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1.
Infect Dis (Lond) ; 55(12): 857-873, 2023 12.
Article in English | MEDLINE | ID: mdl-37729076

ABSTRACT

BACKGROUND: Granulocyte-macrophage colony stimulating factor (GM-CSF) inhalation may alleviate pulmonary inflammation caused by viral pneumonia. To investigate this, we evaluated its efficacy on COVID-19 pneumonia. METHODS: This double-blind, randomised, placebo-controlled study (ClinicalTrials.gov: NCT04642950) evaluated patients in the first half of 2021 at seven Japanese hospitals. Hospitalised patients with COVID-19 pneumonia with moderate hypoxaemia inhaled sargramostim or placebo for 5 days. The primary endpoint was days to achieve a ≥ 2-category improvement from baseline on a modified 7-category ordinal scale. Secondary endpoints included degree of oxygenation, defined by amount of oxygen supply, and serum CCL17 level. RESULTS: Seventy-five patients were randomly assigned in a 2:1 ratio to receive sargramostim or placebo, of which 47 and 23 were analysed, respectively. No difference was observed between groups regarding the primary endpoint (8.0 and 7.0 days for sargramostim and placebo, respectively) or in the secondary endpoints, except for CCL17. A post hoc sub-analysis indicated that endpoint assessments were influenced by concomitant corticosteroid therapy. When the cumulative corticosteroid dose was ≤500 mg during Days 1-5, recovery and oxygenation were faster in the sargramostim group than for placebo. Bolus dose corticosteroids were associated with temporarily impaired oxygenation and delayed clinical recovery. The increase in serum CCL17, a candidate prognostic factor, reflected improvement with sargramostim inhalation. The number of adverse events was similar between groups. Two serious adverse events were observed in the sargramostim group without causal relation. CONCLUSIONS: Inhaled sargramostim was likely to be effective for COVID-19 pneumonia unless the concomitant corticosteroid dose was high.


Subject(s)
COVID-19 , Humans , Granulocyte-Macrophage Colony-Stimulating Factor/adverse effects , Adrenal Cortex Hormones/therapeutic use , Steroids , Double-Blind Method , Treatment Outcome
2.
Int J Urol ; 29(4): 289-296, 2022 04.
Article in English | MEDLINE | ID: mdl-34929761

ABSTRACT

OBJECTIVES: To evaluate the efficacy of intravesical KRP-116D, 50% dimethyl sulfoxide solution, in interstitial cystitis/bladder pain syndrome patients with Hunner lesions (Hunner-type interstitial cystitis), and to evaluate the correlations between efficacy variables and global response assessment to determine what constitutes a minimal clinically important change. METHODS: We performed a post hoc analysis of the Japanese phase III trial of KRP-116D. Changes at Week 12 from baseline in objective and subjective outcomes were compared between the KRP-116D and placebo groups in Hunner-type interstitial cystitis or non-Hunner-type interstitial cystitis patients. Correlations between efficacy variables at Week 12 and global response assessment were analyzed. Area under the receiver operating characteristic curve and the cut-off value of efficacy valuables were calculated to determine clinically meaningful changes. RESULTS: The effectiveness of intravesical treatment with KRP-116D was demonstrated in Hunner-type interstitial cystitis, but not in non-Hunner-type interstitial cystitis patients. Global response assessment was closely correlated with subjective outcomes including O'Leary-Sant Interstitial Cystitis Symptom Index, O'Leary-Sant Interstitial Cystitis Problem Index, and a numeric rating scale for bladder pain, but was less correlated with voiding variables including micturition frequency, voided volume, and maximum voided volume. In the receiver operating characteristic curve analyses, the cut-off value for the O'Leary-Sant Interstitial Cystitis Symptom Index was -5 (sensitivity 81.3%, specificity 83.3%). CONCLUSIONS: Clinical benefit of intravesical KRP-116D in Hunner-type interstitial cystitis patients was confirmed in this post hoc analysis. A five-point reduction in O'Leary-Sant Interstitial Cystitis Symptom Index is a clinically meaningful indicator for assessing patient satisfaction with KRP-116D treatment in patients with Hunner-type interstitial cystitis.


Subject(s)
Cystitis, Interstitial , Administration, Intravesical , Cystitis, Interstitial/diagnosis , Cystitis, Interstitial/drug therapy , Cystitis, Interstitial/pathology , Dimethyl Sulfoxide/therapeutic use , Humans , Japan , Treatment Outcome
3.
Int J Urol ; 28(5): 545-553, 2021 05.
Article in English | MEDLINE | ID: mdl-33580603

ABSTRACT

OBJECTIVE: To evaluate the efficacy and safety of intravesical KRP-116D, 50% dimethyl sulfoxide solution compared with placebo, in interstitial cystitis/bladder pain syndrome patients. METHODS: Japanese interstitial cystitis/bladder pain syndrome patients with an O'Leary-Sant Interstitial Cystitis Symptom Index score of ≥9, who exhibited the bladder-centric phenotype of interstitial cystitis/bladder pain syndrome diagnosed by cystoscopy and bladder-derived pain, were enrolled. Patients were allocated to receive either KRP-116D (n = 49) or placebo (n = 47). The study drug was intravesically administered every 2 weeks for 12 weeks. RESULTS: For the primary endpoint, the change in the mean O'Leary-Sant Interstitial Cystitis Symptom Index score from baseline to week 12 was -5.2 in the KRP-116D group and -3.4 in the placebo group. The estimated difference between the KRP-116D and placebo groups was -1.8 (95% confidence interval -3.3, -0.3; P = 0.0188). Statistically significant improvements for KRP-116D were also observed in the secondary endpoints including O'Leary-Sant Interstitial Cystitis Problem Index score, micturition episodes/24 h, voided volume/micturition, maximum voided volume/micturition, numerical rating scale score for bladder pain, and global response assessment score. The adverse drug reactions were mild to moderate, and manageable. CONCLUSIONS: This first randomized, double-blind, placebo-controlled trial shows that KRP-116D improves symptoms, voiding parameters, and global response assessment, compared with placebo, and has a well-tolerated safety profile in interstitial cystitis/bladder pain syndrome patients with the bladder-centric phenotype.


Subject(s)
Cystitis, Interstitial , Administration, Intravesical , Cystitis, Interstitial/drug therapy , Dimethyl Sulfoxide/therapeutic use , Double-Blind Method , Humans , Japan , Treatment Outcome
4.
Bioorg Med Chem Lett ; 23(19): 5311-6, 2013 Oct 01.
Article in English | MEDLINE | ID: mdl-23988356

ABSTRACT

We previously identified KCA-1490 [(-)-6-(7-methoxy-2-trifluoromethyl-pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone], a dual PDE3/4 inhibitor. In the present study, we found highly potent selective PDE4 inhibitors derived from the structure of KCA-1490. Among them, N-(3,5-dichloropyridin-4-yl)-7-methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridine-4-carboxamide (2a) had good anti-inflammatory effects in an animal model.


Subject(s)
Anti-Inflammatory Agents , Drug Design , Phosphodiesterase 4 Inhibitors , Pyrazoles/chemical synthesis , Pyridines , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Enzyme Activation/drug effects , Inhibitory Concentration 50 , Models, Animal , Molecular Structure , Phosphodiesterase 4 Inhibitors/chemical synthesis , Phosphodiesterase 4 Inhibitors/chemistry , Phosphodiesterase 4 Inhibitors/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/pharmacology , Rats , Structure-Activity Relationship
5.
Bioorg Med Chem Lett ; 23(1): 375-81, 2013 Jan 01.
Article in English | MEDLINE | ID: mdl-23200255

ABSTRACT

(-)-6-(7-Methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (KCA-1490) exhibits moderate dual PDE3/4-inhibitory activity and promises as a combined bronchodilatory/anti-inflammatory agent. N-alkylation of the pyridazinone ring markedly enhances potency against PDE4 but suppresses PDE3 inhibition. Addition of a 6-aryl-4,5-dihydropyridazin-3(2H)-one extension to the N-alkyl group facilitates both enhancement of PDE4-inhibitory activity and restoration of potent PDE3 inhibition. Both dihydropyridazinone rings, in the core and extension, can be replaced by achiral 4,4-dimethylpyrazolone subunits and the core pyrazolopyridine by isosteric bicyclic heteroaromatics. In combination, these modifications afford potent dual PDE3/4 inhibitors that suppress histamine-induced bronchoconstriction in vivo and exhibit promising anti-inflammatory activity via intratracheal administration.


Subject(s)
Anti-Inflammatory Agents/chemistry , Bronchodilator Agents/chemistry , Phosphodiesterase 3 Inhibitors/chemistry , Phosphodiesterase 4 Inhibitors/chemistry , Administration, Inhalation , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Bronchoalveolar Lavage Fluid/cytology , Bronchodilator Agents/chemical synthesis , Bronchodilator Agents/pharmacology , Cyclic Nucleotide Phosphodiesterases, Type 3/chemistry , Cyclic Nucleotide Phosphodiesterases, Type 3/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 4/chemistry , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Drug Design , Leukocytes/drug effects , Phosphodiesterase 3 Inhibitors/chemical synthesis , Phosphodiesterase 3 Inhibitors/pharmacology , Phosphodiesterase 4 Inhibitors/chemical synthesis , Phosphodiesterase 4 Inhibitors/pharmacology , Protein Binding , Pyridazines/chemistry , Pyridines/chemistry , Rats , Structure-Activity Relationship
6.
Bioorg Med Chem Lett ; 22(18): 5833-8, 2012 Sep 15.
Article in English | MEDLINE | ID: mdl-22884989

ABSTRACT

(-)-6-(7-Methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490) is a dual PDE3/4 inhibitor that exhibits potent combined bronchodilatory and anti-inflammatory activity. Here we show that a 4,4-dimethylpyrazolone subunit serves as an effective surrogate for the 5-methyl-4,5-dihydropyridazin-3(2H)-one ring of KCA-1490 whilst lacking a stereogenic centre. The 2- and 7-substituents in the pyrazolo[1,5-a]pyridine subunit markedly influence the PDE-inhibitory profile and can be adjusted to afford either potent PDE4-selective inhibitors or dual PDE3/4 inhibitors. A survey of bicyclic heteroaromatic replacements for the pyrazolo[1,5-a]pyridine allowed further refinement of the inhibitory profile and identified 3-(8-methoxy-2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)-4,4-dimethyl-1H-pyrazol-5(4H)-one as an orally active, achiral KCA-1490 analog with well-balanced dual PDE3/4-inhibitory activity.


Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemistry , Cyclic Nucleotide Phosphodiesterases, Type 3/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Drug Design , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacology , Pyrazolones/chemistry , Pyridazines/pharmacology , Pyridines/pharmacology , Dose-Response Relationship, Drug , Models, Molecular , Molecular Structure , Phosphodiesterase Inhibitors/chemistry , Pyridazines/chemical synthesis , Pyridazines/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Stereoisomerism , Structure-Activity Relationship
7.
Bioorg Med Chem Lett ; 21(18): 5451-6, 2011 Sep 15.
Article in English | MEDLINE | ID: mdl-21764304

ABSTRACT

A structural survey of pyrazolopyridine-pyridazinone phosphodiesterase (PDE) inhibitors was made with a view to optimization of their dual PDE3/4-inhibitory activity for respiratory disease applications. These studies identified (-)-6-(7-methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridine-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490, compound 2ac) as a compound with potent combined bronchodilatory and anti-inflammatory activity and an improved therapeutic window over roflumilast.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Bronchodilator Agents/pharmacology , Drug Design , Phosphodiesterase 3 Inhibitors/pharmacology , Phosphodiesterase 4 Inhibitors/pharmacology , Pyrazoles/pharmacology , Pyridines/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Bronchodilator Agents/chemical synthesis , Bronchodilator Agents/chemistry , Cyclic Nucleotide Phosphodiesterases, Type 3/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Guinea Pigs , Molecular Structure , Phosphodiesterase 3 Inhibitors/chemical synthesis , Phosphodiesterase 3 Inhibitors/chemistry , Phosphodiesterase 4 Inhibitors/chemical synthesis , Phosphodiesterase 4 Inhibitors/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Rats , Stereoisomerism , Structure-Activity Relationship
8.
Biochem Biophys Res Commun ; 326(3): 521-6, 2005 Jan 21.
Article in English | MEDLINE | ID: mdl-15596131

ABSTRACT

Aquaporin-5 (AQP5), a major water channel in lung epithelial cells, plays an important role in maintaining water homeostasis in the lungs. Cell surface expression of AQP5 is regulated by not only mRNA and protein synthesis but also changes in subcellular distribution. We investigated the effect of lipopolysaccharide (LPS) on the subcellular distribution of AQP5 in a mouse lung epithelial cell line (MLE-12). LPS caused significant increases in AQP5 in the plasma membrane at 0.5-2 h. Immunofluorescence and Western blotting strongly suggested that LPS altered AQP5 subcellular distribution from an intracellular vesicular compartment to the plasma membrane. The specific p38 MAP kinase inhibitor SB 203580 apparently prevented LPS-induced changes in AQP5 distribution. Furthermore, LPS increased the osmotic water permeability of MLE-12 cells. These findings demonstrate that LPS increases cell surface AQP5 expression by changing its subcellular distribution and increases membrane osmotic water permeability through activation of p38 MAP kinase.


Subject(s)
Aquaporins/metabolism , Cell Membrane Permeability/drug effects , Cell Membrane/drug effects , Lipopolysaccharides/pharmacology , Membrane Proteins/metabolism , Water/metabolism , Animals , Aquaporin 5 , Dose-Response Relationship, Drug , Epithelium/metabolism , Lung/metabolism , Mice , Microscopy, Confocal
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