Chapter 17 - Drugs used in the management of heart disease and cardiac arrhythmias

New Mn(II), Fe(III), Co(II), and Ni(II) complexes with urate lowing drug febuxostat (FEB) and 2,2′-bipyridine (Bipy) were designed and depicted. Elemental analysis, molar conductance, magnetic measurements, FT-IR, UV–visible, ¹H NMR, mass spectrometry (MS), X-ray diffraction (XRD) and thermal analyses (TG-DTG) studies were used to depict complexes. The FT-IR data revealed that the FEB and Bipy have two donating sites, the oxygen of the carboxylate group and the sulfur atom of the thiazole ring in FEB while, Bipy has two nitrogens of the pyridyl ring. Based on information from the magnetic and electronic spectra, an octahedral geometry was suggested for complexes. The nature of the water molecules and their thermal stability were investigated using TG-DTG analyses. By Coats-Redfern equations determined thermodynamic properties in addition to Horowitz-Metzger equations. The purpose XRD examination of compounds was used to determine the compounds (crystalline or amorphous), average crystallite size (C_s) and Crystallographic data. The bond angles, bond lengths, dipole moment, total energy and equilibrium geometry of metal complexes were investigated by DFT calculations. FEB exhibited an antioxidant action in addition to its metal complexes, with IC₅₀ values of 0.124, 0.316, 0.635, 0.186 and 2.234 mg/mL for FEB, Mn(II), Fe(III), Co(II) and Ni(II) compounds, respectively. The molecular docking data demonstrated that the complexes have competent stabilizing scores of −6.66, −6.50, −7.18 and −7.59 kcal/mol, respectively. The data of Co(II) complex revealed the most promising potential xanthine oxidase inhibitory activity.

Cardiovascular (CV) effects represent a major safety issue during drug development. Typically, this risk is mitigated by preclinical in vivo CV studies, based on which measured CV readouts are analyzed independently. Here, we apply a regression approach to simultaneously integrate CV readouts, i.e., heart rate (HR), mean arterial pressure (MAP) and QT from five dog telemetry studies. These CV studies comprise data on verapamil, captopril, dofetilide, pimobendan, and formoterol, and are combined with the respective dog pharmacokinetic (PK) profiles. A published PK/CV model structure for rats is extended by a semi-mechanistic parameterization of the interaction between HR and QT specific to dogs. This semi-mechanistic modelling approach allows differentiation between compound-independent system-specific parameters (e.g., HR baseline) and compound-specific parameters (e.g., EC₅₀). Compared to previous results in rodents, estimated parameters for dogs indicate stronger dependency of stroke volume on HR, slower HR response, faster QT response and steeper concentration-response relationships. In addition, we illustrate how to practically apply the PK/CV model to derive concentration-response relationships for CV readouts. This approach allows a more detailed quantitative evaluation based on the maximum effect on CV effects (E_max), the EC₅₀, and the steepness of this relation (Hill coefficient) especially for HR-independent effects on QT interval duration (QTc) while taking the systemic feedback into account. This approach also allows to derive plasma concentrations associated with relevant CV effects (“threshold concentration”; C_THRESH). The presented modelling analysis highlights the potential of an integrative evaluation of CV data and provides a framework for obtaining quantitative insights from safety pharmacology evaluations.

Alzheimer's disease (AD) is currently the third most progressive neurodegenerative disorder people facing across globally. The brains of AD patients undergo significant changes because of damage in brain nerve cells in regions like learning, thinking, and cognitive functions (memory) and ensuing experiences memory loss and speech damage, etc. In this situation, they start to face difficulties in common activities such as trouble to recalling earlier conversations, names/events. Therefore, AD patients are become bed-bound and need help around the clock and can eventually lead to malignancy. The current therapeutic targets of AD include the amelioration of β-amyloid plaque, cholinesterase inhibitors, tau-protein hyper-phosphorylation, biometal dyshomeostasis, and oxidative stress. In this state, pyridine analogues have been accredited as a promising anti-Alzheimer therapeutic leads. Since donepezil and tacrine are two pyridine analogues in the FDA-approved five drugs for the preliminary treatment of AD. Further, pyridine is an important key template for the existence of several natural molecules such as Vitamin B3, β-picoline, quinoline, trigonelline, and coenzymes (e.g., NADP), etc. The Hantzsch synthesis, Emil Knoevenagel process, Aleksei Chichibabin, Bonnemann cyclization, Gattermann–Skita synthesis, and Ciamician–Dennstedt rearrangement are the well-known methods for the synthesis of pyridine analogues. The production of industrial-scale pyridine analogues became easier after the invention of Chichiban synthesis by Russian chemist “Aleksei Chichibabin” through inexpensive staring materials and a more efficient route that is still practiced. Thus, it expands the importance of pyridine analogues for the treatment of AD and hence further studies are recommended for the development of potent anti-Alzheimer drugs. Therefore, the present chapter describes the role of pyridine analogues and their recent developments in the management of multisyndrome AD.

Atrial fibrillation (AF) is the most common non-physiological arrhythmia in dogs and humans. Its high prevalence in both species and the impact it has on survival time and quality of life of affected patients, makes it a very relevant topic for medical research. In dogs, the diagnosis of AF is usually fairly straightforward, but optimal management can be complicated. Rate control is the most commonly used strategy; rhythm control can also be considered in very specific cases. Concurrent congestive heart failure is frequently identified, which represents an extra challenge for the clinicians. This article reviews the current recommendations for the diagnosis and management considerations of AF in dogs. Future perspectives, focusing on new drugs that may prevent development of AF based on recent discoveries, will also be discussed.

Four drug-conjugated poly(2-alkyl-2-oxazoline) (PAOx) networks with different hydrophobicity were synthesized via copolymerization of either 2-methyl-, 2-ethyl-, 2-propyl- or 2-butyl-2-oxazoline with the functional monomer, 2-dec-9-enyl-2-oxazoline. The incorporation of a labile ester linkage between the polymer and the drug benazepril allowed for sustained drug release over periods of months with the release rates strongly depending on the hydrophobicity of the polymer pendant groups. Drug loading of 13 ± 2 wt% was used with 10 mol% crosslinking sites simply by tuning the thiol-ene stoichiometry. The networks exhibited negligible cell toxicity but cell repulsion was observed for hydrogels based on poly(2-methyl-2-oxazoline) and poly(2-ethyl-2-oxazoline) while those based on poly(2-n-propyl-2-oxazoline) and poly(2-n-butyl-2-oxaoline) showed cell adhesion. These results suggest that PAOx networks have great potential as drug delivery devices for long-lasting drug release applications.