Current and Future MR Contrast Agents: Seeking a Better Chemical Stability and Relaxivity for Optimal Safety and Efficacy.

This review summarizes 30 years of experience in the development and clinical use of magnetic resonance (MR) contrast agents. Despite their undisputable usefulness for disease diagnosis, gadolinium (Gd)-based contrast agents (GBCAs) have gone through 2 major safety crises. Approximately 10 years ago, the regulatory agencies decided to restrict the use of GBCAs to minimize the risk of nephrogenic systemic fibrosis in patients with severe renal insufficiency.

Future of Diagnostic Computed Tomography: An Update on Physicochemical Properties, Safety, and Development of X-ray Contrast Media.

Iodinated contrast media (CM) are utilized in approximately 40% of the 300 million computed tomography (CT) scans undertaken annually. This review focuses on the physicochemical properties and safety of iodinated CM, and the development of new x-ray CM, and it explores methods to optimize CT scanning parameters. It concludes that good x-ray CM should have high structural stability, hydrophilicity, and CT attenuation; low viscosity, osmolality, and protein binding; no metabolism and tissue accumulation; and a complete elimination.

Randomized study of the effect of gadopiclenol, a new gadolinium-based contrast agent, on the QTc interval in healthy subjects.

Aims: We investigated the effect of gadopiclenol, a new gadolinium-based contrast agent, on the QTc interval at clinical and supraclinical dose, considering the relative hyperosmolarity of this product.

Methods: This was a single centre, randomized, double-blind, placebo- and positive-controlled, 4-way crossover study. Forty-eight healthy male and female subjects were included to receive single intravenous (i.

Gadolinium Retention as a Safety Signal: Experience of a Manufacturer.

Objectives: The purpose of this manuscript is to review the successive regulatory actions and decisions following the initial publication by Kanda and colleagues in 2014 regarding gadolinium retention in the human brain after multiple gadolinium-based contrast agents (GBCAs) administrations.

Materials And Methods: Starting from 2014, the actions and decisions made by all regulatory authorities were collected and summarized region by region. Volumes of GBCA sales in 2018 per region and main countries are also presented as an indicator of patients' exposure to those products.

Assessment of Pharmacokinetic, Pharmacodynamic Profile, and Tolerance of Gadopiclenol, A New High Relaxivity GBCA, in Healthy Subjects and Patients With Brain Lesions (Phase I/IIa Study).

Objectives: The aim of this study was to evaluate the pharmacokinetics, safety profile, and pharmacodynamics of gadopiclenol, a new high relaxivity macrocyclic gadolinium-based contrast agent, in healthy subjects and patients with brain lesions.

Materials And Methods: This was a single ascending dose phase I/IIa study. Phase I was double-blind, randomized, placebo-controlled and included 54 healthy subjects.

Adverse Reactions to Gadoterate Meglumine: Review of Over 25 Years of Clinical Use and More Than 50 Million Doses.

Objective: The aim of this study was to evaluate the safety profile of gadoterate meglumine from clinical trials, postmarketing observational studies, and pharmacovigilance reports of adverse drug reactions (ADRs) encompassing 25 years of clinical use and over 50 million administered doses.

Materials And Methods: Assessment of the safety of gadoterate meglumine through processing and review of all safety data was collected after magnetic resonance imaging procedures. All ADRs originated from 3 major sources: (1) a clinical study database including 50 phase I to IV studies involving 2822 patients, (2) a safety database including 8 postmarketing safety studies (PMSs) involving 151,050 patients, and (3) a pharmacovigilance database compiling safety experience following over 50 million doses administered between March 1989 and September 2015.

Effects of gadolinium-based contrast agent concentrations (0.5 M or 1.0 M) on the diagnostic performance of magnetic resonance imaging examinations: systematic review of the literature.

Background To date there is no agreement as to what is the optimal concentration for gadolinium-based contrast agents (GBCAs). Purpose To assess whether diagnostic performance differences exist between 0.5 M and 1.

Effects of angiotensin converting enzyme inhibition on crossbridge properties of diaphragm in cardiomyopathic hamsters of the dilated bio 53-58 strain.

Crossbridge properties of cardiomyopathic Syrian hamster (CSH) diaphragm from the dilated Bio 53-58 strain were analyzed after 5-mo of treatment with the angiotensin converting enzyme (ACE) inhibitor perindopril (1 mg/kg/d by oral gavage). Three groups were studied: control F1B hamsters (C; n = 14); CSH given placebo (PL; n = 11 ); and perindopril-treated CSH (PE; n = 11). Peak isometric tension was lower in PL than in C, in both twitch (21.

Peripheral artery structure and endothelial function in heart failure: effect of ACE inhibition.

Chronic heart failure (CHF) induces peripheral vasoconstriction and impairs endothelium-dependent relaxation of large arteries. We investigated in a rat model of CHF (coronary artery ligation) 1) whether endothelial dysfunction also exists in resistance arteries, 2) whether this is associated with vascular morphological changes, and 3) the effect of angiotensin-converting enzyme (ACE) inhibition on these parameters. After 1 mo or 1 yr, CHF reduced the vasodilatory response to acetylcholine of isolated, perfused femoral and mesenteric artery segments.

Vascular and myocardial protective effects of converting enzyme inhibition in experimental heart failure.

Systemic vasoconstriction due to stimulation of the sympathetic and renin-angiotensin-aldosterone systems is a hallmark of heart failure and this is accompanied by impaired endothelium-dependent relaxations at the level of large arteries. This study investigated, in a rat model of heart failure, whether such an endothelial dysfunction also exists at the level of the resistance artery, and whether this is associated with morphologic changes, as well as the effects of chronic treatment with the angiotensin-converting enzyme inhibitor perindopril (2 mg/kg/day). After 12 months, arterial pressure, left ventricular (LV) end diastolic pressure (LVEDP), and LV dP/dt were measured in anesthetized rats.

Sarcoplasmic reticulum Ca2+ pumps in heart and diaphragm of cardiomyopathic hamster: effects of perindopril.

The polymyopathy of the Syrian hamster is associated with alterations of cellular calcium regulation and contractile performance of cardiac and skeletal muscles and, in particular, the diaphragm. Angiotensin-converting enzyme (ACE) inhibitors have been shown to preserve contractile performance. Therefore we analyzed the expression of the genes coding for the sarco(endo)plasmic reticulum Ca(2+)-adenosinetriphosphatase (SERCA) in heart and diaphragm of the cardiomyopathic Syrian hamster (CSH) from the dilated strain Bio 53-58, and we tested the influence of ACE inhibition on accumulation of the different SERCA mRNAs.

Prevention of endothelial dysfunction in small and large arteries in a model of chronic heart failure. Effect of angiotensin converting enzyme inhibition.

Chronic heart failure (CHF) impairs endothelium-dependent vasodilatation of large conductance arteries. We investigated whether a similar reduction also occurs in small arteries, and whether such a reduction can be prevented by the angiotensin converting enzyme inhibitor perindopril (P) in a rat model of CHF (left coronary artery ligation). After 1 month treatment with placebo or P (2 mg/kg/day), rats were anesthetized and arterial pressure, left ventricular end-diastolic pressure, and central venous pressure were measured with a micromanometer.

Relations between myocardial contractility, myosin phenotype, and plasma angiotensin-converting enzyme activity in the cardiomyopathic hamster.

Angiotensin-converting enzyme (ACE) inhibitors have been shown to preserve myocardial contractility in the cardiomyopathic Syrian hamster (CSH). To determine if this was related to changes in myosin heavy-chain (MHC) phenotype, myosin isoform patterns and mechanical properties were studied in the same left ventricular papillary muscle from CSH of the Bio 53.58-dilated strain.

Effects of early and late therapy with perindopril on survival and myocardial inotropic state in experimental dilated cardiomyopathy.

We wished to test (a) whether single-drug therapy with a low dose of the angiotensin-converting enzyme (ACE) inhibitor perindopril has the capacity to improve early survival of the cardiomyopathic Syrian hamster (CSH); (b) whether early treatment with perindopril modifies CSH survival to a greater extent than perindopril treatment initiated later in the course of the disease; and (c) the effects of early and late perindopril therapy on the intrinsic contractility of left ventricular (LV) papillary muscle. We studied CSH from the Bio 53.58 dilated strain (n = 76), in which myocardial necrosis is known to develop from age 30 days, whereas congestive heart failure (CHF) is observed only after age 6 months.

Perindopril plus nifedipine versus perindopril plus hydrochlorothiazide in mild to severe hypertension: a double-blind multicentre study. The Multicentre Study Group on Treatment Association with Perindopril.

Thiazide diuretics are considered as the choice drug to combine with ACE inhibitors for the treatment of hypertension. However, there is much evidence showing that the combination of ACE inhibitors with a calcium channel blocker is effective and safe. We compared the safety and efficacy of perindopril 8 mg once daily plus nifedipine SR 10 mg twice daily with perindopril 8 mg once daily plus hydrochlorothiazide (HCTZ) 12.

Intrinsic alterations of diaphragm muscle in experimental cardiomyopathy.

Diaphragmatic function was investigated in the cardiomyopathic Syrian hamster (CSH) from the dilated Bio 53:58 strain, after long-term therapy with the angiotensin-converting enzyme inhibitor perindopril. Twenty-two 1-month old CSHs were treated during a 5-month period by either oral gavage with perindopril (1 mg/kg/day) (n = 11) or placebo (n = 11). Control hamsters from the F1B strain received placebo (n = 7).

Efficacy and acceptability of perindopril in mild to moderate chronic congestive heart failure.

The aim of this 3-month double-blind, placebo-controlled, multicenter trial was to evaluate the clinical efficacy and safety of perindopril, a new long-acting angiotensin-converting enzyme inhibitor in the second-line treatment of mild to moderate chronic congestive heart failure. After a run-in period of at least 14 days, 125 patients with grade II or III New York Heart Association chronic congestive heart failure on baseline diuretic therapy were randomized to perindopril, 2 mg (n = 61), or placebo (n = 64), once daily. Assessment was at 2-week intervals for the first month and then monthly for the 2 following months.

Acceptability of perindopril in mild-to-moderate chronic congestive heart failure. Results of a long-term open study in 320 patients.

The long-term acceptability of perindopril in mild-to-moderate chronic heart failure (CHF) was evaluated in a multicenter open study. A total of 320 patients with a mean age of 62 +/- 1 years and CHF of New York Heart Association (NYHA) class I (2 patients), II (204 patients), or III (114 patients) were included after a 2-week run-in period during which time vasodilators were stopped and diuretic and/or digoxin therapy stabilized. Perindopril treatment was started at 2 mg, increasing to 4 mg once daily after 2 weeks if supine systolic blood pressure remained > 100 mm Hg.