Effect of complicated, untreated and uncontrolled diabetes and pre-diabetes on treatment outcome among patients with pulmonary tuberculosis.

BACKGROUND AND OBJECTIVE: Patients with tuberculosis and diabetes have a higher risk of unfavourable anti-tuberculosis treatment outcomes. In the present study, we aimed to evaluate the effects of various diabetes statuses on the outcomes of patients with pulmonary tuberculosis. METHODS: Among the patients with pulmonary tuberculosis enrolled in the Korea Tuberculosis Cohort (KTBC) registry and the multicentre prospective cohort study of pulmonary tuberculosis (COSMOTB), those with diabetes and complicated diabetes were identified. The primary and secondary outcomes were unfavourable outcomes and mortality, respectively. The effect of diabetes and complicated diabetes on the outcomes was assessed using multivariable logistic regression analysis. Using COSMOTB, subgroup analyses were performed to assess the association between various diabetes statuses and outcomes. RESULTS: In the KTBC, diabetes (adjusted odds ratio [aOR] = 1.93, 95% CI = 1.64-2.26) and complicated diabetes (aOR = 1.96, 95% CI = 1.67-2.30) were significantly associated with unfavourable outcomes, consistent with the COSMOTB data analysis. Based on subgroup analysis, untreated diabetes at baseline was an independent risk factor for unfavourable outcomes (aOR = 2.72, 95% CI = 1.26-5.61). Prediabetes and uncontrolled diabetes increased unfavourable outcomes and mortality without statistical significance. CONCLUSION: Untreated and complicated diabetes at the time of tuberculosis diagnosis increases the risk of unfavourable outcomes and mortality.

Role of lung ornithine aminotransferase in idiopathic pulmonary fibrosis: regulation of mitochondrial ROS generation and TGF-ß1 activity.

Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant lung remodeling and the excessive accumulation of extracellular matrix (ECM) proteins. In a previous study, we found that the levels of ornithine aminotransferase (OAT), a principal enzyme in the proline metabolism pathway, were increased in the lungs of patients with IPF. However, the precise role played by OAT in the pathogenesis of IPF is not yet clear. The mechanism by which OAT affects fibrogenesis was assessed in vitro using OAT-overexpressing and OAT-knockdown lung fibroblasts. The therapeutic effects of OAT inhibition were assessed in the lungs of bleomycin-treated mice. OAT expression was increased in fibrotic areas, principally in interstitial fibroblasts, of lungs affected by IPF. OAT levels in the bronchoalveolar lavage fluid of IPF patients were inversely correlated with lung function. The survival rate was significantly lower in the group with an OAT level >75.659 ng/mL than in the group with an OAT level ≤75.659 ng/mL (HR, 29.53; p = 0.0008). OAT overexpression and knockdown increased and decreased ECM component production by lung fibroblasts, respectively. OAT knockdown also inhibited transforming growth factor-ß1 (TGF)-ß1 activity and TGF-ß1 pathway signaling. OAT overexpression increased the generation of mitochondrial reactive oxygen species (ROS) by activating proline dehydrogenase. The OAT inhibitor L-canaline significantly attenuated bleomycin-induced lung injury and fibrosis. In conclusion, increased OAT levels in lungs affected by IPF contribute to the progression of fibrosis by promoting excessive mitochondrial ROS production, which in turn activates TGF-ß1 signaling. OAT may be a useful target for treating patients with fibrotic lung diseases, including IPF.

Metabolic Disorders Are Associated With Drug-Induced Liver Injury During Antituberculosis Treatment: A Multicenter Prospective Observational Cohort Study in Korea.

Background: Drug-induced liver injury (DILI) may lead to the discontinuation of antituberculosis (anti-TB) treatment (ATT). Some studies have suggested that metabolic disorders increase the risk of DILI during ATT. This study aimed to identify risk factors for DILI, particularly metabolic disorders, during ATT. Methods: A multicenter prospective observational cohort study to evaluate adverse events during ATT was conducted in Korea from 2019 to 2021. Drug-susceptible patients with TB who had been treated with standard ATT for 6 months were included. The patients were divided into 2 groups depending on the presence of 1 or more metabolic conditions, such as insulin resistance, hypertension, obesity, and dyslipidemia. We monitored ATT-related adverse events, including DILI, and treatment outcomes. The incidence of DILI was compared between individuals with and without metabolic disorders, and related factors were evaluated. Results: Of 684 patients, 52 (7.6%) experienced DILI, and 92.9% of them had metabolic disorders. In the multivariable analyses, underlying metabolic disorders (adjusted hazard ratio [aHR], 2.85; 95% CI, 1.01-8.07) and serum albumin <3.5 g/dL (aHR, 2.26; 95% CI, 1.29-3.96) were risk factors for DILI during ATT. In the 1-month landmark analyses, metabolic disorders were linked to an elevated risk of DILI, especially significant alanine aminotransferase elevation. The treatment outcome was not affected by the presence of metabolic disorders. Conclusions: Patients with metabolic disorders have an increased risk of ATT-induced liver injury compared with controls. The presence of metabolic disorders and hypoalbuminemia adversely affects the liver in patients with ATT.

CD98hc is a target for brain delivery of biotherapeutics.

Brain exposure of systemically administered biotherapeutics is highly restricted by the blood-brain barrier (BBB). Here, we report the engineering and characterization of a BBB transport vehicle targeting the CD98 heavy chain (CD98hc or SLC3A2) of heterodimeric amino acid transporters (TVCD98hc). The pharmacokinetic and biodistribution properties of a CD98hc antibody transport vehicle (ATVCD98hc) are assessed in humanized CD98hc knock-in mice and cynomolgus monkeys. Compared to most existing BBB platforms targeting the transferrin receptor, peripherally administered ATVCD98hc demonstrates differentiated brain delivery with markedly slower and more prolonged kinetic properties. Specific biodistribution profiles within the brain parenchyma can be modulated by introducing Fc mutations on ATVCD98hc that impact FcγR engagement, changing the valency of CD98hc binding, and by altering the extent of target engagement with Fabs. Our study establishes TVCD98hc as a modular brain delivery platform with favorable kinetic, biodistribution, and safety properties distinct from previously reported BBB platforms.

Overexpression of fatty acid synthase attenuates bleomycin induced lung fibrosis by restoring mitochondrial dysfunction in mice.

Proper lipid metabolism is crucial to maintain alveolar epithelial cell (AEC) function, and excessive AEC death plays a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The mRNA expression of fatty acid synthase (FASN), a key enzyme in the production of palmitate and other fatty acids, is downregulated in the lungs of IPF patients. However, the precise role of FASN in IPF and its mechanism of action remain unclear. In this study, we showed that FASN expression is significantly reduced in the lungs of IPF patients and bleomycin (BLM)-treated mice. Overexpression of FASN significantly inhibited BLM-induced AEC death, which was significantly potentiated by FASN knockdown. Moreover, FASN overexpression reduced BLM-induced loss of mitochondrial membrane potential and the production of mitochondrial reactive oxygen species (ROS). Oleic acid, a fatty acid component increased by FASN overexpression, inhibited BLM-induced cell death in primary murine AECs and rescue BLM induced mouse lung injury/fibrosis. FASN transgenic mice exposed to BLM exhibited attenuated lung inflammation and collagen deposition compared to controls. Our findings suggest that defects in FASN production may be associated with the pathogenesis of IPF, especially mitochondrial dysfunction, and augmentation of FASN in the lung may have therapeutic potential in preventing lung fibrosis.

A TREM2-activating antibody with a blood-brain barrier transport vehicle enhances microglial metabolism in Alzheimer's disease models.

Loss-of-function variants of TREM2 are associated with increased risk of Alzheimer's disease (AD), suggesting that activation of this innate immune receptor may be a useful therapeutic strategy. Here we describe a high-affinity human TREM2-activating antibody engineered with a monovalent transferrin receptor (TfR) binding site, termed antibody transport vehicle (ATV), to facilitate blood-brain barrier transcytosis. Upon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced signaling compared to a standard anti-TREM2 antibody. In human induced pluripotent stem cell (iPSC)-derived microglia, ATV:TREM2 induced proliferation and improved mitochondrial metabolism. Single-cell RNA sequencing and morphometry revealed that ATV:TREM2 shifted microglia to metabolically responsive states, which were distinct from those induced by amyloid pathology. In an AD mouse model, ATV:TREM2 boosted brain microglial activity and glucose metabolism. Thus, ATV:TREM2 represents a promising approach to improve microglial function and treat brain hypometabolism found in patients with AD.

The efficacy and safety of DW1601 in patients with acute bronchitis: a multi-center, randomized, double-blind, phase III clinical trial.

BACKGROUND/AIMS: DW1601, an oral fixed dose combination syrup composed of DW16011 and Pelargonium sidoides, was developed to enhance the symptom relief effect in patients with acute bronchitis. We evaluated the efficacy and safety of DW1601 compared to DW16011 or P. sidoides for treatment of acute bronchitis using a randomized, double-blind, placebocontrolled, multi-centre trial design. METHODS: A total of 204 patients with acute bronchitis was randomized 1:1:1 to receive DW1601 (n = 67), DW16011 (n = 70), or P. sidoides (n = 64) for 7 days. The primary outcome was efficacy of DW1601 compared to DW16011 or P. sidoides in reducing the total bronchitis severity score (BSS) at day 4 of treatment. Secondary endpoints were changes in total and symptomspecific BSS, response rate and patient satisfaction rate. Safety analysis was assessed at day 7. RESULTS: At 4 days after medication, decrease of total BSS from baseline was significantly greater in the DW1601 group than in the DW16011 group (-3.51 ± 0.18 vs. -2.65 ± 0.18, p = 0.001) or P. sidoides group (-3.56 ± 0.18 vs. -2.64 ± 0.19, p < 0.001). In addition, the BSS total score at day 7 and the BSS cough and sputum component scores at days 4 and 7 were significantly more improved with DW1601 treatment compared with the DW16011 group or P. sidoides group. Participants treated with DW1601 showed higher rates of response and satisfaction than control groups (response rate, DW1601, 100% vs. DW16011, 85.7% vs. P. sidoides, 85.9%; satisfaction rate, DW1601, 92.6% vs. DW16011, 82.9% vs. P. sidoides, 81.2%). Significant adverse events were not observed in the DW1601 group. CONCLUSION: DW1601 is superior to DW16011 or P. sidoides in improving symptoms of acute bronchitis.

Molecular architecture determines brain delivery of a transferrin receptor-targeted lysosomal enzyme.

Delivery of biotherapeutics across the blood-brain barrier (BBB) is a challenge. Many approaches fuse biotherapeutics to platforms that bind the transferrin receptor (TfR), a brain endothelial cell target, to facilitate receptor-mediated transcytosis across the BBB. Here, we characterized the pharmacological behavior of two distinct TfR-targeted platforms fused to iduronate 2-sulfatase (IDS), a lysosomal enzyme deficient in mucopolysaccharidosis type II (MPS II), and compared the relative brain exposures and functional activities of both approaches in mouse models. IDS fused to a moderate-affinity, monovalent TfR-binding enzyme transport vehicle (ETV:IDS) resulted in widespread brain exposure, internalization by parenchymal cells, and significant substrate reduction in the CNS of an MPS II mouse model. In contrast, IDS fused to a standard high-affinity bivalent antibody (IgG:IDS) resulted in lower brain uptake, limited biodistribution beyond brain endothelial cells, and reduced brain substrate reduction. These results highlight important features likely to impact the clinical development of TfR-targeting platforms in MPS II and potentially other CNS diseases.

Association of the Tight Junction Protein Claudin-4 with Lung Function and Exacerbations in Chronic Obstructive Pulmonary Disease.

PURPOSE: Chronic obstructive pulmonary disease (COPD) imposes a major healthcare burden. A tight junction protein, claudin-4 (CLDN4), may play a protective role in acute lung injury, but its role in COPD is unclear. To investigate the relationship between CLDN4 and COPD, we evaluated the association of CLDN4 with the clinical parameters of COPD, including exacerbations. PATIENTS AND METHODS: We analyzed a cohort of 30 patients with COPD and 25 healthy controls and evaluated their clinical parameters, including lung function. The plasma CLDN4 level in stable and exacerbated COPD was measured. RESULTS: The COPD patients were all males and predominantly smokers; their initial lung function was poorer than the healthy controls. The mean CLDN4 plasma level was 0.0219 ± 0.0205 ng/mg in the control group, 0.0086 ± 0.0158 ng/mg in the stable COPD group (COPD-ST) and 0.0917 ± 0.0871 ng/mg in the exacerbated COPD (COPD-EXA) group. The plasma CLDN4 level was significantly lower in the COPD-ST than the control group, but was significantly elevated in the COPD-EXA group. The plasma CLDN4 level was inversely correlated with forced vital capacity and forced expiratory volume in 1 second in the COPD-EXA group (r=0.506, P=0.001 and r=0.527, P<0.001, respectively). CONCLUSION: The plasma CLDN4 level is closely correlated with COPD exacerbations and decreased lung function. This suggests that CLDN4 has potential as a severity marker for COPD.

Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic.

GRN mutations cause frontotemporal dementia (GRN-FTD) due to deficiency in progranulin (PGRN), a lysosomal and secreted protein with unclear function. Here, we found that Grn-/- mice exhibit a global deficiency in bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid we identified as a pH-dependent PGRN interactor as well as a redox-sensitive enhancer of lysosomal proteolysis and lipolysis. Grn-/- brains also showed an age-dependent, secondary storage of glucocerebrosidase substrate glucosylsphingosine. We investigated a protein replacement strategy by engineering protein transport vehicle (PTV):PGRN-a recombinant protein linking PGRN to a modified Fc domain that binds human transferrin receptor for enhanced CNS biodistribution. PTV:PGRN rescued various Grn-/- phenotypes in primary murine macrophages and human iPSC-derived microglia, including oxidative stress, lysosomal dysfunction, and endomembrane damage. Peripherally delivered PTV:PGRN corrected levels of BMP, glucosylsphingosine, and disease pathology in Grn-/- CNS, including microgliosis, lipofuscinosis, and neuronal damage. PTV:PGRN thus represents a potential biotherapeutic for GRN-FTD.

Clinical impact of forced vital capacity on exercise performance in patients with chronic obstructive pulmonary disease.

BACKGROUND: Forced vital capacity (FVC) has been suggested to be a good biomarker for decreased exercise performance in patients with chronic obstructive pulmonary disease (COPD). However, as FVC is highly correlated with forced expiratory volume in 1 second (FEV1), the relationship between FVC and exercise capacity should be assessed within the category of FEV1, i.e., COPD severity. However, this was not considered in previous studies. Thus, limited data are available on the association between reduced FVC and exercise capacity measured by 6-min walk distance (6MWD) based on COPD severity. METHODS: We performed a cross-sectional study using data from the Korean COPD Subgroup Study (KOCOSS) cohort. We evaluated 1,386 patients with moderate (n=895) and severe-to-very severe (n=491) COPD. Reduced FVC was defined as FVC <80% predicted and short 6MWD as <350 m. Multivariable logistic regression was used to evaluate the association between reduced FVC and short 6MWD. RESULTS: There were no significant differences in respiratory symptoms and quality of life between the patients with reduced FVC and those with preserved FVC. However, patients with reduced FVC had shorter 6MWD (30.5 cm in moderate and 34.5 cm in severe-to-very severe COPD) and higher BODE index scores than those with preserved FVC. The cubic spline model revealed 6MWD peaked around 93% predicted of FVC in moderate COPD, whereas FVC showed a positive association with 6MWD in severe-to-very severe COPD. Multivariable analyses showed that reduced FVC was significantly associated with short 6MWD in both moderate [adjusted odds ratio (aOR) =1.44, 95% confidence interval (CI): 1.03-2.02] and severe-to-very severe (adjusted OR =1.55, 95% CI: 1.01-2.40) COPD. CONCLUSIONS: Reduced FVC was significantly associated with shorter 6MWD in moderate-to-very severe COPD patients, suggesting that reduced FVC might be reflective of 6MWD-measured exercise capacity in moderate-to-very severe COPD.

Impact of capsaicin concentration evoking coughs on clinical variables in patients with asthma.

BACKGROUND: Inhaled capsaicin (8-methyl-N-vanillyl-6-nonenamide) has been used to induce cough in a safe and dose-dependent manner. Chronic cough is associated with an increased sensitivity to inhaled capsaicin in patients with asthma. The aim of this study was to evaluate clinical impact of capsaicin provocation test for chronic cough, and to find relationship between capsaicin concentration producing coughs and clinical variables in patients with asthma. Methods: 385 patients with chronic cough [capsaicin provocation test (+, n = 152)] vs. [capsaicin provocation test (-, n = 233)] who has done with capsaicin provocation test recruited and evaluated by asthma diagnosis and clinical variables. Asthma diagnoses were based on the Global Initiative for Asthma guidelines. Results: Capsaicin positivity was more prevalent in patient with asthma diagnosis than in patients without asthma diagnosis (129/304 vs. 24/81, p = 0.037). Capsaicin positivity was more prevalent in female patients than in male patients (123/271 = 45.4% vs. 30/114 = 26.3%, p = 0.001). Capsaicin concentration producing coughs correlated with smoke amount (r = 0.126, p = 0.014). Capsaicin positivity was more prevalent in nonsmoker patients than in smoker patients (133/295 = 45.1% vs. 20/90 = 22.2%, p = 0.001). Capsaicin concentration producing coughs negatively correlated with methacholine PC20 (4 mg mL-1, p = 0.037), (16 mg mL-1, p = 0.069) and (20 mg mL-1, p = 0.045). Capsaicin concentration producing coughs correlated with BMI (r = 0.120, p = 0.019). Capsaicin concentration producing coughs negatively correlated with FEV1/FVC % pred. (r = -0.137, p = 0.007). There was no relationship between capsaicin concentration producing coughs and age, IgE, and atopy. Conclusions: Capsaicin test for asthma diagnosis should be considered for variable clinical factors. Key message Cough in asthmatic patients is not only common and troublesome but also predicts disease severity and poor prognosis. The capsaicin cough challenge test is a simple and reproducible provocation method for assessing cough susceptibility in patients with cough. Capsaicin test for asthma diagnosis should be considered for variable clinical factors.

Spermidine attenuates bleomycin-induced lung fibrosis by inducing autophagy and inhibiting endoplasmic reticulum stress (ERS)-induced cell death in mice.

Spermidine is an endogenous biological polyamine that plays various longevity-extending roles and exerts antioxidative, antiaging, and cell growth-promoting effects. We previously reported that spermidine levels were significantly reduced in idiopathic pulmonary fibrosis (IPF) of the lung. The present study assessed the potential beneficial effects of spermidine on lung fibrosis and investigated the possible mechanism. Lung fibrosis was established in mice using bleomycin (BLM), and exogenous spermidine was administered daily by intraperitoneal injection (50 mg/kg in phosphate-buffered saline). BLM-induced alveolar epithelial cells showed significant increases in apoptosis and endoplasmic reticulum stress (ERS)-related mediators, and spermidine attenuated BLM-induced apoptosis and activation of the ERS-related pathway. Senescence-associated ß-gal staining and decreased expression of p16 and p21 showed that spermidine ameliorated BLM-induced premature cellular senescence. In addition, spermidine enhanced beclin-1-dependent autophagy and autophagy modulators in IPF fibroblasts and BLM-induced mouse lungs, in which inflammation and collagen deposition were significantly decreased. This beneficial effect was related to the antiapoptotic downregulation of the ERS pathway, antisenescence effects, and autophagy activation. Our findings suggest that spermidine could be a therapeutic agent for IPF treatment.

Brain delivery and activity of a lysosomal enzyme using a blood-brain barrier transport vehicle in mice.

Most lysosomal storage diseases (LSDs) involve progressive central nervous system (CNS) impairment, resulting from deficiency of a lysosomal enzyme. Treatment of neuronopathic LSDs remains a considerable challenge, as approved intravenously administered enzyme therapies are ineffective in modifying CNS disease because they do not effectively cross the blood-brain barrier (BBB). We describe a therapeutic platform for increasing the brain exposure of enzyme replacement therapies. The enzyme transport vehicle (ETV) is a lysosomal enzyme fused to an Fc domain that has been engineered to bind to the transferrin receptor, which facilitates receptor-mediated transcytosis across the BBB. We demonstrate that ETV fusions containing iduronate 2-sulfatase (ETV:IDS), the lysosomal enzyme deficient in mucopolysaccharidosis type II, exhibited high intrinsic activity and degraded accumulated substrates in both IDS-deficient cell and in vivo models. ETV substantially improved brain delivery of IDS in a preclinical model of disease, enabling enhanced cellular distribution to neurons, astrocytes, and microglia throughout the brain. Improved brain exposure for ETV:IDS translated to a reduction in accumulated substrates in these CNS cell types and peripheral tissues and resulted in a complete correction of downstream disease-relevant pathologies in the brain, including secondary accumulation of lysosomal lipids, perturbed gene expression, neuroinflammation, and neuroaxonal damage. These data highlight the therapeutic potential of the ETV platform for LSDs and provide preclinical proof of concept for TV-enabled therapeutics to treat CNS diseases more broadly.

Brain delivery of therapeutic proteins using an Fc fragment blood-brain barrier transport vehicle in mice and monkeys.

Effective delivery of protein therapeutics to the central nervous system (CNS) has been greatly restricted by the blood-brain barrier (BBB). We describe the development of a BBB transport vehicle (TV) comprising an engineered Fc fragment that exploits receptor-mediated transcytosis for CNS delivery of biotherapeutics by binding a highly expressed brain endothelial cell target. TVs were engineered using directed evolution to bind the apical domain of the human transferrin receptor (hTfR) without the use of amino acid insertions, deletions, or unnatural appendages. A crystal structure of the TV-TfR complex revealed the TV binding site to be away from transferrin and FcRn binding sites, which was further confirmed experimentally in vitro and in vivo. Recombinant expression of TVs fused to anti-ß-secretase (BACE1) Fabs yielded antibody transport vehicle (ATV) molecules with native immunoglobulin G (IgG) structure and stability. Peripheral administration of anti-BACE1 ATVs to hTfR-engineered mice and cynomolgus monkeys resulted in substantially improved CNS uptake and sustained pharmacodynamic responses. The TV platform readily accommodates numerous additional configurations, including bispecific antibodies and protein fusions, yielding a highly modular CNS delivery platform.

Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region.

Triggering receptor expressed on myeloid cells 2 (TREM2) is essential for the transition of homeostatic microglia to a disease-associated microglial state. To enhance TREM2 activity, we sought to selectively increase the full-length protein on the cell surface via reducing its proteolytic shedding by A Disintegrin And Metalloproteinase (i.e., α-secretase) 10/17. We screened a panel of monoclonal antibodies against TREM2, with the aim to selectively compete for α-secretase-mediated shedding. Monoclonal antibody 4D9, which has a stalk region epitope close to the cleavage site, demonstrated dual mechanisms of action by stabilizing TREM2 on the cell surface and reducing its shedding, and concomitantly activating phospho-SYK signaling. 4D9 stimulated survival of macrophages and increased microglial uptake of myelin debris and amyloid ß-peptide in vitro. In vivo target engagement was demonstrated in cerebrospinal fluid, where nearly all soluble TREM2 was 4D9-bound. Moreover, in a mouse model for Alzheimer's disease-related pathology, 4D9 reduced amyloidogenesis, enhanced microglial TREM2 expression, and reduced a homeostatic marker, suggesting a protective function by driving microglia toward a disease-associated state.

TREM2 Regulates Microglial Cholesterol Metabolism upon Chronic Phagocytic Challenge.

Loss-of-function (LOF) variants of TREM2, an immune receptor expressed in microglia, increase Alzheimer's disease risk. TREM2 senses lipids and mediates myelin phagocytosis, but its role in microglial lipid metabolism is unknown. Combining chronic demyelination paradigms and cell sorting with RNA sequencing and lipidomics, we find that wild-type microglia acquire a disease-associated transcriptional state, while TREM2-deficient microglia remain largely homeostatic, leading to neuronal damage. TREM2-deficient microglia phagocytose myelin debris but fail to clear myelin cholesterol, resulting in cholesteryl ester (CE) accumulation. CE increase is also observed in APOE-deficient glial cells, reflecting impaired brain cholesterol transport. This finding replicates in myelin-treated TREM2-deficient murine macrophages and human iPSC-derived microglia, where it is rescued by an ACAT1 inhibitor and LXR agonist. Our studies identify TREM2 as a key transcriptional regulator of cholesterol transport and metabolism under conditions of chronic myelin phagocytic activity, as TREM2 LOF causes pathogenic lipid accumulation in microglia.

HL301 in the treatment of acute bronchitis: a phase 2b, randomized, double-blind, placebocontrolled, multicenter study.

BACKGROUND/AIMS: There is insufficient quality data to recommend the use of herbs for the treatment of acute bronchitis. Small number of randomized trials of plant extracts for this purpose were determined to be low quality and there are concerns for the safety. HL301 is a combined product of seven medicinal plants. In the present study, we tried to evaluate the efficacy and safety of HL301 for the treatment of acute bronchitis with a randomized, double-blind, placebo-controlled, multicenter trial design. METHODS: A total of 166 patients with acute bronchitis were randomized to receive placebo or HL301 (600 mg/day) for 7 days. The primary endpoint was change in bronchitis severity score (BSS) from baseline visit (visit 2) to the end of treatment (visit 3). Other efficacy variables were the change of each component of the BSS (cough, sputum, dyspnea, chest pain, and crackle) with treatment, response rate, improvement rate, satisfaction rate and number of rescue medications taken. RESULTS: Changes in the BSS from visit 2 to visit 3 were higher in the HL301 group than in the placebo group both in the full analysis set (4.57 ± 1.82 vs. 3.15 ± 3.08, p < 0.01) and in the per protocol set (4.62 ± 1.81 vs. 3.30 ± 3.03, p < 0.01). Four BSS components (cough, sputum, dyspnea, and chest pain) improved more with HL301 treatment than with placebo treatment. Participants treated with HL301 showed higher response, improvement, and satisfaction rates and less use of rescue medication than the placebo group. CONCLUSION: HL301 (600 mg/day) was effective and safe for symptomatic treatment of acute bronchitis.