Treatment with inhaled α1-antitrypsin: a square peg in a round hole?

Barrecheguren, Miriam; Miravitlles, Marc

doi:10.1183/13993003.01894-2019

Cited by 6 publications

(2 citation statements)

References 28 publications

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“…In addition to cystic fibrosis, research has focused on the potential benefits for emphysema prevention [77]. Inhaled α 1 -antitrypsin formulations have also been tested in clinical trials [78,79], and although some trials have highlighted limitations in efficacy, certain patient subgroups may benefit [80,81].…”

Section: Metabolism Of Biologic Drugs and Excipientsmentioning

confidence: 99%

Drug metabolism in the lungs: opportunities for optimising inhaled medicines

Enlo-Scott

Bäckström

Mudway

et al. 2021

Expert Opinion on Drug Metabolism & Toxicology

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Introduction:The lungs possess many xenobiotic metabolizing enzymes which influence the pharmacokinetics and safety of inhaled medicines. Anticipating metabolism in the lungs provides an opportunity to optimize new inhaled medicines and overcome challenges in their development.Areas covered: This article summarizes current knowledge on xenobiotic metabolizing enzymes in the lungs. The impact of metabolism on inhaled medicines is considered with examples of how this impacts small molecules, biologics and macromolecular formulation excipients. Methods for measuring and predicting xenobiotic lung metabolism are critically reviewed and the potential for metabolism to influence inhalation toxicology is acknowledged. Expert opinion: Drugs can be optimized by molecular modification to (i) reduce systemic exposure using a 'soft drug' approach, (ii) improve bioavailability by resisting metabolism, or (iii) use a prodrug approach to overcome pharmacokinetic limitations. Drugs that are very labile in the lungs may require a protective formulation. Some drug carriers being investigated for PK-modification rely on lung enzymes to trigger drug release or biodegrade. Lung enzyme activity varies with age, race, smoking status, diet, drug exposure and preexisting lung disease. New experimental technologies to study lung metabolism include tissue engineered models, improved analytical capability and in silico models.

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Section: Metabolism Of Biologic Drugs and Excipientsmentioning

confidence: 99%

Drug metabolism in the lungs: opportunities for optimising inhaled medicines

Enlo-Scott

Bäckström

Mudway

et al. 2021

Expert Opinion on Drug Metabolism & Toxicology

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“…Перева гою інгаляційної форми замісної терапії є низька доза діючої речовини, що дає змогу проводити лікування в більшості (у 3-4 рази) пацієнтів порівняно з дозою ААТ в ін'єкційній формі. Замісна терапія ААТ також показана при муко вісцидозі, бронхоектатичній хворобі [6,20,28].…”

Section: лікування пацієнтів із недостатністю α1 антитрипсинуunclassified

Characteristics of diseases in children with inherited α1-antitrypsin deficiency

Tsymbalista¹

2021

MPU

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The article presents the current views on genetics, features of metabolic disorders, course of various clinical manifestations, diagnostic criteria, and treatment principles for monogenic enzymopathy — an inherited α1;antitrypsin (AAT) deficiency. Inherited AAT deficiency manifests itself as four clinical syndromes: respiratory disease (pulmonary emphysema, chronic obstructive pulmonary disease (COPD), bronchial asthma, spontaneous pneumothorax, bronchiectasis); liver disease and blood vessel damage. Respiratory disease manifests itself between the ages of 20–40 years. Chronic pulmonary emphysema is typical for homozygous PiZZ gene carriers. The most unfavorable clinical course variant including persistent cough, COPD development, bronchial asthma, pneumonia, co-existence of various respiratory diseases and severe disorders of external respiration is the PISZ phenotype. Bronchial asthma has severe clinical course with torpid purulent endobronchitis; is often uncontrolled despite background therapy. In COPD patients, exacerbations are frequent, severe, and prolonged. The reduction in the vessels of the pulmonary circulation results in pulmonary hypertension, right ventricular failure. In AAT deficiency, there is a high incidence of bronchiectasis, lung cancer. Liver diseases manifest themselves as neonatal hepatitis, biliary atresia, liver cirrhosis, infectious complications. Chronic form is characterized by subclinical changes in the biochemical parameters of liver function most of which (up to 70%) normalize before the age of 18 years. In patients until the age of 20 years, disease slowly progresses and leads to the development of liver cirrhosis in 30% of cases, while older patients develop liver cirrhosis in 30–50% of cases. Some patients have a benign course of liver disease and present with hepatomegaly. Hemorrhagic syndrome occurs when protease inhibitor gene product acquires the properties of antithrombin. Vascular disease manifests itself as necrotizing panniculitis, severe hemorrhagic vasculitis with serum antineutrophil cytoplasmic antibodies to proteinase (С-АNСА). AAT deficiency may coexist with systemic vasculitis, vascular aneurysm, many other diseases, as well as with the development of aplastic processes of various localization. In addition to clinical manifestations, diagnosis of inherited AAT deficiency includes screening programs, instrumental (X-ray, spirometry, ECG, ultrasound), laboratory (liver function, coagulation profile, immunogram, serum AAT concentration), genetic investigations, exclusion testing for cystic fibrosis, viral hepatitis, and other diseases. Treatment of patients with inherited AAT deficiency consists in adequate nutrition and physical activity; treatment of pre-existing conditions; prevention and timely therapy for respiratory infections; pathogenetic therapy. Pathogenetic therapy for AAT deficiency is a replacement (augmentation) therapy with exogenous α1-antitrypsin concentrate. Replacement therapy is indicated only in patients >18 years of age with the PiZZ phenotype or other rare AAT phenotypes. No conflict of interest was declared by the author. Key words: children, inherited α1-antitrypsin deficiency, diagnosis, therapy.

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Advances in the design of new types of inhaled medicines

Czechtizky

Ripa

et al. 2022

Progress in Medicinal Chemistry

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Treatment with inhaled α1-antitrypsin: a square peg in a round hole?

Cited by 6 publications

References 28 publications

Drug metabolism in the lungs: opportunities for optimising inhaled medicines

Drug metabolism in the lungs: opportunities for optimising inhaled medicines

Characteristics of diseases in children with inherited α1-antitrypsin deficiency

Advances in the design of new types of inhaled medicines

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