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Biomedical subjects

John S Patton

Publications and source records attributed to John S Patton.

5 recordsLinked to original sources
PubMed2007

Inhaling medicines: delivering drugs to the body through the lungs.

Remarkably, with the exception of anaesthetic gases, the ancient human practice of inhaling substances into the lungs for systemic effect has only just begun to be adopted by modern medicine. Treatment of asthma by inhaled drugs began in earnest in the 1950s, and now such 'topical' or targeted treatment with inhaled drugs is considered for treating many other lung diseases. More recently, major advances have led to increasing interest in systemic delivery of drugs by inhalation. Small molecules can be delivered with very rapid action, low metabolism and high bioavailability; and macromolecules can be delivered without injections, as highlighted by the recent approval of the first inhaled insulin product. Here, we review these advances, and discuss aspects of lung physiology and formulation composition that influence the systemic delivery of inhaled therapeutics.

Absorption↗
PubMed2005

Unlocking the opportunity of tight glycaemic control. Innovative delivery of insulin via the lung.

As the incidence of diabetes reaches epidemic proportions, the use of new, alternative routes of insulin delivery to manage glycaemic control is becoming an ever more active area of research. The high permeability and large surface area of the lung make it an attractive alternative to subcutaneous (SC) insulin injections. This review discusses the technical factors that influence the efficacy of pulmonary drug delivery and describes how an appreciation of these issues has enabled the design of Exubera, a novel, non-invasive, pulmonary dry-powder human insulin delivery system currently in development by Pfizer and the Sanofi-Aventis Group in collaboration with Nektar Therapeutics. While clinical trials of this novel aerosol delivery of insulin are still ongoing in patients with diabetes, the results so far suggest it is simple to use and can provide reproducible doses of insulin in therapeutic amounts with only a few inhalations per dose. In addition, it has been shown to be comparable in terms of efficacy and safety to a conventional SC insulin injection regimen. Delivering aerosolized drugs via the lungs avoids the necessity for SC injections and thereby may increase the patient's acceptability of an insulin-based therapeutic regimen.

Administration, Inhalation↗
PubMed2004

The lungs as a portal of entry for systemic drug delivery.

The lung is naturally permeable to all small-molecule drugs studied and to many therapeutic peptides and proteins. Absorption can be estimated using a simple animal test, intratracheal instillation. Inhalation offers a noninvasive route for the delivery of peptides and proteins that otherwise must be injected. Peptides that have been chemically altered to inhibit peptidase enzymes exhibit very high bioavailabilities by the pulmonary route. Natural mammalian peptides, less than about 30 amino acids, are broken down in the lung by ubiquitous peptidases and have very poor bioavailabilities. In general, proteins with molecular weights between 6,000 and 50,000 D are relatively resistant to most peptidases and have good bioavailabilities following inhalation. For larger proteins the bioavailability picture is not clear. Although the lung is rich in antiproteases, aggregation of inhaled proteins will stimulate opsonization (coating) by special proteins in the lung lining fluids, which will then mark the aggregated proteins for phagocytosis and intracellular enzymatic destruction. Small peptides and proteins are absorbed more rapidly after inhalation than after subcutaneous injection. For other small molecules, inhalation is also a fast way to get into the body because drug efflux transporters and metabolizing enzymes are present in the lung at much lower levels than the gastrointestinal tract. Lipophilic small molecules are absorbed extremely fast, t(1/2) (abs) approximately 1 to 2 minutes. Water-soluble small molecules are absorbed rapidly t(1/2) (abs) approximately 65 minutes. Small molecules can exhibit prolonged absorption if they are highly insoluble or highly cationic. Encapsulation in slow release particles such as liposomes can also be used to control absorption.

Administration, Inhalation↗
PubMed2004

Clinical pharmacokinetics and pharmacodynamics of inhaled insulin.

The benefits of intensive insulin therapy in the prevention of complications in patients with diabetes mellitus are now well established. However, the current methods of insulin administration fall well short of the ideal. Consequently, alternative routes of insulin administration have been investigated. The pulmonary route has received the most attention, helped by advances in inhaler devices and insulin formulation technology. As a result, several insulin inhalation systems are at varying stages of development, with one already filed for marketing approval in Europe. Knowledge of the pharmacokinetic and pharmacodynamic characteristics of the various inhaled insulin formulations will help to determine their positioning in current and evolving diabetes treatment strategies. For instance, a rapid onset and short duration of action would be desirable for use in postprandial glucose control. Pharmacokinetic studies with inhaled insulin reveal that serum insulin concentrations peak earlier and decay more rapidly following inhalation compared with subcutaneously administered regular insulin, and pharmacodynamic studies measuring glucose infusion rate under euglycaemic glucose clamp show corresponding rapid changes in glucose control. Furthermore, intrapatient variability in the pharmacokinetics and pharmacodynamics of inhaled insulin is low; variability is similar to (or perhaps less than) that seen when insulin is administered subcutaneously. Estimates of the bioavailability and bioefficacy achievable with the current inhalation systems are typically in the region of 10% of that experienced with subcutaneously administered insulin. Most of the losses are in the device, mouth and throat, with approximately 30-50% of the insulin deposited in the lungs being absorbed. Clinical experience to date indicates that inhaled insulin has the potential to be an effective treatment in patients with diabetes, and that it may have particular utility in the treatment of postprandial hyperglycaemia.

Administration, Inhalation↗