat group (P < 0.05). SIGNIFICANCE: Vericiguat demonstrated cardioprotective effects on cardiac function, BP, and fibrosis by preserving mitochondrial quality in rats with HF due to MR.
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Insuficiência Cardíaca , Compostos Heterocíclicos com 2 Anéis , Insuficiência da Valva Mitral , Animais , Ratos , Insuficiência da Valva Mitral/tratamento farmacológico , Pirimidinas/uso terapêutico , Ratos Sprague-Dawley , Volume SistólicoRESUMO
Stress is associated with cardiovascular disease. One accepted mechanism is autonomic imbalance. In this study, we investigated the effects of chronic mild stress (CMS) on cardiac autonomic control, cardiac structure and renin-angiotensin-aldosterone system (RAAS) activity in adult male Sprague Dawley rats. The CMS model provides a more realistic simulation of daily stress. The animals were divided into control and CMS, and were exposed to 4-week mild stressors. The electrocardiogram recording, sucrose intake and parameters related to stress, cardiac alterations and RAAS were determined. The results showed that CMS had lower body weight and higher sucrose intake. The heart rate variability (HRV) revealed that CMS increased autonomic activity without affecting its balance. The increased RAAS activity with upregulated angiotensin type 1 receptor mRNA expression was shown in CMS. The increased sympathetic activity or RAAS was correlated with stress. Moreover, the altered cardiac structure (i.e., heart weight and cardiomyocyte cross-sectional area) were correlated with stress-, sympathetic- and RAAS-related parameters. These indicated that CMS-induced cardiac hypertrophy was the result of both sympathetic and RAAS activation. Therefore, it could be concluded that 4-week CMS in male rats induced negative emotion as shown by increased sucrose intake, and increased cardiac autonomic and RAAS activities, which may be responsible for mild cardiac hypertrophy. The cardiac hypertrophy herein was possibly in an adaptive, not pathological, stage, and the cardiac autonomic function was preserved as the autonomic activities were in balance.
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Stress is associated with cardiovascular diseases. One possible mechanism is the reduction in gamma-aminobutyric acid (GABA)ergic transmission at the paraventricular nucleus (PVN), which contributes to the disinhibition of sympathoexcitatory circuits and activates sympathetic outflow. At present, the mechanism of chronic mild stress (CMS) on GABAergic transmission at the PVN and cardiac autonomic activity is not yet fully clarified. Therefore, this study was designed to investigate the effects of CMS on the GABAergic system at the PVN and on the cardiac autonomic activity. Adult male Sprague-Dawley rats were randomly assigned to control (left undisturbed in their home cage) or CMS (subjected to various mild stressors for 4 weeks). Cardiac autonomic activities were determined by heart rate variability (HRV) analysis, and GABAergic alterations at the PVN were determined from GABA levels and mRNA expression of GABA-related activities. Results showed that the CMS group had decreased HRV as determined by the standard deviation of all R-R intervals (SDNN). The low frequency (LF) and high frequency (HF) powers of the CMS group were higher than those of the control. Hence, the LF/HF ratio was consequently unaffected. These findings indicated that despite the increase in sympathetic and parasympathetic activities, the autonomic balance was preserved at 4 weeks post CMS. For the GABAergic-related parameters, the CMS group had decreased mRNA expression of glutamic acid decarboxylase-65 (GAD-65), the GABA-synthesizing enzyme, and increased mRNA expression of gamma-aminobutyric acid transporter-1 (GAT-1). Moreover, the GAD-65 mRNA expression was negatively correlated with LF. In conclusion, 4-week CMS exposure in male rats could attenuate GABAergic transmission at the PVN and alter cardiac autonomic activities.
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Hipotálamo , Núcleo Hipotalâmico Paraventricular , Animais , Hipotálamo/metabolismo , Masculino , RNA Mensageiro , Ratos , Ratos Sprague-Dawley , Ácido gama-Aminobutírico/metabolismoRESUMO
Oral capsule and tablet formulations of pimobendan are widely used but may present difficulties for accurately dosing small patients. This study aimed to compare the pharmacokinetic (PK) characteristics, bioequivalence, and cardiovascular effects of a custom-made oral pimobendan solution (PS) formulation compared to a reference solution (RS) formulation in conscious, healthy dogs. A randomized crossover design was performed on dogs that received RS and PS formulations at a dose of 0.3 mg/kg. Blood samples were collected at 0, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, and 24 h after oral administration for PK analysis; bioequivalence was also calculated. Echocardiography was also performed to assess the cardiovascular effects. The results revealed that the plasma concentrations of pimobendan and o-desmethyl-pimobendan (active metabolite) in the case of both formulations were comparable. The relative ratios of geometric mean concentrations for all significant parameters of PK were within a range of 80-125%, indicating bioequivalence. In addition, both formulations increased cardiac contraction significantly when compared with the baseline, and no differences in cardiac contractility were detected between the formulations. The PS formulation can be used as alternative to the RS formulation for the management of congestive heart disease because of the bioequivalence between the two formulations.
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Protease enzymes contribute to the initiation of cardiac remodeling and heart failure after myocardial ischemic/reperfusion (I/R) injury. Protease inhibitors attenuate protease activity and limit left ventricular dysfunction and remodeling. Previous studies showed the cardioprotective effect of secretory leukocyte protease inhibitor (SLPI) against I/R injury. However, overexpression of SLPI gene in cardiovascular diseases has only been investigated in an in vitro experiment. Here, cardiac-selective expression of the human secretory leukocyte protease inhibitor (hSLPI) gene and its effect on I/R injury were investigated. Adeno-associated virus (AAV) serotype 9 carrying hSLPI under the control of cardiac-selective expression promoter (cardiac troponin, cTn) was intravenously administered to Sprague-Dawley rats for 4 weeks prior to coronary artery ligation. The results showed that myocardial-selective expression of hSLPI significantly reduced infarct size, cardiac troponin I (cTnI), creatine kinase-MB (CK-MB), and myoglobin levels that all served to improve cardiac function. Moreover, overexpression of hSLPI showed a reduction in inflammatory cytokines, oxidatively modified protein carbonyl (PC) content, ischemia-modified albumin (IMA), and necrosis and cardiac tissue degeneration. In conclusion, this is the first study to demonstrate cardiac-selective gene delivery of hSLPI providing cardioprotection against myocardial I/R injury in an in vivo model.
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A newly standardised extract of Centella asiatica (Centell-S) with better water solubility than the previous standardised extract of C. asiatica (ECa 233) was developed, and pharmacokinetic profiles of bioactive triterpenoids were investigated in beagle dogs. The test substances were administered via intravenous or oral administration with single and multiple doses for 7 days. The concentrations of major bioactive triterpenoids, including madecassoside, asiaticoside, madecassic acid, and asiatic acid, in biological samples were measured by liquid chromatography-tandem mass spectrometry. The dogs in this study showed good tolerability to all test substances, based on the physical appearance and blood chemistry 24 h after dosing. The major bioactive triterpenoids found in systemic blood circulation were madecassoside, asiaticoside, and asiatic acid; the concentration of these components ranged from 1 to 10,000 µg/L after intravenous administration of 1.0 mg/kg Centell-S. Oral administration of 10 and 20 mg/kg Centell-S generated approximately twofold higher plasma levels of both madecassoside and asiaticoside compared with equivalent doses of ECa 233. In addition, there was an accumulation of triterpenoid glycosides after multiple oral administrations of Centell-S for 7 days, while triterpenic acids showed little tendency for accumulation. Beagles had good tolerability to both standardised extracts of C. asiatica, and showed a similar pattern of bioactive triterpenoids to humans. Centell-S increased oral bioavailability of major triterpenoid glycosides and can be further developed into a phytopharmaceutical product.
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Glicosídeos/farmacocinética , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacocinética , Triterpenos/farmacocinética , Água , Administração Oral , Animais , Disponibilidade Biológica , Centella/química , Cães , Glicosídeos/análise , Triterpenos Pentacíclicos/análise , Triterpenos Pentacíclicos/farmacocinética , Extratos Vegetais/química , Solubilidade , Triterpenos/administração & dosagem , Triterpenos/análise , Triterpenos/químicaRESUMO
Centell-S is a water-soluble extract of Centella asiatica containing more than 80% w/w triterpenoid glycosides. Madecassoside and asiaticoside are two major components of the extract and can be converted into active metabolites, triterpenic acids in large mammal species. In this study, the pharmacokinetic profiles and metabolomic changes generated by the bioactive triterpenoids of Centell-S alone, and in combination with the bioenhancers piperine and curcumin, were investigated in beagle dogs. The test substances were orally administered over multiple doses for 7 consecutive days. At day 1 and 7 after receiving the test compounds, the level of major bioactive triterpenoids and related metabolites were measured using triple quadrupole and high-resolution accurate mass orbitrap models of LCMS to determine pharmacokinetic and metabolomic profiles, respectively. Centell-S was well tolerated, alone and in all combination groups. The combination of Centell-S and piperine significantly increased (p < 0.05) the systemic exposure of madecassoside on day 1 and asiatic acid on day 7, by approximately 1.5 to 3.0-fold of Cmax and AUC values as compared to the Centell-S alone, while the addition of curcumin did not provide a significant improvement. Several metabolomic changes were observed from pre-dose to 4 h post-dose, with some biomarkers of neurodegenerative diseases including L-glutamine, lysophosphatidylcholine (17:0), taurochenodeoxycholic acid, uric acid, stearic acid, palmitic acid, and lactic acid showing good correlation with the systemic exposure of the bioactive triterpenoids (asiatic acid). Thus, the combining of piperine to Centell-S exhibits the improvement of bioactive triterpenoids which are related to the biomarkers of neurodegenerative diseases. These promising results might be useful for the development of this standardised extract to become a more effective phytomedicine for neurodegenerative diseases.
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Curcumina , Triterpenos , Cães , Animais , Curcumina/farmacologia , Triterpenos/farmacologia , Metaboloma , Extratos Vegetais/farmacologia , MamíferosRESUMO
Inhibition of proteases shows therapeutic potential. Our previous studies demonstrated the cardioprotection by the Secretory Leukocyte Protease Inhibitor (SLPI) against myocardial ischaemia/reperfusion (I/R) injury. However, it is unclear whether the cardioprotective effect of SLPI seen in our previous works is due to the inhibition of protease enzymes. Several studies demonstrate that the anti-protease independent activity of SLPI could provide therapeutic benefits. Here, we show for the first time that recombinant protein of anti-protease deficient mutant SLPI (L72K, M73G, L74G) (mt-SLPI) could significantly reduce cell death and intracellular reactive oxygen species (ROS) production against an in vitro simulated I/R injury. Furthermore, post-ischaemic treatment of mt-SLPI is found to significantly reduce infarct size and cardiac biomarkers lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) activity, improve cardiac functions, attenuate I/R induced-p38 MAPK phosphorylation, and reduce apoptotic regulatory protein levels, including Bax, cleaved-Caspase-3 and total Capase-8, in rats subjected to an in vivo I/R injury. Additionally, the beneficial effect of mt-SLPI was not significantly different from the wildtype (wt-SLPI). In summary, SLPI could provide cardioprotection without anti-protease activity, which could be more clinically beneficial in terms of providing cardioprotection without interfering with basal serine protease activity.
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The present study aims to determine the effects of long-term exposure to electromagnetic radiation from mobile phones (MPs) on heart rate variability (HRV), cardiac function, blood profiles, body surface temperature, and semen quality in healthy dogs. Eight male dogs were exposed to MPs (1962-1966 MHz; specific absorption rate 0.96 W/kg) for 2 h/day, 5 days/week, for 10 weeks. Holter monitoring for HRV analysis was performed at baseline (BL) and every 2 weeks, until the end of the study. Electrocardiograms (ECG), blood pressure (BP), echocardiography, cardiac troponin I (cTnI), hematology and biochemistry profiles, body surface temperature, and semen quality were evaluated at BL, week 5, and week 10 during exposure. The results showed that most of the HRV parameters did not significantly differ among timepoints, except for the mean of an interval between continuous normal R waves in week 6 that was higher than that at BL (p = 0.022). The RR and QT intervals from ECG in week 5 were prolonged, compared to the BL values (p = 0.001 and p = 0.003, respectively), but those parameters were within the normal limits. The echocardiography, BP, cTnI concentrations, body surface temperature, and semen quality results were not different from BL values. In conclusion, this study found no evidence suggesting an adverse effect of cell phone exposure on HRV, cardiac function, blood profiles, body surface temperature, or semen quality in healthy dogs, when exposed for 10 weeks.
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Multiple-drug prescriptions can cause drug-drug interactions (DDIs), which increase risks associated with healthcare in veterinary medicine. Moreover, many human medicines are used in canine patients under the responsibility of veterinarians and may cause severe problems due to off-label use. Currently, many electronic databases are being used as tools for potential DDI prediction, for example, Micromedex and Drugs.com, which may benefit the prediction of potential DDIs for drugs used in canine. The purpose of this study was to examine different abilities for the identification of potential DDIs in companion animal medicine, especially in canine patients, by Micromedex and Drugs.com. Micromedex showed 429 pairs of potential DDIs, while Drugs.com showed 842 pairs of potential DDIs. The analysis comparing results between the two databases showed 139 pairs (12.28%) with the same severity and 993 pairs (87.72%) with different severities. The major mechanisms of contraindicated and major potential DDIs were cytochrome P450 induction-inhibition and QT interval prolongation. Veterinarians should interpret potential DDIs from several databases with caution and keep in mind that the results might not be reliable due to differences in sensitivity to drugs, drug-metabolizing enzymes, and elimination pathway between animals and humans.
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Background and Objective: Sacubitril/valsartan (SV) is an angiotensin receptor-neprilysin inhibitor that works by inhibiting the neprilysin enzyme as well as blocking angiotensin receptors. The benefits of using SV in congestive heart failure patients has been demonstrated in several clinical trials; however, limited data are available for dogs with heart failure. The aim of this study was to investigate the short-term effects of SV in comparison with ramipril in the standard therapy of symptomatic dogs suffering from myxomatous mitral valve disease (MMVD). Methods: In this prospective, randomized, single-blind study, 21 dogs with MMVD stage C were randomly assigned to received SV (20 mg/kg orally twice a day) or ramipril (0.125 mg/kg, orally once a day) in addition to pimobendan and furosemide. Echocardiography, electrocardiography, blood pressure, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and urinary aldosterone per creatinine ratio were obtained at baseline (D0) and at follow-up (4 weeks). Results: When comparing the percent change from baseline between groups, the left atrium to aortic root ratio (LA/Ao) and left ventricular internal diameter diastole normalized to body weight (LVIDDN) were significantly reduced in the SV group (P < 0.001 and P < 0.01, respectively). The end-diastolic volume index (EDVI), end-systolic volume index (ESVI), and stroke volume were lower in the SV group (P < 0.001, P < 0.05, and P < 0.01, respectively). No changes were observed between groups for NTproBNP, blood pressure, ECG parameters, and urinary aldosterone per creatinine ratio. Conclusion: The current study suggested that the short-term effects of SV can reverse myocardial remodeling, as inferred from several echocardiographic indices (i.e., the reduction in LA/Ao, LVIDDN, EDVI and ESVI) in dogs with MMVD stage C. These findings would support the use of SV in clinically symptomatic heart failure in dogs.
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Myocardial ischemia/reperfusion (I/R) injury is a major cause of mortality and morbidity worldwide. Among factors contributing to I/R injury, proteolytic enzymes could also cause cellular injury, expand the injured area and induce inflammation, which then lead to cardiac dysfunction. Therefore, protease inhibition seems to provide therapeutic benefits. Previous studies showed the cardioprotective effect of secretory leukocyte protease inhibitor (SLPI) against myocardial I/R injury. However, the effect of a post-ischemic treatment with SLPI in an in vivo I/R model has never been investigated. In the present study, recombinant human (rh) SLPI (rhSLPI) was systemically injected during coronary artery occlusion or at the onset of reperfusion. The results show that post-ischemic treatment with rhSLPI could significantly reduce infarct size, Lactate Dehydrogenase (LDH) and Creatine kinase-MB (CK-MB) activity, inflammatory cytokines and protein carbonyl levels, as well as improving cardiac function. The cardioprotective effect of rhSLPI is associated with the attenuation of p38 MAPK phosphorylation, Bax, caspase-3 and -8 protein levels and enhancement of pro-survival kinase Akt and ERK1/2 phosphorylation. In summary, this is the first report showing the cardioprotective effects against myocardial I/R injury of post-ischemic treatments with rhSLPI in vivo. Thus, these results suggest that SLPI could be used as a novel therapeutic strategy to reduce myocardial I/R injury.