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Optimizing the Development Strategy of Combination Therapy in Respiratory Medicine: From Isolated Airways to Patients.

ABSTRACT: The current recommendations for the treatment of chronic obstructive pulmonary disease (COPD) are pushing towards triple combination therapy based on the combination of an inhaled corticosteroid (ICS) associated with two bronchodilator agents. However, dual bronchodilation remains the cornerstone for the treatment of most COPD patients. Combining a long-acting ?2 adrenoceptor agonist (LABA) with a long-acting muscarinic antagonist (LAMA) induces appreciable synergistic bronchorelaxant effect in human airways, especially when the medications are combined at isoeffective concentrations. Thus, each LABA/LAMA combination is characterized by a specific range of concentration-ratio at which the drug mixture may induce sustained synergistic interaction. Results of a recent randomized controlled trial (RCT, NCT00696020) and evidences from pre-clinical studies in human isolated airways poses the question whether combining tiotropium 5 ?g with olodaterol 5 ?g is the best combination option: tiotropium/olodaterol 5/5 ?g has the same efficacy profile of tiotropium/olodaterol 5/2 ?g, and it is less effective than tiotropium/olodaterol 5/10 ?g. Furthermore, tiotropium/olodaterol 5/2 ?g, 5/5 ?g, and 5/10 ?g combinations are generally characterized by the same safety profile. Indeed tiotropium/olodaterol 5/5 ?g is effective and safe in COPD, but a different development strategy based on solid data obtained from human isolated airways would have driven towards a better-balanced FDC to be tested in Phase III RCTs. Accurate bench-to-bedside plans are needed also in the development of triple combination therapies for asthma and COPD, in which the presence of an ICS in the formulation may further modulate the beneficial interaction between the LABA and the LAMA.

SUBMITTER: Calzetta L

PROVIDER: S-EPMC6860506 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Optimizing the Development Strategy of Combination Therapy in Respiratory Medicine: From Isolated Airways to Patients.

Calzetta Luigino L Matera Maria Gabriella MG Cazzola Mario M Rogliani Paola P

Advances in therapy 20191025 12

The current recommendations for the treatment of chronic obstructive pulmonary disease (COPD) are pushing towards triple combination therapy based on the combination of an inhaled corticosteroid (ICS) associated with two bronchodilator agents. However, dual bronchodilation remains the cornerstone for the treatment of most COPD patients. Combining a long-acting β<sub>2</sub> adrenoceptor agonist (LABA) with a long-acting muscarinic antagonist (LAMA) induces appreciable synergistic bronchorelaxant ...[more]

PMID: 31654332

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Project description:Background Lycopene is increasing in demand due to its widespread use in the pharmaceutical and food industries. Metabolic engineering and synthetic biology technologies have been widely used to overexpress the heterologous mevalonate pathway and lycopene pathway in Escherichia coli to produce lycopene. However, due to the tedious metabolic pathways and complicated metabolic background, optimizing the lycopene synthetic pathway using reasonable design approaches becomes difficult. Results In this study, the heterologous lycopene metabolic pathway was introduced into E. coli and divided into three modules, with mevalonate and DMAPP serving as connecting nodes. The module containing the genes (MVK, PMK, MVD, IDI) of downstream MVA pathway was adjusted by altering the expression strength of the four genes using the ribosome binding sites (RBSs) library with specified strength to improve the inter-module balance. Three RBS libraries containing variably regulated MVK, PMK, MVD, and IDI were constructed based on different plasmid backbones with the variable promoter and replication origin. The RBS library was then transformed into engineered E. coli BL21(DE3) containing pCLES and pTrc-lyc to obtain a lycopene producer library and employed high-throughput screening based on lycopene color to obtain the required metabolic pathway. The shake flask culture of the selected high-yield strain resulted in a lycopene yield of 219.7 mg/g DCW, which was 4.6 times that of the reference strain. Conclusion A strain capable of producing 219.7 mg/g DCW with high lycopene metabolic flux was obtained by fine-tuning the expression of the four MVA pathway enzymes and visual selection. These results show that the strategy of optimizing the downstream MVA pathway through RBS library design can be effective, which can improve the metabolic flux and provide a reference for the synthesis of other terpenoids. Supplementary Information The online version contains supplementary material available at 10.1186/s12934-022-01843-z.

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Optimizing the Development Strategy of Combination Therapy in Respiratory Medicine: From Isolated Airways to Patients.

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Optimizing the Development Strategy of Combination Therapy in Respiratory Medicine: From Isolated Airways to Patients.

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