Chronic exposure to indoor biomass smoke from the combustion of solid organic fuels is a major cause of disease burden worldwide. Almost 3 billion people use solid fuels such as wood, charcoal, and crop residues for indoor cooking and heating, accounting for approximately 50% of all households and 90% of rural households globally. Biomass smoke contains many hazardous pollutants, resulting in household air pollution (HAP) exposure that often exceeds international standards. Long-term biomass-smoke exposure is associated with Chronic Obstructive Pulmonary Disease (COPD) in adults, a leading cause of morbidity and mortality worldwide, chronic bronchitis, and other lung conditions. Biomass smoke-associated COPD differs from the best-known cigarette smoke-induced COPD in several aspects, such as a slower decline in lung function, greater airway involvement, and less emphysema, which suggests a different phenotype and pathophysiology. Despite the high burden of biomass-associated COPD, the molecular, genetic, and epigenetic mechanisms underlying its pathogenesis are poorly understood. This review describes the pathogenic mechanisms potentially involved in lung damage, the development of COPD associated with wood-derived smoke exposure, and the influence of genetic and epigenetic factors on the development of this disease.

/pdf/mechanisms-of-lung-damage-and-development-of-copd-due-to-3sb2how7.pdf

Mechanisms of Lung Damage and Development of COPD Due to Household Biomass-Smoke Exposure: Inflammation, Oxidative Stress, MicroRNAs, and Gene Polymorphisms

Phosphodiesterase enzymes (PDE) have long been known as regulators of cAMP and cGMP, second messengers involved in various signaling pathways and expressed in a variety of cell types implicated in respiratory diseases such as airway smooth muscle and inflammatory cells making them a key target for the treatment of lung diseases as chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, and pulmonary hypertension (PH). The first reported PDE inhibitor was the xanthine, theophylline, described as a non-specific PDE inhibitor and whilst this drug is effective, it also has a range of unwanted side effects. In an attempt to improve the therapeutic window of xanthines, a number of selective PDE inhibitors have been developed for the treatment of respiratory diseases with only the selective PDE 4 inhibitor, roflumilast, being approved for the treatment of severe COPD. However, roflumilast also has a very narrow therapeutic window due to a number of important doses limiting side effects, particularly in the gastrointestinal tract. However, there continues to be research carried out in this field to identify improved selective PDE inhibitors, both by targeting other PDE subtypes (e.g., PDE 7 found in a number of inflammatory and immune cells) and through development of selective PDE inhibitors for pulmonary administration to reduce systemic exposure and improve the side effect profile. This approach has been exemplified by the development of ensifentrine, a dual PDE 3-PDE 4 inhibitor, an inhaled drug that has recently completed two successful Phase III clinical trials in patients with COPD. 

Phosphodiesterase inhibitors and lung diseases

Measuring quality of life is a key component in the management of Chronic Obstructive Pulmonary Disease (COPD). The COPD assessment test (CAT), an easy to administer and shorter instrument than the standard Saint George’s respiratory questionnaire (SGRQ), could be an alternative tool for measuring the quality of life of COPD patients in rural Uganda. A cross-sectional study was conducted between June and August 2022, consecutively recruiting 113 COPD patients aged > 40 years from the Low-Dose Theophylline for the management of Biomass-associated COPD (LODOT-BCOPD) study. Upon obtaining consent, participants answered an interviewer administered social demographic, CAT and SGRQ questionnaire. Internal consistency for both SGRQ and CAT was determined using Cronbach’s alpha coefficient and values > 0.7 were considered acceptable while correlations were determined using Spearman’s rank correlation. Limits of Agreement were visualised using Bland Altman and pair plots. Of the 113 participants, 51 (45.1%) were female. The mean age was 64 ± 12 years, 19 (16.8%) had history of smoking while majority (112 (99.1%)) reported use of firewood for cooking. There was a strong correlation of 0.791 (p < 0.001) between the CAT and SGRQ total scores with a high internal consistency of CAT, Cronbach’s alpha coefficient of 0.924 (0.901–0.946). The agreement between the absolute CAT scores and the SGRQ scores was good with a mean difference of -0.932 (95% Confidence Interval: -33.49–31.62). In summary, CAT has an acceptable validity and can be used as an alternative to the SGRQ to assess the quality of life of COPD patients in rural Uganda.

/pdf/cross-sectional-validation-of-the-copd-assessment-test-cat-2cy8w6o1.pdf

Cross-sectional validation of the COPD Assessment Test (CAT) among chronic obstructive pulmonary disease patients in rural Uganda

The application of three-dimensional printing (3DP) in the pharmaceutical industry brings a broad spectrum of benefits to patients by addressing individual needs and improve treatment success. This study investigates the sustained release properties of 3DP tablets containing Theophylline (TPH), which is commonly used to treat respiratory diseases and recently having a comeback due to its potential in the treatment of conditions like Covid-19. Since TPH is a narrow therapeutic window (NTW) drug with serious side effects in the event of overdose, the release properties must be observed particularly closely. We employed a state-of-the-art single screw extrusion 3D printer, which is fed with granules containing the drug. By employing a Taguchi orthogonal array design of experiments (DOE), tablet design parameters and factor related process stability were sought to be evaluated fundamentally. Following this, examinations regarding tailored TPH dosages were undertaken and a relationship between the real printed dose of selected tablet designs and their sustained drug release was established. The release profiles were analyzed using different mathematical model fits and compared in terms of mean dissolution times (MDT). Finally, in-vivo/in-vitro correlation (IVIVC) and physiologically based pharmacokinetic (PBPK) modeling showed that a paradigm patient group could be covered with the dosage forms produced. 

Influence of design parameters on sustained drug release properties of 3D-printed theophylline tablets.

Background: COPD due to exposure to combustible biomass is an increasingly recognized phenotype, particularly among women who use traditional ovens, known as ‘Tabouna’, for baking bread. This paper aims to investigate the clinical and functional characteristics of COPD in Tunisian female patients attributed to the use of ‘Tabouna’. Methods: A retrospective single-center cohort study was conducted on patients recruited from the Department of Respiratory Disease at A. Mami Hospital, who were diagnosed with COPD between January 2014 and December 2022. The diagnosis of COPD adhered to the standards defined in GOLD 2022. Results: Out of the 95 women included in the study, 48 (50.5%) were exposed to tobacco smoke, while 47 (49.5%) were exposed to the ‘Tabouna’. The median age was 70.4 ± 11.5 years, ranging from 40 to 95 years. Patients exposed to biomass were notably older, with a median age of 75.4 compared to 64.6 (p = 0.04). A significant association was observed between COPD and biomass smoke exposure, both in women residing in rural and urban areas (p = 0.006). The frequency of patients exposed to biomass with comorbidities was higher than in the group exposed to tobacco, but only hypertension showed statistically significant results (p = 0.01). Tobacco smoke induced more impairment in lung function than biomass in the group with FEV1 ≤ 30% (p = 0.04). Long-acting muscarinic antagonists were more commonly prescribed to smokers (p = 0.04). Serious complications such as chronic respiratory failure and intensive care admissions were similar in both groups (p = 0.8 and 0.4). Conclusions: COPD in women after exposure to the ‘Tabouna’ was observed in older patients and characterized by delayed diagnosis. Despite these clinical differences, poor COPD outcomes were similar in both groups.

COPD after “Tabouna” Exposure: A Distinct Phenotype in Tunisian Women?

COPD is a leading cause of death globally, with the majority of morbidity and mortality occurring in low- and middle-income country (LMIC) settings. While tobacco-smoke exposure is the most important risk factor for COPD in high-income settings, household air pollution from biomass smoke combustion is a leading risk factor for COPD in LMICs. Despite the high burden of biomass smoke-related COPD, few studies have evaluated the efficacy of pharmacotherapy in this context. Currently recommended inhaler-based therapy for COPD is neither available nor affordable in most resource-limited settings. Low-dose theophylline is an oral, once-a-day therapy, long used in high-income countries (HICs), which has been proposed for the management of COPD in LMICs in the absence of inhaled steroids and/or bronchodilators. The Low-dose Theophylline for the Management of Biomass-Associated COPD (LODOT-BCOPD) trial investigates the clinical efficacy and cost-effectiveness of low-dose theophylline for the management of biomass-related COPD in a low-income setting. LODOT-BCOPD is a randomized, double-blind, placebo-controlled trial to test the efficacy of low-dose theophylline in improving respiratory symptoms in 110 participants with moderate to severe COPD in Central Uganda. The inclusion criteria are as follows: (1) age 40 to 80 years, (2) full-time resident of the study area, (3) daily biomass exposure, (4) post-bronchodilator FEV1/FVC below the 5th percentile of the Global Lung Initiative mixed ethnic reference population, and (5) GOLD Grade B-D COPD. Participants will be randomly assigned to receive once daily low-dose theophylline (200 mg ER, Unicontin-E) or placebo for 52 weeks. All participants will receive education about self-management of COPD and rescue salbutamol inhalers. We will measure health status using the St. George’s Respiratory Questionnaire (SGRQ) and quality of life using the EuroQol-5D (EQ-5D) at baseline and every 6 months. In addition, we will assess household air pollution levels, serum inflammatory biomarkers (fibrinogen, hs-CRP), and theophylline levels at baseline, 1 month, and 6 months. The primary outcome is change in SGRQ score at 12 months. Lastly, we will assess the cost-effectiveness of the intervention by calculating quality-adjusted life years (QALYs) from the EQ-5D. ClinicalTrials.gov 
 NCT03984188
 . Registered on June 12, 2019 Low-dose Theophylline for the Management of Biomass-Associated COPD (LODOT-BCOPD)

/pdf/effectiveness-of-low-dose-theophylline-for-the-management-of-4v1x2869cy.pdf

Effectiveness of low-dose theophylline for the management of biomass-associated COPD (LODOT-BCOPD): study protocol for a randomized controlled trial

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Effectiveness of low-dose theophylline for the management of biomass-associated COPD (LODOT-BCOPD): study protocol for a randomized controlled trial