Assessment of Enzyme Inhibition: A Review with Examples from the Development of Monoamine Oxidase and Cholinesterase Inhibitory Drugs.

The actions of many drugs involve enzyme inhibition. This is exemplified by the inhibitors of monoamine oxidases (MAO) and the cholinsterases (ChE) that have been used for several pharmacological purposes. This review describes key principles and approaches for the reliable determination of enzyme activities and inhibition as well as some of the methods that are in current use for such studies with these two enzymes. Their applicability and potential pitfalls arising from their inappropriate use are discussed. Since inhibitor potency is frequently assessed in terms of the quantity necessary to give 50% inhibition (the IC50 value), the relationships between this and the mode of inhibition is also considered, in terms of the misleading information that it may provide. Incorporation of more than one functionality into the same molecule to give a multi-target-directed ligands (MTDLs) requires careful assessment to ensure that the specific target effects are not significantly altered and that the kinetic behavior remains as favourable with the MTDL as it does with the individual components. Such factors will be considered in terms of recently developed MTDLs that combine MAO and ChE inhibitory functions.

Design and rationale of studies of neurohormonal blockade and outcomes in diastolic heart failure using OPTIMIZE-HF registry linked to Medicare data.

BACKGROUND: Heart failure (HF) is the leading cause of hospitalization for Medicare beneficiaries. Nearly half of all HF patients have diastolic HF or HF with preserved ejection fraction (HF-PEF). Because these patients were excluded from major randomized clinical trials of neurohormonal blockade in HF there is little evidence about their role in HF-PEF. METHODS: The aims of the American Recovery & Reinvestment Act-funded National Heart, Lung, and Blood Institute-sponsored "Neurohormonal Blockade and Outcomes in Diastolic Heart Failure" are to study the long-term effects of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and aldosterone antagonists in four separate propensity-matched populations of HF-PEF patients in the OPTIMIZE-HF (Organized Program to Initiate Life-Saving Treatment in Hospitalized Patients with Heart Failure) registry. Of the 48,612 OPTIMIZE-HF hospitalizations occurring during 2003-2004 in 259 U.S. hospitals, 20,839 were due to HF-PEF (EF ≥40%). For mortality and hospitalization we used Medicare national claims data through December 31, 2008. RESULTS: Using a two-step (hospital-level and hospitalization-level) probabilistic linking approach, we assembled a cohort of 11,997 HF-PEF patients from 238 OPTIMIZE-HF hospitals. These patients had a mean age of 75 years, mean EF of 55%, were 62% women, 15% African American, and were comparable with community-based HF-PEF cohorts in key baseline characteristics. CONCLUSIONS: The assembled Medicare-linked OPTIMIZE-HF cohort of Medicare beneficiaries with HF-PEF with long-term outcomes data will provide unique opportunities to study clinical effectivenss of various neurohormonal antagonists with outcomes in HF-PEF using propensity-matched designs that allow outcome-blinded assembly of balanced cohorts, a key feature of randomized clinical trials.

The effect of neurohormonal antagonists in reducing heart failure hospitalizations.

OBJECTIVE: Heart failure (HF) is a major health problem facing the US and studies suggest that the incidence of this condition will rise significantly over the next 10 years. Limiting the incidence or duration of HF hospitalizations would, therefore, have a major impact on healthcare costs. The purpose of this review is to establish and discuss the proposed neurohormonal mechanisms by which HF can occur along with pharmacologic treatments designed to antagonize these pathological states in order to aid in the reduction of HF hospitalization. METHODS: A Medline search (to December 200) was performed to compile published literature and assess numerous large-scale studies regarding the use of neurohormonal antagonists in the treatment of HF. In addition, evaluation of statistics and figures from various organizations dedicated to the improvement of HF care was utilized as aids in understanding the impact of these therapies on hospitalization and healthcare. RESULTS: Heart failure is the most costly cardiovascular disease in the United States, with an estimated annual expenditure in excess of $20 billion. The frequency and duration of HF-associated hospitalizations are the key contributors to this pronounced economic burden. Use of pharmacologic interventions designed to specifically antagonize the renin-angiotensin-aldosterone system and the adrenergic system has had a significant impact on limiting hospitalization with regard to HF. However, the ever burdensome level of re-hospitalization rates for these patients is still problematic and appears to be based on a disconnect between established procedures to effectively treat these patients and the inability to accurately measure performance standards by managed care organization and hospital accreditation bodies. As a consequence, these antagonists, beta-blockers in particular, are still underutilized in the treatment of HF. Studies have shown that many of these hospitalizations could have been avoided had healthcare providers followed effective HF management programs. CONCLUSIONS: Current evidence supports the benefits of neurohormonal blockade in decreasing hospital admissions due to HF. Appropriate use of these agents plus agreed-upon guidelines for treatment can continue to significantly decrease total HF-related hospitalizations and costs. Inclusion of beta-blockers as a performance measure in quality-of-care HF indicators should be considered as an important instrument to increase their utilization and to improve overall HF care.

Neuropharmacological assessment of cocaine self-administration into the medial prefrontal cortex.

Neuronal systems involved in the initiation of reinforcement following the response-contingent delivery of cocaine into the medial prefrontal cortex were investigated. Dose-effect analyses demonstrated that different concentrations of cocaine result in distinguishable patterns of self-administration which could be empirically determined by measuring the relative frequency distribution of the interinfusion intervals. The substitution of equimolar d-amphetamine or lidocaine resulted in rates and patterns of responding similar to vehicle or a low dose of cocaine, suggesting that reinforcement occurs from actions on specific receptors rather than through a local anesthetic neuronal blockade or through properties of a general psychomotor stimulant. The co-infusion of equimolar concentrations of sulpiride attenuated intake and produced patterns of responding similar to those seen after decreasing the cocaine dose consistent with an excitatory role for D2 dopaminergic receptors in these processes. Sulpiride and cocaine may act at separate sites since the decreased intake was not reversed by increasing the concentration of cocaine. D1 dopaminergic, muscarinic-cholinergic and beta-noradrenergic receptor antagonists either did not modulate drug-intake or had minimal effects. Cocaine reinforcement may result in part from an activation of D2 receptors initiating neuronal activity in pathways or circuits mediating reinforcement processes.