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The Development of Beta Receptor Agonist Drugs
Published in Richard Beasley, Neil E. Pearce, The Role of Beta Receptor Agonist Therapy in Asthma Mortality, 2020
Two terbutaline ester prodrugs were designed with these goals in mind. One of these, D 2438, in which the ester is derived fromp-pivaloyloxybenzoic acid109 (Figure 5), had the required properties in dogs but not when tested in humans (esterase activity is higher in humans than in dogs). A more satisfactory drug was the bis-N,N-dimethylcarbamate ester prodrug, bambuterol (Figure 5).110,111 The dimethylcarbamate groups in this compound provided a built-in esterase inhibitory function, that is, bambuterol slowed down its own rate of hydrolysis by reversibly inhibiting pseudocholinesterase. In addition, through oxidative metabolism of the carbamate groups, the drug was metabolized to various additional lipophilic, inactive, metabolite prodrugs. These could then be spontaneously broken down to terbutaline. This feature contributed to the prolonged duration of action of the drug when it was given orally to asthmatic patients. Bambuterol also had the required lung specificity in that both the drug and its metabolites were retained in the lung tissue. The latter may be the explanation why an increased ratio of bronchodilatation to side effects is seen in patients despite low plasma concentrations of terbutaline; the drug may be generating therapeutic levels of terbutaline only in the lungs. Thus, bambuterol provided a new orally active bronchodilator for asthma with a long duration of action and with a favorable bronchodilator: side effects ratio.
Drug Targeting to the Lung: Chemical and Biochemical Considerations
Published in Anthony J. Hickey, Sandro R.P. da Rocha, Pharmaceutical Inhalation Aerosol Technology, 2019
Peter A. Crooks, Narsimha R. Penthala, Abeer M. Al-Ghananeem
Bambuterol (51b), the bis-N-N-dimethylcarbamate of terbutaline, produces a sustained release of terbutaline, a result of the slow, mainly extrapulmonary hydrolysis of the carbamate linkage. Unfortunately, because of its poor metabolism in the lung, it is not effective by the inhalation route. But it has been reported to yield good oral results and can be administered at much less frequent intervals than terbutaline (Holstein-Rathlou et al. 1986). In fact, bambuterol is approved for treatment of asthma in more than 28 countries, in oral tablets as the hydrochloride salt. Bambuterol is stable to pre-systemic elimination and is concentrated by lung tissue after absorption from the gastrointestinal tract. The prodrug is hydrolyzed to terbutaline primarily by butyryl cholinesterase, and lung tissue contains this metabolic enzyme. Bambuterol is also oxidatively metabolized to products that can be hydrolyzed to terbutaline (Sitar 1996). Bambuterol displays high first-pass hydrolytic stability and is only slowly hydrolyzed to terbutaline; hence, it can be administered orally, as infrequently as once a day. Bambuterol and its metabolites appear to be preferentially distributed to the lung, where an advantageous distribution and metabolism to active drug occurs. Thus, the prodrug is able to generate adequate concentrations of terbutaline levels in the lung. It has been reported that bronchodilator effects at low dosage are greater than can be predicted by plasma concentrations of terbutaline (Svensson 1987). This may explain the significantly reduced systemic side effects compared to other oral bronchodilators. A study (Svensson 1985) has postulated that several explanations can account for the disparity between plasma levels and drug effects as observed for several of the pulmonary products: (a) the prodrug is metabolized in lung to an unknown, but potent and long-acting pharmacological agent, (b) the prodrug releases small amounts of the parent drug at sites in lung from which it does not readily efflux, and (c) small amounts of the prodrug not reflected by bulk concentrations of prodrug in lung or plasma may sequester specific sites in the lung.
Design, synthesis and cholinesterase inhibitory properties of new oxazole benzylamine derivatives
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Ivana Šagud, Nikolina Maček Hrvat, Ana Grgičević, Tena Čadež, Josipa Hodak, Milena Dragojević, Kornelija Lasić, Zrinka Kovarik, Irena Škorić
AChE has an essential physiological role in the body as it controls the transmission of nerve impulses in the cholinergic synapses of the central and peripheral nervous system by hydrolysis of the neurotransmitter acetylcholine. It also has a role in neuritogenesis, cell adhesion, proliferation and cell interactions, synaptogenesis, dopamine neuronal activation, the formation of amyloid fibres characteristic for Alzheimer's disease, haematopoiesis and thrombopoiesis7–9. The role of BChE is not physiologically essential but it could be assigned to the detoxification of xenobiotics (organophosphates and carbamate pesticides, cocaine, aspirin, succinyldicholine, etc.) and bioactivation of drugs (bambuterol, heroin, etc.)10,11. Also, BChE serves as a co-regulator of cholinergic neurotransmission and is capable of catalysing the hydrolysis of acetylcholine12. It was found that high BChE levels are associated with neuritic plaques and neurofibrillary tangles, the neuropathologic hallmarks of Alzheimer’s disease (AD)13,14. Therefore, both cholinesterases are pharmacologically relevant targets in neurodegenerative disorders, and today’s treatment includes cholinesterase inhibitors like donepezil, galantamine, physostigmine, rivastigmine, ect.15. Many other compounds acting as inhibitors of cholinesterase are therefore considered as potential AD therapeutics16–18.
The efficacy and safety of different long-acting β2-agonists combined with inhaled glucocorticoid regimens in patients with asthma: a network meta-analysis
Published in Journal of Asthma, 2019
Ying Tang, Caiyun Zhang, Zhigang Zhang, Jinhui Tian
This study has some limitations. First, the sample size of the Kirsten [24] was small, only 22 cases. It can easily reduce the authenticity of the study. Second, some studies did not specify the methods of allocation hiding and blinding, which lead to methodological quality bias. Third, we were unable to include conference abstracts and report written in languages other than English. Besides, some treatment regimens were excluded because we cannot obtain the full articles or detailed data at the outcomes, such as oulotetra/ICS, bambuterol/ICS, or indacaterol/mometasone furoate. Furthermore, we did not state different inhalers and recommended individualized regimens for patients. In addition, there were fewer studies that met the inclusion criteria, and we did not carry out subgroup analysis. Finally, we did not identify which patients are being treated with advanced therapies, such as monoclonal antibodies for IgE or IL-5 therapies, and it did not include the type of asthma patients suffer from, such as allergic asthma. These will be the goal of future studies.
A patent review of butyrylcholinesterase inhibitors and reactivators 2010–2017
Published in Expert Opinion on Therapeutic Patents, 2018
Vincenza Andrisano, Marina Naldi, Angela De Simone, Manuela Bartolini
Butyrylcholinesterase (BuChE) is one of the two major cholinesterases (ChE) in mammals. BuChE differs from the other cholinesterase enzyme, namely acetylcholinesterase (AChE), in substrate specificity, kinetics, and localization in brain [1]. While the physiological role of AChE in neurotransmission is known, being the major serine hydrolase involved in the termination of the cholinergic nerve impulse at the central nervous system (CNS) [2], the physiological function of BuChE is still unknown. It is well known that plasma BuChE plays a detoxification role against organophosphate and carbamate inhibitors (as pesticides and chemical weapons), preventing toxic AChE inhibition. Furthermore, BuChE is involved in the inactivation of some drugs (e.g., cocaine, aspirin) and activation of prodrugs such as bambuterol [3]. Other than in plasma, BuChE is widely distributed in the CNS, which points to its possible involvement in neural function. Indeed, studies with AChE-knockout mice and human brain tissue revealed that BuChE may play a compensating role in the hydrolysis of acetylcholine (ACh) when AChE is depleted [4,5].