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Journal of Clinical Immunology Nov 2023Stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI) is a very rare autoinflammatory disease related to STING1 mutation. SAVI is...
Stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI) is a very rare autoinflammatory disease related to STING1 mutation. SAVI is mainly characterized by fever attacks and skin and respiratory manifestations such as interstitial lung disease or alveolar hemorrhage. Respiratory involvement occurs in 80% of cases and might progress to severe lung fibrosis and require lung transplantation (LT). Three patients with SAVI who underwent LT have been reported to date. Two of the three patients died months or years after LT due to multiple organ failure or sepsis. However, the diagnosis of SAVI was made after LT, thus preventing the use of targeted therapy, such as the Janus kinase 1 and 2 inhibitor (JAK1/2i) ruxolitinib, which might be beneficial for the respiratory status of these patients. We aimed to report our experience in managing three patients who were followed in three large lung transplantation centers in France and who benefited from ruxolitinib before undergoing LT. We describe posttransplant complications that occurred as well as outcomes.
Topics: Humans; Janus Kinase Inhibitors; Lung Transplantation; Syndrome; Pyrazoles; Rare Diseases
PubMed: 37814086
DOI: 10.1007/s10875-023-01595-4 -
Pest Management Science Dec 2023Fertilizers and pesticides are commonly used simultaneously in agriculture. However, the effects of common fertilizers on the dissipation, enantioselectivity, and...
BACKGROUND
Fertilizers and pesticides are commonly used simultaneously in agriculture. However, the effects of common fertilizers on the dissipation, enantioselectivity, and metabolites of the chiral insecticide fipronil in soil are yet to be reported.
RESULT
An enantioselective method for detecting fipronil enantiomers and their metabolites in different soil matrices was developed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The results showed that organic and compound fertilizers significantly decreased the degradation of S- and R-fipronil, whereas phosphate and microbial fertilizers slightly reduced fipronil dissipation. The half-life values for S- and R-fipronil were 43.3 and 28.9 days, 99.0 and 63.0 days, 69.3 and 43.3 days, 46.2 and 30.1 days, and 43.3 and 31.5 days, respectively, in the control and the four fertilizer treatments, respectively. The enantioselectivity of fipronil enantiomers occurred and R-fipronil exhibited preferential degradation with an enantiomeric fraction (EF) of 0.4900-0.6238 in all treatments; but the four tested fertilizers decreased enantioselectivity with EF values changed from 0.4970 to 0.6238 in the control to 0.4900-0.6171 in fertilizer treatments. Two metabolites, fipronil sulfone and sulfide, were produced, and their amounts increased with culture time in all treatments. Fertilization reduced the content of fipronil sulfide and sulfone but hardly reduced the total amount of fipronil and its metabolites.
CONCLUSION
Fertilizers affect the environmental behavior of fipronil in the soil. Fertilization alters the soil bacterial community, which may be an important factor. This influence is relatively complicated and should be comprehensively considered in the environmental risk assessment of pesticides. © 2023 Society of Chemical Industry.
Topics: Soil; Fertilizers; Chromatography, Liquid; Tandem Mass Spectrometry; Pesticides; Sulfides; Fertilization; Pyrazoles
PubMed: 37615248
DOI: 10.1002/ps.7737 -
Anti-inflammatory & Anti-allergy Agents... 2024Pyrazole is a well-known nucleus in the pharmacy field with a wide range of other activities in addition to anti-inflammatory and analgesic, i.e., anticonvulsant,...
BACKGROUND
Pyrazole is a well-known nucleus in the pharmacy field with a wide range of other activities in addition to anti-inflammatory and analgesic, i.e., anticonvulsant, antiviral, and anticancer activities. There are well-known marketed drugs having pyrazole moiety as celecoxib, and lonazolac as COX-II inhibitors.
AIMS
We aim to synthesize better anti-inflammatory than existing ones. Thiophene is also known for its analgesic and anti-inflammatory action. Thus, the fusion of both gives better anti-inflammatory agents. In the present studies, derivatives from two series of pyrazole were prepared by reacting substituted chalcone (3a-3f) derivatives prepared from 2-acetyl thiophene. They substituted aromatic aldehydes with phenyl hydrazine to form (5a-5f) and with 2, 4-dinitro phenyl hydrazine giving compounds (6a-6f) separately.
METHODS
Purified and characterized pyrazoles have been analyzed for analgesic and anti-inflammatory activities by using standard methods. Compounds 5e, 5f, and 6d were proved to be potent analgesics and series (5a-5f) was found to have anti-inflammatory action, which was further validated using docking and ADME studies.
RESULTS
The ADME profile of synthesized compounds was found to be satisfactory.
CONCLUSION
The synthesized compounds can serve as lead for further drug designing.
Topics: Pyrazoles; Animals; Analgesics; Molecular Docking Simulation; Anti-Inflammatory Agents; Male; Mice; Structure-Activity Relationship; Edema; Humans; Rats; Pain; Rats, Wistar
PubMed: 38828869
DOI: 10.2174/0118715230275741231207115011 -
Annals of Medicine Dec 2023The therapeutic options for thrombocytopenia in non-severe aplastic anaemia (NSAA) are limited. Avatrombopag (AVA) is prescribed for thrombocytopenic diseases but not... (Clinical Trial)
Clinical Trial
INTRODUCTION
The therapeutic options for thrombocytopenia in non-severe aplastic anaemia (NSAA) are limited. Avatrombopag (AVA) is prescribed for thrombocytopenic diseases but not for NSAA.
METHODS
Herein, we conducted a phase 2, non-randomized, single-arm trial to explore the efficacy and safety of AVA in refractory/relapsed/intolerant NSAA. AVA dose was initiated at 20 mg/d and titrated to a maximum of 60 mg/d. The primary endpoint was the haematological response at 3 months.
RESULTS
Twenty-five patients were analyzed. The overall response rate (ORR) at 3 months was 56% (14/25), with 12% (3/25) achieving a complete response (CR). At a median follow-up of 7 (3-10) months, the OR and CR rates were 52% and 20%, respectively. Responders had a shorter duration of diagnosis of AVA administration than non-responders (10 (6-80) 37 (6-480) months, = 0.027) and belonged to the relapsed/intolerant NSAA type (71% 27%, = 0.047); 44% (8/18) patients previously treated with eltrombopag before enrollment responded at 3 months, with an average prior eltrombopag dose of median 72.5 (50-100) mg/d and an average AVA dose for a response of median 43.5 (20-60) mg/d. 3-month ORR had no significant correlation with eltrombopag exposure ( = 0.09), prior eltrombopag length (=0.11), or cumulative eltrombopag dose (=0.30). Only one patient relapsed after stopping AVA for 1 month. No serious AVA-related side effects or clone evolution were detected.
CONCLUSION
AVA is effective and well-tolerated in NSAA patients who are refractory, relapsed, or intolerant to CsA/tacrolimus ± eltrombopag. Earlier treatment and relapsed/intolerant AA may show a better short-term response rate. More studies are needed to define the optimal dose and the long-term efficacy (NCT04728789).
Topics: Humans; Anemia, Aplastic; Receptors, Thrombopoietin; Pyrazoles
PubMed: 37318085
DOI: 10.1080/07853890.2023.2224044 -
European Journal of Medicinal Chemistry Sep 2023Chemotherapeutics occupy a pivotal role in the medication of different types of cancers, but the prevalence and mortality rates of cancer remain high. The drug... (Review)
Review
Chemotherapeutics occupy a pivotal role in the medication of different types of cancers, but the prevalence and mortality rates of cancer remain high. The drug resistance and low specificity of current available chemotherapeutics are the main barriers for the effective cancer chemotherapy, evoking an immediate need for the development of novel anticancer agents. Pyrazole is a highly versatile five-membered heterocycle with two adjacent nitrogen atoms and possesses remarkable therapeutic effects and robust pharmacological potency. The pyrazole derivatives especially pyrazole hybrids have demonstrated potent in vitro and in vivo efficacies against cancers through multiple mechanisms, inclusive of apoptosis induction, autophagy regulation, and cell cycle disruption. Moreover, several pyrazole hybrids such as crizotanib (pyrazole-pyridine hybrid), erdafitinib (pyrazole-quinoxaline hybrid) and ruxolitinib (pyrazole-pyrrolo [2,3-d]pyrimidine hybrid) have already been approved for the cancer therapy, revealing that pyrazole hybrids are useful scaffolds to develop novel anticancer agents. The purpose of this review is to summarize the current scenario of pyrazole hybrids with potential in vivo anticancer efficacy along with mechanisms of action, toxicity, and pharmacokinetics, covering papers published in recent 5 years (2018-present), to facilitate further rational exploitation of more effective candidates.
Topics: Humans; Structure-Activity Relationship; Neoplasms; Antineoplastic Agents; Pyrazoles; Azoles
PubMed: 37209450
DOI: 10.1016/j.ejmech.2023.115495 -
Acta Physiologica (Oxford, England) May 2024Mechanical ventilation (MV) results in diminished diaphragm size and strength, termed ventilator-induced diaphragm dysfunction (VIDD). VID increases dependence, prolongs...
AIM
Mechanical ventilation (MV) results in diminished diaphragm size and strength, termed ventilator-induced diaphragm dysfunction (VIDD). VID increases dependence, prolongs weaning, and increases discharge mortality rates. The Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway is implicated in VIDD, upregulated following MV. JAK/STAT inhibition alleviates chronic muscle wasting conditions. This study aimed to explore the therapeutic potential of Ruxolitinib, an FDA approved JAK1/2 inhibitor (JI) for the treatment of VIDD.
METHODS
Rats were subjected to 5 days controlled MV (CMV) with and without daily Ruxolitinib gavage. Muscle fiber size and function were assessed. RNAseq, mitochondrial morphology, respirometry, and mass spectrometry were determined.
RESULTS
CMV significantly reduced diaphragm size and specific force by 45% (p < 0.01), associated with a two-fold P-STAT3 upregulation (p < 0.001). CMV disrupted mitochondrial content and reduced the oxygen consumption rate (p < 0.01). Expression of the motor protein myosin was unaffected, however CMV alters myosin function via post-translational modifications (PTMs). Daily administration of JI increased animal survival (40% vs. 87%; p < 0.05), restricted P-STAT3 (p < 0.001), and preserved diaphragm size and specific force. JI was associated with preserved mitochondrial content and respiratory function (p < 0.01), and the reversal or augmentation of myosin deamidation PTMs of the rod and head region.
CONCLUSION
JI preserved diaphragm function, leading to increased survival in an experimental model of VIDD. Functional enhancement was associated with maintenance of mitochondrial content and respiration and the reversal of ventilator-induced PTMs of myosin. These results demonstrate the potential of repurposing Ruxolitinib for treatment of VIDD.
Topics: Animals; Diaphragm; Pyrimidines; Nitriles; Rats; Respiration, Artificial; Male; Pyrazoles; Rats, Sprague-Dawley
PubMed: 38551103
DOI: 10.1111/apha.14128 -
Journal of the American Chemical Society May 2024We describe the synthesis and biological testing of ruthenium-bipyridine ruxolitinib (RuBiRuxo), a photoreleasable form of ruxolitinib, a JAK inhibitor used as an...
We describe the synthesis and biological testing of ruthenium-bipyridine ruxolitinib (RuBiRuxo), a photoreleasable form of ruxolitinib, a JAK inhibitor used as an antitumoral agent in cutaneous T-cell lymphomas (CTCL). This novel caged compound is synthesized efficiently, is stable in aqueous solution at room temperature, and is photoreleased rapidly by visible light. Irradiation of RuBiRuxo reduces cell proliferation and induces apoptosis in a light- and time-dependent manner in a CTCL cell line. This effect is specific and is mediated by a decreased phosphorylation of STAT proteins. Our results demonstrate the potential of ruthenium-based photocompounds and light-based therapeutic approaches for the potential treatment of cutaneous lymphomas and other pathologies.
Topics: Humans; Antineoplastic Agents; Cell Proliferation; Nitriles; Pyrimidines; Apoptosis; Pyrazoles; Cell Line, Tumor; Janus Kinase Inhibitors; Ruthenium; Light; Molecular Structure; Janus Kinases
PubMed: 38700457
DOI: 10.1021/jacs.4c01720 -
Drugs May 2024Topical ruxolitinib 1.5% cream (Opzelura), a Janus kinase (JAK) inhibitor, is the first treatment to be approved in several countries for use in patients aged... (Review)
Review
Topical ruxolitinib 1.5% cream (Opzelura), a Janus kinase (JAK) inhibitor, is the first treatment to be approved in several countries for use in patients aged ≥ 12 years with non-segmental vitiligo. In the identical phase III TRuE-V1 and TRuE-V2 trials, significantly more ruxolitinib cream recipients were able to achieve statistically significant and clinically meaningful facial and total body repigmentation, as well as reductions in vitiligo noticeability, compared with vehicle recipients. Efficacy was sustained in longer-term analyses to week 104 of treatment. Ruxolitinib 1.5% cream was generally tolerable in these trials; the most common treatment-related adverse events were acne, pruritus and exfoliation, all at the application site. As with orally administered JAK inhibitors, topical ruxolitinib carries boxed warnings in the USA for serious infections, mortality, malignancy, major adverse cardiovascular events (MACE) and thrombosis, although the incidences were low with topical application. Thus, topical ruxolitinib 1.5% cream is an effective and generally tolerable treatment option for patients aged ≥ 12 years with non-segmental vitiligo.
Topics: Nitriles; Humans; Pyrimidines; Vitiligo; Pyrazoles; Skin Cream; Janus Kinase Inhibitors; Child; Administration, Topical
PubMed: 38625661
DOI: 10.1007/s40265-024-02027-2 -
The Lancet. Rheumatology Nov 2023The phase 2b Riociguat Safety and Efficacy in Patients with Diffuse Cutaneous Systemic Sclerosis (RISE-SSc) trial investigated riociguat versus placebo in early diffuse... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The phase 2b Riociguat Safety and Efficacy in Patients with Diffuse Cutaneous Systemic Sclerosis (RISE-SSc) trial investigated riociguat versus placebo in early diffuse cutaneous systemic sclerosis. The long-term extension evaluated safety and exploratory treatment effects for an additional year.
METHODS
Patients were enrolled to RISE-SSc between Jan 15, 2015, and Dec 8, 2016. Those who completed the 52-week, randomised, parallel-group, placebo-controlled, double-blind phase were eligible for the long-term extension. Patients originally assigned to riociguat continued therapy (riociguat-riociguat group). Those originally assigned to placebo were switched to riociguat (placebo-riociguat group), adjusted up to 2·5 mg three times daily in a 10-week, double-blind dose-adjustment phase, followed by an open-label phase. Statistical analyses were descriptive. Safety including adverse events and serious adverse events was assessed in the long-term safety analysis set (all patients randomly assigned and treated with study medication in the double-blind phase who continued study medication in the long-term extension). The RISE-SSc trial is registered with ClinicalTrials.gov, NCT02283762.
FINDINGS
In total, 87 (72%) of 121 patients in the main RISE-SSc study entered the long-term extension (riociguat-riociguat, n=42; placebo-riociguat, n=45). 65 (75%) of 87 patients were women, 22 (25%) were men, and 62 (71%) were White. Overall, 82 (94%) of 87 patients in the long-term extension had an adverse event; most (66 [76%] of 87) were of mild to moderate severity, with no increase in pulmonary-related serious adverse events in patients with interstitial lung disease.
INTERPRETATION
No new safety signals were observed with long-term riociguat in patients with early diffuse cutaneous systemic sclerosis. Study limitations include the absence of a comparator group in this open-label extension study.
FUNDING
Bayer and Merck Sharp & Dohme.
Topics: Female; Humans; Male; Patients; Pyrazoles; Pyrimidines; Research Design; Scleroderma, Diffuse
PubMed: 38251533
DOI: 10.1016/S2665-9913(23)00238-2 -
The American Journal of Psychiatry Sep 2023
Topics: Humans; Depression; Pregnanes; Pyrazoles
PubMed: 37654113
DOI: 10.1176/appi.ajp.20230537