Sodium houttuyfonate: A review of its antimicrobial, anti-inflammatory and cardiovascular protective effects.

There is an almost unlimited interest in searching and developing new drugs, especially when we are in an era that are witnessing more and more emerging pathogens. Natural products from traditional medicines represent a large library for searching lead compounds with novel bioactivities. Sodium houttuyfonate is such one bioactive compound derived from Houttuynia cordata Thunb which has been employed in traditional medicine for treating infectious and inflammatory diseases. Sodium houttuyfonate has demonstrated multiple kinds of pharmacological effects, including antifungal, antibacterial, anti-inflammatory, and cardiovascular protective activities, which are discussed here to provide insights into our understanding of the pharmacological effects of SH and the underlying mechanisms.

Dioscin and diosgenin: Insights into their potential protective effects in cardiac diseases.

BACKGROUND AND ETHNOPHARMACOLOGICAL RELEVANCE: Dioscin and diosgenin derived from plants of the genus Dioscoreaceae such as D. nipponica and D. panthaica Prain et Burk. Were utilized as the main active ingredients of traditional herbal medicinal products for coronary heart disease in the former Soviet Union and China since 1960s. A growing number of research showed that dioscin and diosgenin have a wide range of pharmacological activities in heart diseases. AIM OF THE STUDY: To summarize the evidence of the effectiveness of dioscin and diosgenin in cardiac diseases, and to provide a basis and reference for future research into their clinical applications and drug development in the field of cardiac disease. METHODS: Literatures in this review were searched in PubMed, ScienceDirect, Google Scholar, China National Knowledge Infrastructure (CNKI) and Web of Science. All eligible studies are analyzed and summarized in this review. RESULTS: The pharmacological activities and therapeutic potentials of dioscin and diosgenin in cardiac diseases are similar, can effectively improve hypertrophic cardiomyopathy, arrhythmia, myocardial I/R injury and cardiotoxicity caused by doxorubicin. But the bioavailability of dioscin and diosgenin may be too low as a result of poor absorption and slow metabolism, which hinders their development and utilization. CONCLUSION: Dioscin and diosgenin need further in-depth experimental research, clinical transformation and structural modification or research of new preparations before they can be expected to be developed into new therapeutic drugs in the field of cardiac disease.

Ginsenosides for cardiovascular diseases; update on pre-clinical and clinical evidence, pharmacological effects and the mechanisms of action.

Cardiovascular disease (CVD) remains the major cause of death worldwide, accounting for almost 31% of the global mortality annually. Several preclinical studies have indicated that ginseng and the major bioactive ingredient (ginsenosides) can modulate several CVDs through diverse mechanisms. However, there is paucity in the translation of such experiments into clinical arena for cardiovascular ailments due to lack of conclusive specific pathways through which these activities are initiated and lack of larger, long-term well-structured clinical trials. Therefore, this review elaborates on current pharmacological effects of ginseng and ginsenosides in the cardiovascular system and provides some insights into the safety, toxicity, and synergistic effects in human trials. The review concludes that before ginseng, ginsenosides and their preparations could be utilized in the clinical treatment of CVDs, there should be more preclinical studies in larger animals (like the guinea pig, rabbit, dog, and monkey) to find the specific dosages, address the toxicity, safety and synergistic effects with other conventional drugs. This could lead to the initiation of large-scale, long-term well-structured randomized, and placebo-controlled clinical trials to test whether treatment is effective for a longer period and test the efficacy against other conventional therapies.

Ginsenoside Rb1 ameliorates cardiotoxicity triggered by aconitine via inhibiting calcium overload and pyroptosis.

BACKGROUND: Aconitine-induced cardiotoxicity limits the clinical treatment of cardiotonic, cancers and immune-related diseases. Ginsenoside Rb1 (Rb1) is an active ingredient of traditional Chinese medicine with cardioprotective effect. PURPOSE: This study aims to study the mechanism of aconitine cardiotoxicity and the detoxification mechanism of Rb1. STUDY DESIGN: METHODS: The regulatory effect of Rb1 on aconitine was evaluated in vitro and in vivo by myocardial enzyme indicators, pathological analysis, CardioECR detection, calcium transient analysis, western blotting and immunohistochemistry. RESULTS: Rb1 (10, 20, 40 mg/kg) alleviated apoptotic myocardial damage caused by aconitine in rats. Furthermore, Rb1 (25, 50, 100 µM) restored the contractile function and field potential of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) by regulating calcium channels and reduced myocardial cell damage by inhibiting the calcium transients of adult rat ventricular myocytes (ARVMs). Rb1 significantly reduced calcium levels in hiPSC-CMs, directly indicating that aconitine-induced calcium overload was alleviated by Rb1. Further, aconitine caused calcium overload by changing the expression of calcium pathway proteins, while Rb1 effectively restored calcium homeostasis. In addition, Rb1 also had a cardioprotective role by inhibiting cell pyroptosis. These results suggested that the maintenance of calcium homeostasis helped to suppress the inflammatory response related to pyroptosis of the heart. CONCLUSION: Aconitine-induced cardiotoxicity can be alleviated by Rb1 via restoring calcium homeostasis and inhibiting apoptosis and pyroptosis.

Oxidative stability of Echium plantagineum oil / Estabilidade Oxidativa do óleo de echium plantagineum

The evidences about the cardioprotective effects of omega-3 fatty acids (n-3 FA), especially EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid), have increased the consumption of these fatty acids. Echium plantagineum is a plant from Boragenacea family, known as potential source of non-marine omega-3 fatty acids (n-3 FA). Echium seeds presents 12-16% of stearidonic acid (SDA), that can be converted to EPA and DHA at a more elevated rate than the conversion obtained from α-linolenic acid (ALA), present in several other vegetable oils. However, echium oil is highly susceptible to oxidation because it has a high proportion of polyunsaturated fatty acids. Thus, the objective of this study was to combine three natural strategies to inhibit the oxidative damage in echium oil. In the first step, a mixture containing hydrophilic (HM: synaptic + ascorbic + citric acids) or lipophilic (LM: α-tocopherol + ascorbyl palmitate + citric acid) antioxidants was applied in the flaxseed oil, kept at 40oC/ 15 days. The oxidative markers were compared with the oil added of TBHQ (120 ppm) and EDTA (75 ppm), both artificial compounds. The results showed that LM and HM had an oxidative protection similar to the artificial antioxidants and that, HM promoted a better protection than LM. Based on this result, HM was selected as a strategy to be applied in the next step. In the second part of this study, Echium oil was obtained by two process: continuous screew pressing (PRESS) and extraction using hexane (SOLV). Both samples were added of HM combined with a high oleic sunflower oil and kept at different temperatures during storage. Two conditions were analyzed: 6 months into sealed flasks and 30 days into opened flasks. Oxidation reaction was followed by measuring the concentration of hydroperoxide, malondialdehyde, tocopherol and volatile compounds. In general, results showed that temperature reduction was enough to keep the oils stability during storage. Thus, the focus of the strategy's combination was directed toward samples after exposition to oxygen. In this context, better results were obtained by blending 20% of high oleic sunflower oil and the hydrophilic antioxidant mixture (500 ppm of synaptic acid, 250 ppm of ascorbic acid and 150 ppm of citric acid). In this condition it was observed 37-41% reduction in the hydroperoxide values and 40-75% in the malondialdehyde concentration in the samples prepared according to the optimized condition, when compared with the standard conditions by which the oil is currently extracted and processed

As evidências do efeito cardioprotetor dos ácidos graxos ômega 3 (AG n-3), principalmente do ácido eicosapentenoico (EPA) e docosahexaenoico (DHA), tem aumentado o consumo desses ácidos graxos. Echium plantagineum é uma planta da família Boragenacea, conhecida como uma fonte potencial AG n-3 de origem não marinha. As sementes de Echium apresentam 12-16% de ácido estearidônico (SDA), que pode ser convertido em EPA e DHA a uma maior taxa que a obtida através do consumo do ácido alfa linolênico (ALA), presente em diversos óleos vegetais. Porém, o óleo de echium é extremamente suscetível à oxidação, por ter um alto teor de ácidos graxos poli-insaturados. Portanto, o objetivo desse estudo foi combinar três estratégias naturais para inibir a oxidação no óleo de echium. Na primeira parte do estudo, misturas contendo antioxidantes hidrofílicos (HM: ácido sinápico + ácido ascórbico + ácido cítrico) ou lipofílicos (LM: alfa-tocoferol + palmitado de ascobila + ácido cítrico) foram aplicados no óleo de linhaça, e mantidos a 40oC por 15 dias. Os marcadores de oxidação foram comparados com óleo de linhaça no qual foram adicionados compostos artificiais: TBHQ (120 ppm) e EDTA (75 ppm). Os resultados mostraram que LM e HM apresentaram uma proteção antioxidante similar ao efeito apresentado pelos compostos artificiais, e que a mistura HM promoveu uma melhor proteção antioxidante que a mistura LM. A partir desse resultado, a mistura HM foi selecionada como estratégia a ser aplicada na etapa seguinte. Assim, na segunda parte do estudo, o óleo de echium foi obtido por dois processos de extração: prensagem mecânica continua (PRESS) e extração usando hexano (SOLV). A mistura HM e o óleo de girassol alto oleico foram selecionados como estratégias antioxidantes, além da redução de temperatura de estocagem. Duas condições foram analisadas: 6 meses em frascos fechados e 30 dias em frascos abertos. A oxidação foi quantificada através da determinação das concentrações de hidroperóxido, malonaldeído, tocoferol e compostos voláteis. No geral, os resultados mostraram que a redução de temperatura foi suficiente para manter a estabilidade do óleo durante o estoque. Portanto, objetivou-se combinar estratégias para aumentar a estabilidade oxidativa das amostras expostas ao oxigênio. Neste contexto, os melhores resultados foram obtidos quando 20% de óleo de girassol alto oleico foi combinado com a mistura hidrofílica de antioxidantes naturais (500 ppm de ácido sinápico, 250 ppm de ácido ascórbico e 150 ppm de ácido cítrico). Nessa condição, foi observada uma redução de 37-41% nos valores de hidroperóxidos e 40-75% na concentração de malonaldeído, quando comparado com a condição padrão

Cardiac rehabilitation activities during the COVID-19 pandemic in Italy. Position Paper of the AICPR (Italian Association of Clinical Cardiology, Prevention and Rehabilitation).

The COVID-19 outbreak is having a significant impact on both cardiac rehabilitation (CR) inpatient and outpatient healthcare organization. The variety of clinical and care scenarios we are observing in Italy depends on the region, the organization of local services and the hospital involved. Some hospital wards have been closed to make room to dedicated beds or to quarantine the exposed health personnel. In other cases, CR units have been converted or transformed into COVID-19 units.  The present document aims at defining the state of the art of CR during COVID-19 pandemic, through the description of the clinical and management scenarios frequently observed during this period and the exploration of the future frontiers in the management of cardiac rehabilitation programs after the COVID-19 outbreak.

Safety, Pharmacokinetics, and Pharmacodynamics of TD-0714, a Novel Potent Neprilysin Inhibitor in Healthy Adult and Elderly Subjects.

TD-0714 is an orally active, potent, and selective inhibitor of human neprilysin (NEP) in development for the treatment of chronic heart failure. Oral administration of TD-0714 in rats resulted in dose-dependent and sustained increases in plasma cyclic guanosine monophosphate (cGMP) over 24 hours consistent with NEP target engagement. Randomized, double-blind, placebo controlled, single ascending dose (50-600 mg TD-0714) and multiple ascending dose (10-200 mg TD-0714 q.d. for 14 days) studies were conducted in healthy volunteers. TD-0714 was generally well-tolerated and no serious adverse events or clinically significant effects on vital signs or electrocardiogram parameters were observed. TD-0714 exhibited dose-proportional pharmacokinetics (PKs) with high oral bioavailability, minimal accumulation after once daily dosing, and negligible renal elimination. Pharmacodynamic (PD) responses were observed at all dose levels studied, as reflected by statistically significant increases in plasma cGMP concentrations. The increases in cGMP were significantly above the baseline (~ 50-100%) on day 14 for the entire 24-hour interval indicating that sustained cGMP elevations are achieved at steady-state. Maximal steady-state cGMP response was observed in plasma and urine at doses ≥ 50 mg. The TD-0714 PK-PD relationship and safety profile were similar in elderly vs. younger adult subjects. The TD-0714 PK and PD profiles support further clinical development of TD-0714 and suggest the potential for once-daily administration and predictable exposure in patients with cardiorenal diseases regardless of their renal function.

Clinical efficacy and safety of Shenqi Fuzheng injection for the treatment of chronic heart failure: Protocol for a meta-analysis and systematic review.

BACKGROUND: Chronic heart failure (CHF) is one of the most serious cardiovascular diseases. Shenqi Fuzheng injection (SQFZI), as a Chinese herbal injection, is usually used for the treatment of CHF. However, the clinical evidence of SQFZI for the treatment of CHF is unclear. METHODS: Two researchers will dependently search literatures of SQFZI for CHF from Chinese National Knowledge Infrastructure database, VIP database, Chinese Biological and Medicine database, Wangfang database, MEDLINE, EMBASE, Cochrane Library and Web of Science. These inclusive data of included studies will be conducted by RevMan 5.3 software. RESULTS: This meta-analysis and systematic review will provide a series of outcome measures to verify clinical efficacy and safety of SQFZI for treating CHF, including New York Heart Association (NYHA) function classification, left ventricular ejection fraction, left ventricular end-diastolic dimension, cardiac output, stroke volume, brain natriuretic peptide, N-terminal pro-brain natriuretic peptide, and adverse events. CONCLUSIONS: This meta-analysis and systematic review will provide up-to-date clinical evidence to assess SQFZI treatment efficacy for CHF patients.

Management of valvulopathies with acute severe heart failure and cardiogenic shock.

Cardiogenic shock is a critical clinical situation, requiring rapid diagnosis, aetiological assessment and immediate initiation of therapy. In industrialized countries, aortic stenosis is the most frequent left-sided valvulopathy, followed by mitral regurgitation, aortic regurgitation and mitral stenosis. Severe valvulopathies leading to cardiogenic shock are not rare conditions, but few data are available on their optimal management. Therapeutic options for such critical conditions include inotropic agents, mechanical support (when feasible) and rapid valvular intervention. Although surgery remains the gold-standard treatment for severe valvular disease, mortality is frequently prohibitive in the setting of cardiogenic shock, necessitating consideration of alternative therapies. Percutaneous management of valvulopathies has emerged as an alternative treatment for patients deemed at high surgical risk in a stable condition. Although few published data are available, catheter-based interventions may be feasible in the cardiogenic shock setting. This review offers an overview of different valvulopathies in the cardiogenic shock setting, and summarizes the different therapeutic options currently available in such critical situations.

The cardioprotective properties and the involved mechanisms of NaoXinTong Capsule.

NaoXinTong Capsule (NXT), a prescribed traditional Chinese medicine, is made up of 16 natural herbal materials with more than 200 identified bioactive compounds. Multiple protective effects of NXT on cardiovascular diseases including atherosclerosis, coronary artery disease, acute coronary syndrome, coronary microembolization, myocardial infarction, ischemic stroke and ischemia-reperfusion injury, have been reported by both clinical and basic studies. Biologically, these cardioprotective effects can be correlated to the actions of NXT on inflammation, apoptosis, oxidative stress, neovascularization, insulin sensitivity and lipid/glucose metabolism. NXT alone or in combination with the conventional interventions has been demonstrated potent therapeutic effects on cardiovascular diseases without causing significant adverse events, like the major bleeding. Compared with the conventional drugs, patients have a good tolerance and little resistance to NXT treatment. With the data and evidence reported from lab benches to clinical beds, we will update the cardioprotective properties of NXT and the involved mechanisms in this review. We hope the information provided in this review can help readers to better understand the insights for the long practice of this traditional Chinese medicine, and offer fresh perspectives.

Omega-3 Fatty Acid and Cardiovascular Outcomes: Insights From Recent Clinical Trials.

PURPOSE OF REVIEW: Omega-3 fatty acids (ω-3 FA) are among the most well-recognized health supplements but their cardiovascular benefits have long been controversial owing to inconsistent results from previous cardiovascular outcomes trials (CVOT). In this article, we provide a short review of existing literature followed by recent randomized clinical trial data, with a discussion of the potential clinical implications of these new findings. RECENT FINDINGS: Data from the randomized, controlled trial REDUCE-IT, when viewed within the context of other recently published trials ASCEND and VITAL, add to a growing body of evidence on the use of ω-3 FA therapies in the treatment of atherosclerotic cardiovascular disease (ASCVD). Given the different formulations, dosages, and patient populations studied, CVOTs of ω-3 FA have provided valuable insight into the use of these agents in cardioprotection. Current data suggest that higher dosages of pure eicosapentaenoic acid ω-3 FA formulations provide additional benefit in reduction of ASCVD events.

Fish, Fish Oils and Cardioprotection: Promise or Fish Tale?

Fish and commercially available fish oil preparations are rich sources of long-chain omega-3 polyunsaturated fatty acids. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the most important fatty acids in fish oil. Following dietary intake, these fatty acids get incorporated into the cell membrane phospholipids throughout the body, especially in the heart and brain. They play an important role in early brain development during infancy, and have also been shown to be of benefit in dementia, depression, and other neuropsychiatric disorders. Early epidemiologic studies show an inverse relationship between fish consumption and the risk of coronary heart disease. This led to the identification of the cardioprotective role of these marine-derived fatty acids. Many experimental studies and some clinical trials have documented the benefits of fish oil supplementation in decreasing the incidence and progression of atherosclerosis, myocardial infarction, heart failure, arrhythmias, and stroke. Possible mechanisms include reduction in triglycerides, alteration in membrane fluidity, modulation of cardiac ion channels, and anti-inflammatory, anti-thrombotic, and anti-arrhythmic effects. Fish oil supplements are generally safe, and the risk of toxicity with methylmercury, an environmental toxin found in fish, is minimal. Current guidelines recommend the consumption of either one to two servings of oily fish per week or daily fish oil supplements (around 1 g of omega-3 polyunsaturated fatty acids per day) in adults. However, recent large-scale studies have failed to demonstrate any benefit of fish oil supplements on cardiovascular outcomes and mortality. Here, we review the different trials that evaluated the role of fish oil in cardiovascular diseases.

Clinical Use of Digitalis: A State of the Art Review.

The history of digitalis is rich and interesting, with the first use usually attributed to William Withering and his study on the foxglove published in 1785. However, some knowledge of plants with digitalis-like effects used for congestive heart failure (CHF) was in evidence as early as Roman times. The active components of the foxglove (Digitalis purpurea and Digitalis lanata) are classified as cardiac glycosides or cardiotonic steroids and include the well-known digitalis leaf, digitoxin, and digoxin; ouabain is a rapid-acting glycoside usually obtained from Strophanthus gratus. These drugs are potent inhibitors of cellular membrane sodium-potassium adenosine triphosphatase (Na+/K+-ATPase). For most of the twentieth century, digitalis and its derivatives, especially digoxin, were the available standard of care for CHF. However, as the century closed, many doubts, especially regarding safety, were raised about their use as other treatments for CHF, such as decreasing the preload of the left ventricle, were developed. Careful attention is needed to maintain the serum digoxin level at ≤ 1.0 ng/ml because of the very narrow therapeutic window of the medication. Evidence for benefit exists for CHF with reduced ejection fraction (EF), also referred to as heart failure with reduced EF (HFrEF), especially when considering the combination of mortality, morbidity, and decreased hospitalizations. However, the major support for using digoxin is in atrial fibrillation (AF) with a rapid ventricular response when a rate control approach is planned. The strongest support of all for digoxin is for its use in rate control in AF in the presence of a marginal blood pressure, since all other rate control medications contribute to additional hypotension. In summary, these days, digoxin appears to be of most use in HFrEF and in AF with rapid ventricular response for rate control, especially when associated with hypotension. The valuable history of the foxglove continues; it has been modified but not relegated to the garden or the medical history book, as some would advocate.

Curcumin ameliorates doxorubicin-induced cardiotoxicity by abrogation of inflammation, apoptosis, oxidative DNA damage, and protein oxidation in rats.

Doxorubicin (DXR) is a highly effective drug for chemotherapy. However, cardiotoxicity reduces its clinical utility in humans. The present study aimed to assess the ameliorative effect of curcumin against DXR-induced cardiotoxicity in rats. Rats were subjected to oral treatment of curcumin (100 and 200 mg/kg body weight) for 7 days. Cardiotoxicity was induced by single intraperitoneal injection of DXR (40 mg/kg body weight) on the 5th day and the rats sacrificed on 8th day. Curcumin ameliorated DXR-induced lipid peroxidation, glutathione depletion, decrease in antioxidant (superoxide dismutase, catalase, and glutathione peroxidase) enzyme activities, and cardiac toxicity markers (CK-MB, LDH, and cTn-I). Curcumin also attenuated activities of Caspase-3, cyclooxygenase-2, inducible nitric oxide synthase, and levels of nuclear factor kappa-B, tumor necrosis factor-α, and interleukin-1ß, and cardiac tissue damages that were induced by DXR. Moreover, curcumin decreased the expression of 8-OHdG and 3,3'-dityrosine. This study demonstrated that curcumin has a multi-cardioprotective effect due to its antioxidant, anti-inflammatory, and antiapoptotic properties.

Digoxin and Hypermagnesuria.

In a recent issue of Nephron, Abu-Amer et al.[1] reported the presence of hypermagnesuria in patients following acute intravenous administration of digoxin and suggested that the Na+/K+-ATPase γ-subunit, which is the pharmacological target of digoxin, can play a role in this process. Hypermagnesuria induced by digoxin may have important clinical consequences, particularly in the presence of inherited and acquired conditions associated with hypermagnesuria and hypomagnesemia. Moreover, the co-administration of digoxin with other drugs that reduce gastrointestinal absorption (i.e., proton pump inhibitors) or increase urinary excretion (i.e., loop diuretics) may increase the likelihood of developing hypomagnesemia. In this article, we reviewed the main causes of hypermagnesuria and discussed potential drug interactions that can enhance the magnesuric effect of digoxin. We suggest that during the administration of digoxin, clinicians should consider the presence of other causes of hypomagnesemia and hypermagnesuria that could enhance the magnesuric effect of digoxin, monitor the urinary and serum levels of magnesium and prescribe an oral supplementation of magnesium.

Benefit-Risk Assessment of Crataegus Extract WS 1442: An Evidence-Based Review.

Preparations from Crataegus (hawthorn) have a long history in the treatment of heart failure. WS 1442 is a dry extract from hawthorn leaves with flowers (4-6.6:1), extraction solvent of ethanol 45% (w/w), adjusted to 17.3-20.1% of oligomeric procyanidins. Nonclinical studies show that WS 1442 has positive inotropic and antiarrhythmic properties and protects the myocardium from ischemic damage, reperfusion injury, and hypertension-related hypertrophy, improves endothelial functions such as NO synthesis, and delays endothelial senescence. Randomized, controlled trials in patients with heart failure have demonstrated that the herbal medicinal product increases functional capacity, alleviates disabling symptoms, and improves health-related quality of life, all of which have become important targets of heart failure therapy according to current disease management guidelines. Clinical trials (including a 2-year mortality study with polypharmacy and > 1300 patients exposed) and post-marketing surveillance studies have shown that WS 1442 has a very favorable safety profile both as monotherapy and as add-on therapy, where no drug interactions have been observed. No specific adverse reactions to WS 1442 are known to date. WS 1442 may thus help to close the therapeutic gap between systolic and diastolic heart failure for which evidence of efficacy for other cardioactive drugs is sparse. Scientific evidence shows that WS 1442 is safe and has a beneficial effect in patients with heart failure corresponding to New York Heart Association classes II or III. The benefit-risk assessment for WS 1442 is therefore positive.

Identification of Novel Non-secosteroidal Vitamin D Receptor Agonists with Potent Cardioprotective Effects and devoid of Hypercalcemia.

Vitamin D regulates many biological processes, but its clinical utility is limited by its hypercalcemic effect. Using a virtual screening platform to search novel chemical probes that activate the vitamin D signaling, we report discovery of novel non-steroidal small-molecule compounds that activate the vitamin D receptor (VDR), but are devoid of hypercalcemia. A lead compound (known as VDR 4-1) demonstrated potent transcriptional activities in a VDR reporter gene assay, and significantly ameliorated cardiac hypertrophy in cell culture studies and in animal models. VDR 4-1 also effectively suppressed secondary hyperparathyroidism in 1α-hydroxylase knockout mice. In contrast to 1α,25-dihydroxyvitamin D3 (1,25-D3 or calcitriol), a naturally occurring VDR agonist, VDR 4-1 therapy even at high doses did not induce hypercalcemia. These findings were accompanied by a lack of upregulation of calcium transport genes in kidney and in the gut providing a mechanism for the lack of hypercalcemia. Furthermore, VDR 4-1 therapy significantly suppressed cardiac hypertrophy and progression to heart failure in both vitamin D deficient and normal mice without inducing significant hypercalcemia. In conclusion, we have identified a unique VDR agonist compound with beneficial effects in mouse models of hyperparathyroidism and heart failure without inducing significant hypercalcemia.

PROTECTIVE ROLE OF CARNITINE SYNERGIZED WITH VITAMIN E AGAINST ISOPROTERENOL INDUCED CARDIAC INFARCTION IN RATS.

BACKGROUND: The current study aimed to evaluate the role of carnitine in combination with vitamin E in protection against myocardial infarction induced by isoproterenol (ISO) in rats. MATERIALS AND METHODS: Rats were grouped into 5 (each 10 rats): Group I. Control fed a standard diet. Group III: Rats were injected with vitamin E (100 IU/kg bw, i.p) daily. Group IV: Rats were given carnitine (20 mg/kg bw, i.p) daily. Group V: Rats were injected with both vitamin E (100 IU/kg bw, i.p) and carnitine (20 mg/kg bw, i.p) daily. On 7th, 8th, and 9th day, rats in groups (II-V) were injection i.p with ISO (55mg/kg b.w for successive three days). The treatment with carnitine and vitamin E were continuous for 21 days. RESULTS: Canirine combined with vitamin E significantly increased coronary flow (CF) (P<0.001) in rats injected with ISO. The recovery of rate pressure product (RPP) and left ventricular developed pressure (LVDP) were significantly improved in treated rats in comparison to untreated. The rats administrated with ISO resulted in a significant elevation of serum enzymes (CK-MB and LDH) compared with control group (p<0.001). However, it returned to about normal. ISO administration resulted in a significant elevation in the levels of malondialdehyde (MDA) and nitric oxide (NO) as compared with control (p<0.001) and a significant reduction in the activities of GSPxase and GSRase (p<0.001) compared with control group. The levels of cardiac inflammatory markers interleukine-6 (IL-6) and tumor necrosis factor (TNF-α) were markedly elevated in rats injected with ISO compared with control group. Vitamin E combined with carnitine reversed these effects. However, pretreatment with vitamin E or carnitine or combined together showed a significant reduction in MDA and NO (p<0.001) and a significant elevation in the activities of GSPxase and GSRase (p<0.001) as compared to ISO injected group. The combined effect was more significant than individual ones. CONCLUSION: Vitamin E combined with carnitine exerts potential protective effect against MI through suppression of inflammatory mediators and enhancement of antioxidant activity.

Promising approach for the preclinical assessment of cardiac risks using left ventricular pressure-volume loop analyses in anesthetized monkeys.

INTRODUCTION: Load-independent cardiac parameters obtained from the ventricular pressure-volume relationship are recognized as gold standard indexes for evaluating cardiac inotropy. In this study, for better analyses of cardiac risks, load-independent pressure-volume loop parameters were assessed in addition to load-dependent inotropic, hemodynamic and electrocardiographic changes in isoflurane-anesthetized monkeys. METHODS: The animals were given milrinone (a PDE 3 inhibitor), metoprolol (a ß-blocker), or dl-sotalol (a ß+IKr blocker) intravenously over 10min at two dose levels including clinically relevant doses (n=5/drug). RESULTS: Milrinone and metoprolol produced positive and negative inotropy, respectively. These effects were detected as changes in the slope of the preload-recruitable stroke work, which is a load-independent inotropic parameter. However, dl-sotalol did not alter the slope of the preload-recruitable stroke work. That means dl-sotalol produced no inotropy, although it decreased load-dependent inotropic parameters, including maximal upstroke velocity of left ventricular pressure, attributable to decreased heart rate and blood pressure. Other typical pharmacological effects of the compounds tested were also detected. Both ß-blockers produced PR prolongation, decreased left ventricular end-systolic pressure, increased left ventricular end-diastolic pressure, and increased maximal descending velocity of left ventricular pressure and time constant for isovolumic relaxation. dl-Sotalol also prolonged heart-rate-corrected QT interval. Milrinone induced reflex tachycardia, PR shortening, and decreased left ventricular end-diastolic pressure. DISCUSSION: The overall assessment by not only load-dependent inotropic parameters but also load-independent parameters obtained from the ventricular pressure-volume loop analysis using monkeys can provide further appropriate information for the assessment of drug-induced cardiac risks.