9 research outputs found
Synthesis and Evaluation of Lung Tissue Retentive Prodrugs
In the time of a global respiratory pandemic, there has never been a more pertinent time to improve the current medications responsible for relieving the symptoms of respiratory diseases such as COPD and Asthma. Administration of drugs directly to the site of action through the pulmonary drug delivery route can give significant benefits over other traditional routes of administration i.e. oral. Avoidance of first pass metabolism in the liver, reduced drug dosage and significant reduction of compound exposure to other organs, ultimately leading to fewer side effects, are all benefits of the pulmonary delivery route. However, rapid drug elimination from lung tissue into the pulmonary vein, combined with the pan antagonistic nature of receptor antagonists and heavy presence of muscarinic receptors in other tissues, often leads to increased side effects in other organs, such as the heart.
Aims: The aim of this thesis was to design and evaluate a novel, self-activating, dibasic prodrug system as a possible method of achieving sustained delivery post inhalation. Evaluation of the method of increased lung tissue retention would then be explored using confocal microscopy to probe the lysosomal trapping potential of dibasic compounds. This system, if successful would represent a remarkable achievement in that the prodrug design could be developed to suit a wide range of chemical structures, and thus has the potential improve the inhaled PK profile of a wide variety of inhaled pharmaceuticals and thus massively expedite the development of novel-long acting treatments.
Chapter 1: Outlines the advantages of inhaled administration as a route for targeted drug delivery. In addition, it details the common mechanisms for achieving sustained drug delivery to the lung, alongside describing the pertinent need for new long acting muscarinic receptor antagonists in order to improve the current prevention and treatment of breathing difficulties in COPD and asthmatic patients.
Chapter 2: Describes the use of prodrug systems as mechanisms for improving drug delivery. In addition, it follows the development and implementation of a novel cleavable prodrug system from initial design stages, through to final in-vivo PK studies, as a method of efficaciously delivering an active muscarinic agent over a sustained period in attempt to increase the duration of action of an existing muscarinic receptor drug. It outlines the discovery of compound 24 as a novel, dibasic, pH-sensitive, self-cleaving, muscarinic prodrug capable of withstanding enzymatic cleavage in order to liberate an active muscarinic receptor antagonist at a sustained rate over 24 hours. The subsequent in-vivo pharmacokinetic studies demonstrate that when inhaled independently, over 99% of the active drug was eliminated from the lung tissue within 3 hours, but when delivered as a prodrug, sustained prodrug activation meant that the drug was present in the lung at a pharmaceutically relevant concentration for over 24 hours, with no detected exposure of the drug to blood plasma.
Chapter 3: Develops further the prodrug system introduced in chapter 1, this time focusing on an intracellular PI3K δ target. It follows an attempt to improve an intermediate drug candidate which suffered from poor physiochemical properties and thus did not progress to clinical trials. Included is the design and attempted synthesis of a series of prodrugs, which based on the results of chapter 1, would be interesting candidates for an in-vivo PK study to determine their duration of action relative to the parent drug candidates, and thus feasibility as sustained release delivery agents.
Chapter 4: Investigates how the dibasic moiety of the prodrug design affects the distribution of the prodrug in lung tissue. By taking a lysosome-targeting fluorescent probe, replacing the functionality responsible for its lysosome targeting nature with the dibasic prodrug moiety, a distribution comparison can be created. This chapter attempted to visualise the effect of incorporating a dibasic moiety into the prodrug design on the distribution and organelle sequestration.
Conclusion: A dibasic, self-activating prodrug (Compound 24) has been created which displays a much-increased lung tissue retention relative to the parent drug (Compound 1). Post intratracheal dosing, sustained release of 1 from 24 resulted in a high, pharmaceutically relevant concentration of 1 in the lung tissue for over 24 hours all from a single dose. Thus, the unique approach of using a prodrug system which incorporates lung tissue retentive chemical moieties to extend the lung residency time of a muscarinic antagonist has been successful. Further studies will determine whether an extended pharmacodynamic response has also been achieved and will help to elucidate the mechanism of lung retention
Synthesis and Evaluation of Lung Tissue Retentive Prodrugs
In the time of a global respiratory pandemic, there has never been a more pertinent time to improve the current medications responsible for relieving the symptoms of respiratory diseases such as COPD and Asthma. Administration of drugs directly to the site of action through the pulmonary drug delivery route can give significant benefits over other traditional routes of administration i.e. oral. Avoidance of first pass metabolism in the liver, reduced drug dosage and significant reduction of compound exposure to other organs, ultimately leading to fewer side effects, are all benefits of the pulmonary delivery route. However, rapid drug elimination from lung tissue into the pulmonary vein, combined with the pan antagonistic nature of receptor antagonists and heavy presence of muscarinic receptors in other tissues, often leads to increased side effects in other organs, such as the heart.
Aims: The aim of this thesis was to design and evaluate a novel, self-activating, dibasic prodrug system as a possible method of achieving sustained delivery post inhalation. Evaluation of the method of increased lung tissue retention would then be explored using confocal microscopy to probe the lysosomal trapping potential of dibasic compounds. This system, if successful would represent a remarkable achievement in that the prodrug design could be developed to suit a wide range of chemical structures, and thus has the potential improve the inhaled PK profile of a wide variety of inhaled pharmaceuticals and thus massively expedite the development of novel-long acting treatments.
Chapter 1: Outlines the advantages of inhaled administration as a route for targeted drug delivery. In addition, it details the common mechanisms for achieving sustained drug delivery to the lung, alongside describing the pertinent need for new long acting muscarinic receptor antagonists in order to improve the current prevention and treatment of breathing difficulties in COPD and asthmatic patients.
Chapter 2: Describes the use of prodrug systems as mechanisms for improving drug delivery. In addition, it follows the development and implementation of a novel cleavable prodrug system from initial design stages, through to final in-vivo PK studies, as a method of efficaciously delivering an active muscarinic agent over a sustained period in attempt to increase the duration of action of an existing muscarinic receptor drug. It outlines the discovery of compound 24 as a novel, dibasic, pH-sensitive, self-cleaving, muscarinic prodrug capable of withstanding enzymatic cleavage in order to liberate an active muscarinic receptor antagonist at a sustained rate over 24 hours. The subsequent in-vivo pharmacokinetic studies demonstrate that when inhaled independently, over 99% of the active drug was eliminated from the lung tissue within 3 hours, but when delivered as a prodrug, sustained prodrug activation meant that the drug was present in the lung at a pharmaceutically relevant concentration for over 24 hours, with no detected exposure of the drug to blood plasma.
Chapter 3: Develops further the prodrug system introduced in chapter 1, this time focusing on an intracellular PI3K δ target. It follows an attempt to improve an intermediate drug candidate which suffered from poor physiochemical properties and thus did not progress to clinical trials. Included is the design and attempted synthesis of a series of prodrugs, which based on the results of chapter 1, would be interesting candidates for an in-vivo PK study to determine their duration of action relative to the parent drug candidates, and thus feasibility as sustained release delivery agents.
Chapter 4: Investigates how the dibasic moiety of the prodrug design affects the distribution of the prodrug in lung tissue. By taking a lysosome-targeting fluorescent probe, replacing the functionality responsible for its lysosome targeting nature with the dibasic prodrug moiety, a distribution comparison can be created. This chapter attempted to visualise the effect of incorporating a dibasic moiety into the prodrug design on the distribution and organelle sequestration.
Conclusion: A dibasic, self-activating prodrug (Compound 24) has been created which displays a much-increased lung tissue retention relative to the parent drug (Compound 1). Post intratracheal dosing, sustained release of 1 from 24 resulted in a high, pharmaceutically relevant concentration of 1 in the lung tissue for over 24 hours all from a single dose. Thus, the unique approach of using a prodrug system which incorporates lung tissue retentive chemical moieties to extend the lung residency time of a muscarinic antagonist has been successful. Further studies will determine whether an extended pharmacodynamic response has also been achieved and will help to elucidate the mechanism of lung retention
Design, Synthesis, and Evaluation of Lung-Retentive Prodrugs for Extending the Lung Tissue Retention of Inhaled Drugs
A major limitation of pulmonary delivery is that drugs can exhibit suboptimal pharmacokinetic profiles resulting from rapid elimination from the pulmonary tissue. This can lead to systemic side effects and a short duration of action. A series of dibasic dipeptides attached to the poorly lung-retentive muscarinic M3 receptor antagonist piperidin-4-yl 2-hydroxy-2,2-diphenylacetate (1) through a pH-sensitive-linking group have been evaluated. Extensive optimization resulted in 1-(((R)-2-((S)-2,6-diaminohexanamido)-3,3-dimethylbutanoyl)oxy)ethyl 4-(2-hydroxy-2,2-diphenylacetoxy)piperidine-1-carboxylate (23), which combined very good in vitro stability and very high rat lung binding. Compound 23 progressed to pharmacokinetic studies in rats, where, at 24 h post dosing in the rat lung, the total lung concentration of 23 was 31.2 μM. In addition, high levels of liberated drug 1 were still detected locally, demonstrating the benefit of this novel prodrug approach for increasing the apparent pharmacokinetic half-life of drugs in the lungs following pulmonary dosing
Metabolic rates associated with membrane fatty acids in mice selected for increased maximal metabolic rate
Normative and Positive Social Work in the Context of the Placement Decision: A Defence of Social Workers
The Contract as Social Artifact
This article outlines a distinctive, albeit not entirely unprecedented, research agenda for the sociolegal study of contracts. In the past, law and society scholars have tended to examine contracts either through the intellectual history of contract doctrine ‘‘on the books’’ or through the empirical study of how real-world exchange relations are governed ‘‘in action.’’ Although both of these traditions have contributed greatly to our understanding of contract law, neither has devoted much attention to the most distinctive concrete product of contractual transactionsFcontract documents themselves. Without denying the value of studying either contract doctrine or relational governance, this article argues that contract documents are independently interesting social artifacts and that they should be studied as such. As social artifacts, contracts possess both technical and symbolic properties, and the sociolegal study of contract-as-artifact can profitably apply prevailing social scientific theories of technology and symbolism to understand both: (1) the microdynamics of why and how transacting parties craft individual contract devices, and (2) the macrodynamics of why and how larger social systems generate and sustain distinctive contract regimes. Seen in this light, the microdynamics of contract implicate ‘‘technical’’ theories of transaction cost engineering and private lawmaking, and ‘‘symbolic’’ theories of ceremony and gesture. In a parallel fashion, the macrodynamics of contract implicate ‘‘technical’’ theories of innovation diffusion, path dependence, and technology cycles, and ‘‘symbolic’’ theories of ideology, legitimacy, and communication. Together, these micro and macro explorations suggest that contract artifacts may best be understood as scripts and signalsFcollections of symbols designed to field technically efficacious practical action when interpreted by culture-bearing social actors within the context of preexisting vocabularies and conventions