sildenafil-citrate and pimobendan

Recent advances in our understanding of the pathophysiological and molecular mechanisms involved in pulmonary arterial hypertension have led to the development of novel and rational pharmacological therapies. In addition to conventional therapy (i.e., supplemental oxygen and calcium channel blockers), prostacyclin or endothelin receptor antagonists have been recommended as a first-line therapy for pulmonary arterial hypertension. However, these treatments have potential limitations with regard to their long-term efficacy and improvement in survival. Furthermore, intravenous prostacyclin (epoprostenol) therapy, which is recommended by most experts for patients with New York Heart Association (NYHA) functional class IV, is complicated, uncomfortable for patients, and expensive because of the cumbersome administration system. Considering these circumstances, it is necessary to develop additional novel therapeutic approaches that target the various components of this multifactorial disease.. In this short review, we present an overview of the current treatment options for pulmonary arterial hypertension and describe a case report with primary pulmonary hypertension. A male patient with NYHA functional class IV and showing no response to calcium channel blockers and prostacyclin exhibited significantly improved exercise tolerance and hemodynamics and long-term survival for more than 2.5 years after receiving an oral combination therapy of a phosphodiesterase type 5 inhibitor (sildenafil), phosphodiesterase type 3 inhibitor (pimobendan), and nicorandil.. We also discuss the background and plausible potential mechanisms involved in this case, as well as future perspectives in the treatment of pulmonary arterial hypertension.

Topics: Anticoagulants; Antihypertensive Agents; Calcium Channel Blockers; Diuretics; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Male; Middle Aged; Nicorandil; Nitric Oxide Donors; Oxygen Inhalation Therapy; Phosphodiesterase Inhibitors; Piperazines; Purines; Pyridazines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Cardiovascular adverse effects in drug development are a major source of compound attrition. Characterization of blood pressure (BP), heart rate (HR), stroke volume (SV), and QT-interval prolongation are therefore necessary in early discovery. It is, however, common practice to analyze these effects independently of each other. High-resolution time courses are collected via telemetric techniques, but only low-resolution data are analyzed and reported. This ignores codependencies among responses (HR, BP, SV, and QT-interval) and separation of system (turnover properties) and drug-specific properties (potencies, efficacies). An analysis of drug exposure-time and high-resolution response-time data of HR and mean arterial blood pressure was performed after acute oral dosing of ivabradine, sildenafil, dofetilide, and pimobendan in Han-Wistar rats. All data were modeled jointly, including different compounds and exposure and response time courses, using a nonlinear mixed-effects approach. Estimated fractional turnover rates [h

Topics: Animals; Biomarkers, Pharmacological; Blood Pressure; Cardiotoxicity; Cardiovascular Agents; Heart Rate; Ivabradine; Male; Phenethylamines; Pyridazines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfonamides

Myocardial relaxation and stiffness are influenced by fibrillar collagen content. Cyclic nucleotide signaling regulators have been investigated targeting more effective modulation of collagen deposition during myocardial healing process. To assess the effects of phosphodiesterase type 3 and phosphodiesterase type 5 inhibitors on cardiac function and left ventricular myocardial fibrosis in catecholamine-induced myocardial injury, sildenafil and pimobendan were administered to male Wistar rats 24 hours after isoproterenol injection. Echocardiography and electrocardiogram were performed to assess kinetic and rhythm changes during 45 days of drug administration. At the end of study, type I and type III collagen were measured through immunohistochemistry analysis, and left ventricular pressure was assessed through invasive method. Echocardiography assessment showed increased relative wall thickness at 45 days in pimobendan group with significant diastolic dysfunction and increased collagen I deposition compared with nontreated positive group (3.03 ± 0.31 vs. 2.73 ± 0.28%, P < 0.05). Diastolic pressure correlated positively with type I collagen (r = 0.54, P < 0.05). Type III collagen analysis did not demonstrate difference among the groups. Sildenafil administration attenuated type I collagen deposition (2.15 ± 0.51 vs. positive group, P < 0.05) and suggested to be related to arrhythmic events. Arrhythmic events were not related to the quantity of fibrillar collagen deposition. Although negative modulation of collagen synthesis through cyclic nucleotides signaling have shown promising results, in this study, pimobendan postconditioning resulted in increased collagen type I formation and severe diastolic dysfunction while sildenafil postconditioning reduced collagen type I deposition and attenuated diastolic dysfunction.

Topics: Animals; Arrhythmias, Cardiac; Collagen Type I; Collagen Type III; Disease Models, Animal; Fibrosis; Isoproterenol; Male; Myocardium; Phosphodiesterase 3 Inhibitors; Phosphodiesterase 5 Inhibitors; Pyridazines; Rats, Wistar; Risk Assessment; Sildenafil Citrate; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling

Four dogs, referred for management of heartworm (HW) disease, were found to have HWs entangled in their tricuspid valve apparatus. None of the dogs were actively hemolyzing or showed signs of acute cardiovascular collapse that would have necessitated emergency transvenous HW extraction, and surgery was not performed at time of presentation. The dogs received pimobendan and sildenafil within 24 h of identifying HW in the tricuspid valve apparatus, and the HW moved to the pulmonary arteries within 2 days in most cases (median 2 days, range 1-14 days). All dogs survived to discharge from the original hospital admission and were subsequently treated with adulticide (melarsomine) without complication. All dogs were HW antigen negative 6 months after their last melarsomine injection. Four dogs appeared to respond positively to medical management aimed at decreasing pulmonary arterial pressure and improving the right ventricular function, but movement of HW out of the heart for other reasons cannot be excluded. This therapeutic option is not advised when dogs with HW disease are presented for acute collapse, ongoing hemolysis, and hypotension as surgical extraction is still considered the best option in these cases. It remains unknown if medical management is a safe option for all dogs with intracardiac HW without clinical signs of caval syndrome. Controlled prospective studies are required to determine the efficacy and safety of this treatment regimen in comparison with surgical extraction.

Topics: Animals; Antigens, Helminth; Arsenicals; Dirofilaria; Dirofilariasis; Dog Diseases; Dogs; Female; Filaricides; Male; Pyridazines; Sildenafil Citrate; Triazines; Tricuspid Valve; Vasodilator Agents

In dogs with canine monocytic ehrlichiosis (CME), respiratory signs are uncommon and clinical and radiographic signs of interstitial pneumonia are poorly described. However, in human monocytic ehrlichiosis, respiratory signs are common and signs of interstitial pneumonia are well known. Pulmonary hypertension (PH) is classified based on the underlying disease and its treatment is aimed at reducing the clinical signs and, if possible, addressing the primary disease process. PH is often irreversible, but can be reversible if it is secondary to a treatable underlying etiology. CME is currently not generally recognized as one of the possible diseases leading to interstitial pneumonia and secondary PH in dogs. Only one case of PH associated with CME has been reported worldwide.. A seven-year-old, male intact, mixed breed dog was presented with 2 weeks history of lethargy and dyspnea. The dog previously lived in the Cape Verdean islands. Physical examination showed signs of right-sided congestive heart failure and poor peripheral perfusion. Thoracic radiography showed moderate right-sided cardiomegaly with dilation of the main pulmonary artery and a mild diffuse interstitial lung pattern with peribronchial cuffing. Echocardiography showed severe pulmonary hypertension with an estimated pressure gradient of 136 mm Hg. On arterial blood gas analysis, severe hypoxemia was found and complete blood count revealed moderate regenerative anemia and severe thrombocytopenia. A severe gamma hyperglobulinemia was also documented. Serology for Ehrlichia canis was highly positive. Treatment with oxygen supplementation, a typed packed red blood cell transfusion and medical therapy with doxycycline, pimobendan and sildenafil was initiated and the dog improved clinically. Approximately 2 weeks later, there was complete resolution of all clinical signs and marked improvement of the PH.. This report illustrates that CME might be associated with significant pulmonary disease and should be considered as a possible differential diagnosis in dogs presenting with dyspnea and secondary pulmonary hypertension, especially in dogs that have been in endemic areas. This is important because CME is a treatable disease and its secondary lung and cardiac manifestations may be completely reversible.

Topics: Animals; Antiparasitic Agents; Dog Diseases; Dogs; Doxycycline; Ehrlichiosis; Heart Failure; Hypertension, Pulmonary; Lung Diseases, Interstitial; Male; Pyridazines; Radiography, Thoracic; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

This study was designed to assess the progression of pulmonary arterial hypertension (PAH) and the effectiveness of therapy using recently investigated echocardiographic parameters. PAH is characterized by the progressive elevation of pulmonary artery pressure and right ventricular hypertrophy and dysfunction, which ultimately results in right-sided heart failure and death. Echocardiography results and invasive measurements of right and left ventricular systolic pressures were compared after 3-week administrations of sildenafil (S group), pimobendan (P group), nicorandil (N group), and their combinations (SP and SPN groups) in male rats with monocrotaline (MCT)-induced pulmonary hypertension (M group) and without this condition (C group). The groups that received pimobendan alone and in combinations (SP and SPN groups) showed improvement in their echocardiographic parameters of systolic function. A significant improvement of diastolic function was achieved in the SPN group. Invasive measurements showed the most significant decreases of right ventricular systolic pressure in the N and SPN groups, and the use of pimobendan resulted in a comparatively low risk of adverse hemodynamic effects (left ventricular systolic pressure). Although our results suggested the attenuation of PAH severity in all treatment groups, PAH could not be reversed.

Topics: Animals; Disease Models, Animal; Drug Therapy, Combination; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Monocrotaline; Nicorandil; Phosphodiesterase 3 Inhibitors; Phosphodiesterase 5 Inhibitors; Pyridazines; Rats, Wistar; Recovery of Function; Severity of Illness Index; Sildenafil Citrate; Vasodilator Agents; Ventricular Dysfunction, Right; Ventricular Function, Right