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1.
Arch Dermatol Res ; 316(6): 312, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38822924

ABSTRACT

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with high rates of metastasis and mortality. In vitro studies suggest that selinexor (KPT-330), an inhibitor of exportin 1, may be a targeted therapeutic option for MCC. This selective inhibitor prevents the transport of oncogenic mRNA out of the nucleus. Of note, 80% of MCC tumors are integrated with Merkel cell polyomavirus (MCPyV), and virally encoded tumor-antigens, small T (sT) and large T (LT) mRNAs may require an exportin transporter to relocate to the cytoplasm and modulate host tumor-suppressing pathways. To explore selinexor as a targeted therapy for MCC, we examine its ability to inhibit LT and sT antigen expression in vitro and its impact on the prostaglandin synthesis pathway. Protein expression was determined through immunoblotting and quantified by densitometric analysis. Statistical significance was determined with t-test. Treatment of MCPyV-infected cell lines with selinexor resulted in a significant dose-dependent downregulation of key mediators of the prostaglandin synthesis pathway. Given the role of prostaglandin synthesis pathway in MCC, our findings suggest that selinexor, alone or in combination with immunotherapy, could be a promising treatment for MCPyV-infected MCC patients who are resistant to chemotherapy and immunotherapy.


Subject(s)
Carcinoma, Merkel Cell , Hydrazines , Skin Neoplasms , Triazoles , Hydrazines/pharmacology , Hydrazines/therapeutic use , Humans , Carcinoma, Merkel Cell/virology , Carcinoma, Merkel Cell/drug therapy , Carcinoma, Merkel Cell/pathology , Triazoles/pharmacology , Triazoles/therapeutic use , Skin Neoplasms/drug therapy , Skin Neoplasms/virology , Skin Neoplasms/pathology , Cell Line, Tumor , Prostaglandins/metabolism , Merkel cell polyomavirus , Exportin 1 Protein , Karyopherins/metabolism , Karyopherins/antagonists & inhibitors , Antigens, Viral, Tumor , Receptors, Cytoplasmic and Nuclear/metabolism
2.
BMC Neurol ; 24(1): 190, 2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38844862

ABSTRACT

BACKGROUND: Post-stroke depression (PSD) is a significant impediment to successful rehabilitation and recovery after a stroke. Current therapeutic options are limited, leaving an unmet demand for specific and effective therapeutic options. Our objective was to investigate the safety of Maraviroc, a CCR5 antagonist, as a possible mechanism-based add-on therapeutic option for PSD in an open-label proof-of-concept clinical trial. METHODS: We conducted a 10-week clinical trial in which ten patients with subcortical and cortical stroke, suffering from PSD. were administered a daily oral dose of 300 mg Maraviroc. Participants were then monitored for an additional eight weeks. The primary outcome measure was serious treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation. The secondary outcome measure was a change in the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: Maraviroc was well tolerated, with no reports of serious adverse events or discontinuations due to intolerance. The MADRS scores substantially reduced from baseline to week 10 (mean change: -16.4 ± 9.3; p < 0.001). By the conclusion of the treatment phase, a favorable response was observed in five patients, with four achieving remission. The time to response was relatively short, approximately three weeks. After the cessation of treatment, MADRS scores increased at week 18 by 6.1 ± 9.6 points (p = 0.014). CONCLUSIONS: Our proof-of-concept study suggests that a daily dosage of 300 mg of Maraviroc may represent a well-tolerated and potentially effective pharmacological approach to treating PSD. Further comprehensive placebo-controlled studies are needed to assess the impact of Maraviroc augmentation on PSD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05932550, Retrospectively registered: 28/06/2023.


Subject(s)
CCR5 Receptor Antagonists , Maraviroc , Proof of Concept Study , Stroke , Humans , Maraviroc/administration & dosage , Maraviroc/therapeutic use , Male , Female , Middle Aged , CCR5 Receptor Antagonists/therapeutic use , CCR5 Receptor Antagonists/administration & dosage , Stroke/complications , Stroke/psychology , Stroke/drug therapy , Aged , Depression/drug therapy , Depression/etiology , Treatment Outcome , Triazoles/therapeutic use , Triazoles/administration & dosage , Adult , Receptors, CCR5/metabolism
3.
Georgian Med News ; (348): 99-102, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38807401

ABSTRACT

Accumulation of iron in vital organs is increasingly challenging in clinical settings during the lifespan of thalassemia patients. Iron overload hurdle these organs to redox imbalances. Commonly used iron-chelating agents in (deferasirox and, deferoxamine) could have a positive antioxidant role. Therefore, the aim of this study was designed to compare the effects of deferasirox and, deferoxamine, iron-chelating agents in oxidative stress in patients with ß-thalassemic major. In this case series comparative study, 60 known cases of ß-thalassemic patients receiving chelating agents therapy were divided into two groups of thirty, group one consisted of 30 patients 16 male and14 female, who received oral agent deferasirox tablets at dose 20-40mg/kg. Group two consisted of 30 patients, 16 male and 14 female, on intravenous therapy with Deferoxamine at a dose of 20-50mg/kg, Another thirty healthy individuals matched with age and gender, were kept as a control group. Total antioxidant capacity (TAOC) and Malondialdehyde (MDA) were measured in all studied groups. The three groups were similar in terms of age, and gender, A statistically non-significant difference in age (p>0.05) existed between the control and patient groups (10.9±2.93; 11.2±4.1*;11.6±3.6*) respectively. The number of patients in to control group and male-to-female numbers were matched since the ratios were similar. A statistically non-significant difference in BMI (p>0.05) existed between the control and patient groups (17±2, 17.2±2, 18±2.4*) respectively. TAOC is lower in-patient groups, when compared with the control group (27.8 ± 10.7; 32.5 ± 10.2; and 79.5 ± 7 u/ml) respectively, while the MDA value is higher when compared with the control group (7.2±4.6 and, 6.6±4.42; and 0.57±0.26; nmol/ml) respectively. The TAOC in patients group on Deferoxamine, is higher, while MDA is lower than in patients on Defrasirox. The TAOC in patients was reduced and Oxidative stress was enhanced in patients with thalassemia. Deferoxamine is more effective in modulating redox status.


Subject(s)
Benzoates , Deferasirox , Deferoxamine , Iron Chelating Agents , Malondialdehyde , Oxidative Stress , Triazoles , beta-Thalassemia , Humans , Deferasirox/therapeutic use , beta-Thalassemia/drug therapy , beta-Thalassemia/complications , Oxidative Stress/drug effects , Deferoxamine/therapeutic use , Male , Female , Iron Chelating Agents/therapeutic use , Benzoates/therapeutic use , Benzoates/administration & dosage , Triazoles/therapeutic use , Malondialdehyde/blood , Malondialdehyde/metabolism , Adult , Antioxidants/therapeutic use , Adolescent , Young Adult , Iron Overload/drug therapy
4.
J Exp Clin Cancer Res ; 43(1): 148, 2024 May 22.
Article in English | MEDLINE | ID: mdl-38773631

ABSTRACT

BACKGROUND: Primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (cHL) are distinct hematological malignancies of B-cell origin that share many biological, molecular, and clinical characteristics. In particular, the JAK/STAT signaling pathway is a driver of tumor development due to multiple recurrent mutations, particularly in STAT6. Furthermore, the XPO1 gene that encodes exportin 1 (XPO1) shows a frequent point mutation (E571K) resulting in an altered export of hundreds of cargo proteins, which may impact the success of future therapies in PMBL and cHL. Therefore, targeted therapies have been envisioned for these signaling pathways and mutations. METHODS: To identify novel molecular targets that could overcome the treatment resistance that occurs in PMBL and cHL patients, we have explored the efficacy of a first-in-class HSP110 inhibitor (iHSP110-33) alone and in combination with selinexor, a XPO1 specific inhibitor, both in vitro and in vivo. RESULTS: We show that iHSP110-33 decreased the survival of several PMBL and cHL cell lines and the size of tumor xenografts. We demonstrate that HSP110 is a cargo of XPO1wt as well as of XPO1E571K. Using immunoprecipitation, proximity ligation, thermophoresis and kinase assays, we showed that HSP110 directly interacts with STAT6 and favors its phosphorylation. The combination of iHSP110-33 and selinexor induces a synergistic reduction of STAT6 phosphorylation and of lymphoma cell growth in vitro and in vivo. In biopsies from PMBL patients, we show a correlation between HSP110 and STAT6 phosphorylation levels. CONCLUSIONS: These findings suggest that HSP110 could be proposed as a novel target in PMBL and cHL therapy.


Subject(s)
Exportin 1 Protein , Hodgkin Disease , Karyopherins , Receptors, Cytoplasmic and Nuclear , Humans , Karyopherins/antagonists & inhibitors , Karyopherins/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , Animals , Mice , Hodgkin Disease/drug therapy , Hodgkin Disease/pathology , Hodgkin Disease/metabolism , Hodgkin Disease/genetics , Lymphoma, B-Cell/drug therapy , Lymphoma, B-Cell/metabolism , Lymphoma, B-Cell/pathology , Lymphoma, B-Cell/genetics , HSP110 Heat-Shock Proteins/metabolism , HSP110 Heat-Shock Proteins/genetics , Cell Line, Tumor , Mediastinal Neoplasms/drug therapy , Mediastinal Neoplasms/metabolism , Mediastinal Neoplasms/pathology , Mediastinal Neoplasms/genetics , Xenograft Model Antitumor Assays , Triazoles/pharmacology , Triazoles/therapeutic use , Hydrazines/pharmacology , Hydrazines/therapeutic use , Female , STAT6 Transcription Factor/metabolism , Molecular Targeted Therapy
5.
Blood Cells Mol Dis ; 107: 102859, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38820707

ABSTRACT

We conducted a retrospective cohort study on 663 transfusion-dependent ß-thalassemia patients receiving the same iron chelation monotherapy with deferoxamine, deferiprone, or deferasirox for up to 10 years (median age 31.8 years, 49.9 % females). Patients on all three iron chelators had a steady and significant decline in serum ferritin over the 10 years (median deferoxamine: -170.7 ng/mL, P = 0.049, deferiprone: -236.7 ng/mL, P = 0.001; deferasirox: -323.7 ng/mL, P < 0.001) yet had no significant change in liver iron concentration or cardiac T2*; while noting that patients generally had low hepatic and cardiac iron levels at study start. Median absolute, relative, and normalized changes were generally comparable between the three iron chelators. Patients receiving deferasirox had the highest morbidity and mortality-free survival probability among the three chelators, although the difference was only statistically significant when compared with deferoxamine (P = 0.037). On multivariate Cox regression analysis, there was no significant association between iron chelator type and the composite outcome of morbidity or mortality. In a real-world setting, there is comparable long-term iron chelation effectiveness between the three available iron chelators for patients with mild-to-moderate iron overload.


Subject(s)
Blood Transfusion , Deferasirox , Deferiprone , Deferoxamine , Iron Chelating Agents , Iron , Pyridones , beta-Thalassemia , Humans , Iron Chelating Agents/therapeutic use , beta-Thalassemia/mortality , beta-Thalassemia/therapy , beta-Thalassemia/drug therapy , beta-Thalassemia/complications , Female , Male , Adult , Retrospective Studies , Deferoxamine/therapeutic use , Deferiprone/therapeutic use , Iron/metabolism , Deferasirox/therapeutic use , Pyridones/therapeutic use , Iron Overload/etiology , Iron Overload/drug therapy , Benzoates/therapeutic use , Ferritins/blood , Adolescent , Triazoles/therapeutic use , Young Adult , Child , Treatment Outcome , Middle Aged , Liver/metabolism , Liver/drug effects , Liver/pathology , Cohort Studies
6.
J Med Case Rep ; 18(1): 261, 2024 May 27.
Article in English | MEDLINE | ID: mdl-38797854

ABSTRACT

BACKGROUND: All-trans retinoic acid (ATRA) is an indispensable part of the treatment of acute promyelocytic leukemia (APL). Although, mild cutaneous toxicities like mucocutaneous xerosis, rash, and pruritus are well reported, ATRA associated severe dermatological toxicities are extremely rare. ATRA is primary metabolized by cytochrome P450 (CYP450) enzyme system, and triazole antifungals are notorious for their strong inhibitory effect on CYP450. CASE PRESENTATION: Three Asian APL patients experienced rare ATRA-induced severe dermatological toxicities: exfoliative dermatitis (ED) in cases 1 and 2, and necrotic scrotal ulceration in case 3. Both case 1 (33-year-old female), and case 2 (28-year-old male) landed in emergency department with dehydration, generalized skin erythema and xerosis during their induction chemotherapy. Both of these patients also developed invasive aspergillosis and required concomitant triazole antifungals during their chemotherapy. For ED, intravenous fluids and broad-spectrum antibiotics were started along with application of local emollients to prevent transdermal water loss. Although their general condition improved but skin exfoliation continued with complete desquamation of palms and soles. Dermatology was consulted, and clinical diagnosis of ED was established. Discontinuation of ATRA resulted in complete resolution of ED. Case 3 (15-year-old boy) reported two blackish mildly tender scrotal lesions during induction chemotherapy. He also had mucocutaneous candidiasis at presentation and was kept on triazole antifungal. Local bacterial & fungal cultures, and serological testing for herpes simplex virus were reported negative. Despite adequate local care and optimal antibiotic support, his lesions persisted, and improved only after temporary discontinuation of ATRA. After a thorough literature review and considering the temporal association of cutaneous toxicities with triazole antifungals, we speculate that the concomitant use of triazole antifungals inhibited the hepatic metabolism of ATRA, resulting in higher serum ATRA concentration, and markedly accentuated cutaneous toxicities in our patients. CONCLUSION: By highlighting this crucial pharmacokinetic interaction, we want to caution the fellow oncologists to be mindful of the inhibitory effect of triazole antifungals on CYP450. We propose using a non-myelosuppressive combination of ATRA and arsenic trioxide for management of APL hence, obliterating the need of prophylactic antifungals. However, in the event of invasive fungal infection (IFI), we suggest using alternative class of antifungals.


Subject(s)
Antifungal Agents , Leukemia, Promyelocytic, Acute , Tretinoin , Triazoles , Humans , Leukemia, Promyelocytic, Acute/drug therapy , Male , Antifungal Agents/adverse effects , Antifungal Agents/therapeutic use , Female , Tretinoin/adverse effects , Adult , Triazoles/adverse effects , Triazoles/therapeutic use , Antineoplastic Agents/adverse effects , Aspergillosis/drug therapy , Drug Eruptions/etiology
7.
Front Immunol ; 15: 1398927, 2024.
Article in English | MEDLINE | ID: mdl-38799428

ABSTRACT

Selinexor, a selective inhibitor of nuclear export (SINE), is gaining recognition beyond oncology for its potential in anti-inflammatory therapy. This review elucidates Selinexor's dual action, highlighting its anti-tumor efficacy in various cancers including hematologic malignancies and solid tumors, and its promising anti-inflammatory effects. In cancer treatment, Selinexor has demonstrated benefits as monotherapy and in combination with other therapeutics, particularly in drug-resistant cases. Its role in enhancing the effectiveness of bone marrow transplants has also been noted. Importantly, the drug's impact on key inflammatory pathways provides a new avenue for the management of conditions like sepsis, viral infections including COVID-19, and chronic inflammatory diseases such as Duchenne Muscular Dystrophy and Parkinson's Disease. The review emphasizes the criticality of managing Selinexor's side effects through diligent dose optimization and patient monitoring. Given the complexities of its broader applications, extensive research is called upon to validate Selinexor's long-term safety and effectiveness, with a keen focus on its integration into clinical practice for a diverse spectrum of disorders.


Subject(s)
Hydrazines , Triazoles , Humans , Hydrazines/therapeutic use , Triazoles/therapeutic use , Triazoles/pharmacology , Anti-Inflammatory Agents/therapeutic use , Neoplasms/drug therapy , Neoplasms/therapy , Neoplasms/immunology , COVID-19/immunology , SARS-CoV-2 , Antineoplastic Agents/therapeutic use
8.
Clin Exp Rheumatol ; 42(5): 1043-1050, 2024 May.
Article in English | MEDLINE | ID: mdl-38634362

ABSTRACT

OBJECTIVES: The aim of this study was to evaluate the effectiveness and safety profile of filgotinib, a JAK1 preferential inhibitor, in rheumatoid arthritis (RA) patients included in Italian GISEA (Group for the Study of Early Arthritis) registry. METHODS: Data from RA patients treated with filgotinib, recorded in the GISEA registry, were analysed. Disease activity scores and patient-reported outcomes (PROs) were assessed at baseline, as well as during 12-month follow-up. A difficult-to-treat (D2T) RA patient was defined according with EULAR criteria. Retention rate of filgotinib was estimated by the Kaplan-Meier method and factors influencing drug discontinuation were estimated by Cox regression models. RESULTS: 246 RA patients (female 89%, 57.6±12.2 years old) started filgotinib, mostly as second (22%) or further (43.9%) b/tsDMARDs line of treatment. At 3 and 12 months, 18.8% and 27.5% of patients achieved Clinical Diseases Activity Index based remission and 30.1% and 37.7% obtained a visual analogue scale of pain ≤20 (all p<0.01 vs. baseline). Filgotinib survival rate was 84.5% at the 6-month and 75.8% at 12-month follow-up, and was comparable either in monotherapy or combination therapy, and irrespective of glucocorticoid intake. b/tsDMARD naive patients had the lowest hazard ratio (HR) of filgotinib discontinuation (HR 0.29, 95%CI 0.14-0.64), while D2T-RA the highest (HR 1.82, 95%CI 1.01-3.3). Eight patients (3.3%) discontinued filgotinib due to adverse events. CONCLUSIONS: In an Italian real-life setting, filgotinib is confirmed to be safe and with a good effectiveness profile both in monotherapy and without glucocorticoids.


Subject(s)
Antirheumatic Agents , Arthritis, Rheumatoid , Registries , Humans , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/diagnosis , Female , Middle Aged , Male , Aged , Treatment Outcome , Antirheumatic Agents/therapeutic use , Antirheumatic Agents/adverse effects , Adult , Triazoles/therapeutic use , Triazoles/adverse effects , Italy , Remission Induction , Janus Kinase Inhibitors/adverse effects , Janus Kinase Inhibitors/therapeutic use , Pyridines/therapeutic use , Pyridines/adverse effects , Time Factors , Patient Reported Outcome Measures
9.
Antimicrob Agents Chemother ; 68(5): e0154523, 2024 May 02.
Article in English | MEDLINE | ID: mdl-38557112

ABSTRACT

Ibrexafungerp (formerly SCY-078) is the first member of the triterpenoid class that prevents the synthesis of the fungal cell wall polymer ß-(1,3)-D-glucan by inhibiting the enzyme glucan synthase. We evaluated the in vivo efficacy of ibrexafungerp against pulmonary mucormycosis using an established murine model. Neutropenic mice were intratracheally infected with either Rhizopus delemar or Mucor circinelloides. Treatment with placebo (diluent control), ibrexafungerp (30 mg/kg, PO BID), liposomal amphotericin B (LAMB 10 mg/kg IV QD), posaconazole (PSC 30 mg/kg PO QD), or a combination of ibrexafungerp plus LAMB or ibrexafungerp plus PSC began 16 h post-infection and continued for 7 days for ibrexafungerp or PSC and through day 4 for LAMB. Ibrexafungerp was as effective as LAMB or PSC in prolonging median survival (range: 15 days to >21 days) and enhancing overall survival (30%-65%) vs placebo (9 days and 0%; P < 0.001) in mice infected with R. delemar. Furthermore, median survival and overall percent survival resulting from the combination of ibrexafungerp plus LAMB were significantly greater compared to all monotherapies (P ≤ 0.03). Similar survival results were observed in mice infected with M. circinelloides. Monotherapies also reduce the lung and brain fungal burden by ~0.5-1.0log10 conidial equivalents (CE)/g of tissue vs placebo in mice infected with R. delemar (P < 0.05), while a combination of ibrexafungerp plus LAMB lowered the fungal burden by ~0.5-1.5log10 CE/g compared to placebo or any of the monotherapy groups (P < 0.03). These results are promising and warrant continued investigation of ibrexafungerp as a novel treatment option against mucormycosis.


Subject(s)
Amphotericin B , Antifungal Agents , Glycosides , Mucormycosis , Neutropenia , Triterpenes , Animals , Amphotericin B/therapeutic use , Amphotericin B/pharmacology , Mucormycosis/drug therapy , Mice , Antifungal Agents/therapeutic use , Antifungal Agents/pharmacology , Triterpenes/pharmacology , Triterpenes/therapeutic use , Neutropenia/drug therapy , Neutropenia/complications , Disease Models, Animal , Drug Therapy, Combination , Female , Rhizopus/drug effects , Lung Diseases, Fungal/drug therapy , Lung Diseases, Fungal/microbiology , Mucor/drug effects , Triazoles/therapeutic use , Triazoles/pharmacology
10.
Int J Infect Dis ; 144: 107070, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38663477

ABSTRACT

OBJECTIVES: Information is scarce on clinical experiences with non-neutropenic patients with invasive fungal infection (IFI) receiving isavuconazole. We aimed to report the safety and effectiveness of this drug as a first-line treatment or rescue in real life. METHODS: A retrospective, observational multicentric study of non-neutropenic patients who received isavuconazole as an IFI treatment at 12 different university hospitals (January 2018-2022). All patients met criteria for proven, probable or possible IFI according to EORTC-MSG. RESULTS: A total of 238 IFIs were treated with isavuconazole during the study period. Combination therapy was administered in 27.7% of cases. The primary IFI was aspergillosis (217, 91.2%). Other IFIs treated with isavuconazole were candidemia (n = 10), mucormycosis (n = 8), histoplasmosis (n = 2), cryptococcosis (n = 2), and others (n = 4). Median time of isavuconazole treatment was 29 days. Only 5.9% (n = 14) of cases developed toxicity, mainly hepatic-related (10 patients, 4.2%). Nine patients (3.8%) had treatment withdrawn. Successful clinical response at 12 weeks was documented in 50.5% of patients. CONCLUSION: Isavuconazole is an adequate treatment for non-neutropenic patients with IFIs. Toxicity rates were low and its effectiveness was comparable to other antifungal therapies previously reported.


Subject(s)
Antifungal Agents , Invasive Fungal Infections , Nitriles , Pyridines , Triazoles , Humans , Nitriles/therapeutic use , Nitriles/adverse effects , Pyridines/therapeutic use , Pyridines/adverse effects , Retrospective Studies , Antifungal Agents/therapeutic use , Antifungal Agents/adverse effects , Female , Male , Middle Aged , Triazoles/therapeutic use , Triazoles/adverse effects , Aged , Invasive Fungal Infections/drug therapy , Adult , Treatment Outcome , Aged, 80 and over , Aspergillosis/drug therapy , Young Adult
11.
J Antimicrob Chemother ; 79(6): 1203-1217, 2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38629250

ABSTRACT

Systemic antifungal therapy is critical for reducing the mortality from many invasive and chronic fungal infections. Triazole antifungals are the most frequently prescribed antifungals but require attention to dosing and drug interactions. Nearly 600 severe drug-drug interactions and over 1100 moderate interactions requiring dose modifications are described or anticipated with systemic antifungal agents (see https://www.aspergillus.org.uk/antifungal-drug-interactions/). In this article, we address the common and less common, but serious, drug interactions observed in clinical practice with triazole antifungals, including a group of drugs that cannot be prescribed with all or most triazole antifungals (ivabradine, ranolazine, eplerenone, fentanyl, apomorphine, quetiapine, bedaquiline, rifampicin, rifabutin, sirolimus, phenytoin and carbamazepine). We highlight interactions with drugs used in children and new agents introduced for the treatment of haematological malignancies or graft versus host disease (midostaurin, ibrutinib, ruxolitinib and venetoclax). We also summarize the multiple interactions between oral and inhaled corticosteroids and triazole antifungals, and the strategies needed to optimize the therapeutic benefits of triazole antifungal therapy while minimizing potential harm to patients.


Subject(s)
Antifungal Agents , Drug Interactions , Triazoles , Humans , Antifungal Agents/therapeutic use , Antifungal Agents/administration & dosage , Antifungal Agents/pharmacology , Triazoles/therapeutic use , Triazoles/administration & dosage , Mycoses/drug therapy , Adrenal Cortex Hormones/administration & dosage , Adrenal Cortex Hormones/therapeutic use
12.
Med Mycol ; 62(3)2024 Mar 07.
Article in English | MEDLINE | ID: mdl-38444173

ABSTRACT

Limited data on the clinical management of drug-drug interactions between triazoles and Cystic Fibrosis transmembrane conductance regulator (CFTR) modulators are available. We retrospectively evaluated azole target attainment and dose adaptations in patients from two Dutch CF centres concomitantly receiving triazoles and CFTR modulators. In total, 21 patients with 59 triazole trough concentrations were evaluated. Subtherapeutic concentrations were frequently observed, especially for itraconazole and voriconazole. Of the investigated antifungal agents, posaconazole appears the most preferable option. Our results emphasize the importance of adequate management of this interaction and underpin the added value of therapeutic drug monitoring of triazoles in this population.


Fungal infections are serious complications in Cystic Fibrosis (CF) patients. We evaluated patients concomitantly receiving triazoles and CF transmembrane conductance regulator modulators: subtherapeutic triazole exposure was frequently observed. Posaconazole appears the preferable antifungal agent.


Subject(s)
Cystic Fibrosis Transmembrane Conductance Regulator , Cystic Fibrosis , Humans , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Antifungal Agents/pharmacology , Antifungal Agents/therapeutic use , Cystic Fibrosis/drug therapy , Cystic Fibrosis/veterinary , Retrospective Studies , Triazoles/pharmacology , Triazoles/therapeutic use , Mutation
13.
PLoS One ; 19(3): e0299056, 2024.
Article in English | MEDLINE | ID: mdl-38427635

ABSTRACT

OBJECTIVES: This study aims to evaluate the cost-utility and the budgetary impact of isavuconazole compared to voriconazole in patients with suspected invasive aspergillosis (IA) from the perspective of the Brazilian supplementary health system (SHS). METHODS: In this model, a decision tree was developed and included patients with possible IA. Efficacy parameters were extracted from the clinical studies. Drug acquisition, hospitalization costs and adverse events were also collected. Alternative 3- and 10-year time horizon scenarios were used. In addition, deterministic and probabilistic sensitivity analyses were simulated. A budget impact analysis of isavuconazole versus voriconazole was performed, assuming a time horizon of 5 years. In addition, sensitivity analyses were conducted to assess the robustness of the model. Results are reported in Brazilian Real (BRL), year values 2022. RESULTS: The economic analysis of the base case showed that isavuconazole is associated with a saving of 95,174.00 BRL per patient compared to voriconazole. All other simulated scenarios showed that isavuconazole is dominant versus comparators when considering a willingness to pay 40,688.00 BRL/Quality-Adjusted Life Years (QALY). The results were considered robust by the sensitivity analyses. The budget impact analysis showed that the incorporation of isavuconazole generates savings to the SHS, compared to voriconazole, of approximately 20.5 million BRL in the first year. This reaches about 54 million BRL in the fifth incorporation year, considering the market penetration of 20% in the first year, and 50% in the fifth year. CONCLUSION: Compared with voriconazole, isavuconazole is regarded as a dominant treatment strategy for patients with suspected IA and generates savings for the SHS.


Subject(s)
Aspergillosis , Invasive Fungal Infections , Nitriles , Pyridines , Humans , Voriconazole/therapeutic use , Brazil , Triazoles/therapeutic use , Aspergillosis/drug therapy , Invasive Fungal Infections/drug therapy
14.
J Oncol Pharm Pract ; 30(3): 535-546, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38454813

ABSTRACT

OBJECTIVE: Multiple myeloma cells resist standard therapies due to overexpression of the transport protein, exportin 1. Selinexor is a novel drug that targets the Exportin 1 protein in these cells. DATA SOURCE: A comprehensive search was done, and data showing the efficacy and safety of selinexor in relapsed/refractory multiple myeloma was collected using PubMed, Google Scholar, and clincialtrials.gov. DATA SUMMARY: Results from the clinical trials STORM, BOSTON, and STOMP were included. Parts I and II of the STORM trial revealed a progression-free survival (PFS) of 4.7 and 3.7 months, a median duration of response of 6.2 and 4.4 months, and an overall survival of 7.3 and 8.4 months, respectively. BOSTON trial's SVd arm (selinexor, bortezomib, and dexamethasone) had a median follow-up period of 13.2 months and an mPFS of 13.93 months. The Vd arm (bortezomib and dexamethasone) had a median follow-up duration of 16.5 months and an mPFS of 9.46 months. The STOMP trial is still active and has limited data available. The SKd arm (selinexor, carfilzomib, and dexamethasone) reported an overall response rate of 66.7% in patients with triple refractory multiple myeloma, and 82% in patients with high-risk cytogenetics. The SPd arm (selinexor, pomalidomide, and dexamethasone) shows an overall response rate of 54.30% in pomalidomide naïve-nonrefractory, 35.70% in pomalidomide refractory and 60% in those dosed at RP2D. SRd arm (selinexor, lenalidomide, and dexamethasone) shows an overall response rate of 91.7% in lenalidomide naïve and 12.5% in lenalidomide refractory patients. SVd (selinexor, bortezomib, and dexamethasone) arm reported an overall response rate of 63% in all patients while the SDd arm (selinexor, daratumumab, and dexamethasone) showed an overall response rate of 73%. CONCLUSION: To improve the outcome of patients with relapsed/refractory multiple myeloma, it is critical to develop new therapies, assess potential therapeutic synergies, and overcome drug resistance by determining the efficacy of multiple myeloma therapies across multiple disease subgroups.


Subject(s)
Antineoplastic Agents , Hydrazines , Multiple Myeloma , Triazoles , Humans , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bortezomib/therapeutic use , Dexamethasone/therapeutic use , Drug Resistance, Neoplasm , Exportin 1 Protein , Hydrazines/therapeutic use , Karyopherins/antagonists & inhibitors , Multiple Myeloma/drug therapy , Neoplasm Recurrence, Local/drug therapy , Progression-Free Survival , Receptors, Cytoplasmic and Nuclear , Triazoles/therapeutic use , Clinical Trials as Topic
15.
Expert Opin Pharmacother ; 25(4): 421-434, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38503547

ABSTRACT

INTRODUCTION: Selinexor, an XPO1 inhibitor, has emerged as a promising therapeutic option in the challenging landscape of relapsed/refractory multiple myeloma (RRMM). AREAS COVERED: This article provides a review of selinexor, with a focus on available clinical studies involving MM patients and its safety profile. Clinical trials, such as STORM and BOSTON, have demonstrated its efficacy, particularly in combination regimens, showcasing notable overall response rates (ORR) and prolonged median progressionfree survival (mPFS). Selinexor's versatility is evident across various combinations, including carfilzomibdexamethasone (XKd), lenalidomidedexamethasone (XRd), and pomalidomidedexamethasone (XPd), with efficacy observed even in tripleclass refractory and highrisk patient populations. However, challenges, including resistance mechanisms and adverse events, necessitate careful management. Realworld evidence also underscores selinexor's effectiveness in RRMM, though dose adjustments and supportive measures remain crucial. Ongoing trials are exploring selinexor in diverse combinations and settings, including pomalidomidenaïve patients and postautologous stem cell transplant (ASCT) maintenance. EXPERT OPINION: The evolving landscape of selinexor's role in the sequencing of treatment for RRMM, its potential in highrisk patients, including those with extramedullary disease, as revealed in the most recent international meetings, and ongoing investigations signal a dynamic era in myeloma therapeutics. Selinexor emerges as a pivotal component in multidrug strategies and innovative combinations.


Subject(s)
Hydrazines , Multiple Myeloma , Triazoles , Multiple Myeloma/drug therapy , Humans , Hydrazines/therapeutic use , Hydrazines/adverse effects , Triazoles/therapeutic use , Triazoles/adverse effects , Karyopherins/antagonists & inhibitors , Exportin 1 Protein , Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Progression-Free Survival
16.
Aliment Pharmacol Ther ; 59(11): 1413-1424, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38494867

ABSTRACT

BACKGROUND AND AIMS: While filgotinib, an oral Janus kinase (JAK) 1 preferential inhibitor, is approved for moderately to severely active ulcerative colitis (UC), real-world studies assessing its short- and long-term efficacy and safety are limited. METHODS: This is a multicenter, retrospective study of UC patients who started filgotinib between March 2022 and September 2023. The primary outcome was clinical remission, defined as a partial Mayo score ≤1 with a rectal bleeding score of 0, or Simple Clinical Colitis Activity Index (SCCAI) ≤2 with a blood-in-stool score of 0. Secondary outcomes included clinical response, corticosteroid-free remission, and endoscopic improvement. Outcomes were assessed at 10, 26, and 58 weeks based on patients with available follow-up. Adverse events were evaluated. RESULTS: We identified 238 UC patients and 54% had prior exposure to biologics/JAK inhibitors. The median baseline partial Mayo score and SCCAI were 5 (IQR 3-6) and 4 (IQR 2-7). Clinical remission rates based on per-protocol analysis at 10, 26, and 58 weeks were 47% (70/149), 55.8% (48/86), and 64.6% (31/48), respectively. At a median follow-up of 28 weeks (IQR 10-54) with a discontinuation rate of 39%, the rates of clinical remission, clinical response, corticosteroid-free remission, and endoscopic improvement were 39.9% (81/203), 54.7% (111/203), and 36.5% (74/203), and 43.5% (10/23), respectively. These rates were comparable between biologic/JAK inhibitor-naïve and -experienced patients. While three patients (1.3%) developed herpes zoster infection, no cases of thrombosis or death were reported. CONCLUSIONS: Real-world data demonstrate favourable clinical and safety outcomes of filgotinib for UC.


Subject(s)
Colitis, Ulcerative , Humans , Colitis, Ulcerative/drug therapy , Male , Retrospective Studies , Female , Adult , Middle Aged , Japan , Treatment Outcome , Triazoles/therapeutic use , Triazoles/adverse effects , Pyridines/therapeutic use , Pyridines/adverse effects , Remission Induction , Janus Kinase Inhibitors/therapeutic use , Janus Kinase Inhibitors/adverse effects , Severity of Illness Index , Aged
17.
Vet Rec ; 194(9): e3955, 2024 05 04.
Article in English | MEDLINE | ID: mdl-38462781

ABSTRACT

BACKGROUND: A single-dose, in-clinic, veterinary professional-administered treatment for canine otitis externa was developed to improve compliance and canine welfare. METHODS: This multicentre, controlled, examiner-masked, randomised field trial was conducted in 316 dogs over 42 days. Dogs were treated once, on day 0, with the investigational product containing gentamicin, posaconazole and mometasone furoate (Mometamax Ultra [MU]) or twice (days 0 and 7) with a control product containing florfenicol, terbinafine and betamethasone acetate (CP). The primary endpoint was a composite otitis index score of 4 or less (of 12) on day 14 and 3 or less (of 12) on day 28. RESULTS: On day 28, treatment success was recorded in 128 of 143 MU-treated dogs (89.5%), significantly non-inferior to 116 of 133 (87.2%) CP-treated dogs (Farrington-Manning test, Z = 4.1351, p < 0.0001). For mixed cultures of Staphylococcus pseudintermedius and Malassezia pachydermatis, there was 100% treatment success in MU-treated dogs (n = 33), significantly non-inferior to 90.2% (37 of 41) in CP-treated dogs (Farrington-Manning test, Z = 3.1954, p = 0.0007). LIMITATIONS: Efficacy in chronic otitis externa cases was not investigated. Cytology was not used to aid in diagnosis or for identification of secondary pathogens. CONCLUSION: This unique combination, single-dose product is safe and effective in dogs with otitis externa. It offers enhanced compliance, canine welfare and quality of life by eliminating the owner burden of treating this painful condition.


Subject(s)
Dog Diseases , Gentamicins , Mometasone Furoate , Otitis Externa , Triazoles , Animals , Dogs , Dog Diseases/drug therapy , Otitis Externa/veterinary , Otitis Externa/drug therapy , Otitis Externa/microbiology , Mometasone Furoate/therapeutic use , Mometasone Furoate/administration & dosage , Treatment Outcome , Female , Male , Triazoles/therapeutic use , Triazoles/administration & dosage , Gentamicins/therapeutic use , Gentamicins/administration & dosage , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/administration & dosage , Drug Therapy, Combination/veterinary , Antifungal Agents/therapeutic use , Antifungal Agents/administration & dosage , Suspensions
18.
Bioorg Chem ; 146: 107288, 2024 May.
Article in English | MEDLINE | ID: mdl-38521013

ABSTRACT

Nitroimidazole compounds are well-known bioactive substances, and the structural activity relationship has been reported whereby the position of the nitro group within the imidazole ring has a large influence on the activity. This study focuses on synthesising new trypanocidal agents from the hybridisation of metronidazole with different natural phenols (eugenol, dihydroeugenol and guaiacol). Two different coupling methodologies have been explored in order to analyse the influence of the connector on bioactivity: i) classic direct esterification (AD compounds) and ii) "click" chemistry using a triazole connector (AC compounds). The in vitro trypanocidal tests show good results for both AC and AD hybrid compounds against both epimastigote and trypomastigote forms of T. cruzi. In silico studies showed positive data for most of the synthesised compounds and, in general present low toxicological risks. The AC compounds present lower ClogP (lipophilicity) values than those found for the AD series and higher TPSA (topological polar surface area) values, suggesting lower lipophilicity may be related to the presence of the triazole connector. The AD series compounds have higher Drug Score values than the AC series derivatives, suggesting better general properties for a pharmacological action.


Subject(s)
Chagas Disease , Trypanocidal Agents , Trypanosoma cruzi , Humans , Chagas Disease/drug therapy , Eugenol , Metronidazole/pharmacology , Metronidazole/therapeutic use , Structure-Activity Relationship , Triazoles/therapeutic use , Trypanocidal Agents/chemistry , Guaiacol/chemical synthesis , Guaiacol/chemistry , Guaiacol/pharmacology
19.
Adv Sci (Weinh) ; 11(16): e2308637, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38417121

ABSTRACT

One major obstacle in the drug treatment of pancreatic ductal adenocarcinoma (PDAC) is its highly fibrotic tumor microenvironment, which is replete with activated pancreatic stellate cells (a-PSCs). These a-PSCs generate abundant extracellular matrix and secrete various cytokines to form biophysical and biochemical barriers, impeding drug access to tumor tissues. Therefore, it is imperative to develop a strategy for reversing PSC activation and thereby removing the barriers to facilitate PDAC drug treatment. Herein, by integrating chromatin immunoprecipitation (ChIP)-seq, Assays for Transposase-Accessible Chromatin (ATAC)-seq, and RNA-seq techniques, this work reveals that super-enhancers (SEs) promote the expression of various genes involved in PSC activation. Disruption of SE-associated transcription with JQ1 reverses the activated phenotype of a-PSCs and decreases stromal fibrosis in both orthotopic and patient-derived xenograft (PDX) models. More importantly, disruption of SEs by JQ1 treatments promotes vascularization, facilitates drug delivery, and alters the immune landscape in PDAC, thereby improving the efficacies of both chemotherapy (with gemcitabine) and immunotherapy (with IL-12). In summary, this study not only elucidates the contribution of SEs of a-PSCs in shaping the PDAC tumor microenvironment but also highlights that targeting SEs in a-PSCs may become a gate-opening strategy that benefits PDAC drug therapy by removing stromal barriers.


Subject(s)
Carcinoma, Pancreatic Ductal , Immunotherapy , Pancreatic Neoplasms , Pancreatic Stellate Cells , Tumor Microenvironment , Pancreatic Stellate Cells/drug effects , Pancreatic Stellate Cells/metabolism , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/therapy , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/immunology , Humans , Animals , Mice , Immunotherapy/methods , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunology , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/therapy , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/immunology , Disease Models, Animal , Gemcitabine , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Deoxycytidine/therapeutic use , Azepines/pharmacology , Azepines/therapeutic use , Cell Line, Tumor , Triazoles/pharmacology , Triazoles/therapeutic use
20.
Molecules ; 29(4)2024 Feb 13.
Article in English | MEDLINE | ID: mdl-38398589

ABSTRACT

In this study, 14 structurally novel gefitinib-1,2,3-triazole derivatives were synthesized using a click chemistry approach and characterized by 1H NMR, 13C NMR and high-resolution mass spectrometry (HRMS). Preliminary cell counting kit-8 results showed that most of the compounds exhibit excellent antitumor activity against epidermal growth factor receptor wild-type lung cancer cells NCI-H1299, A549 and NCI-H1437. Among them, 4b and 4c showed the most prominent inhibitory effects. The half maximal inhibitory concentration (IC50) values of 4b were 4.42 ± 0.24 µM (NCI-H1299), 3.94 ± 0.01 µM (A549) and 1.56 ± 0.06 µM (NCI-1437). The IC50 values of 4c were 4.60 ± 0.18 µM (NCI-H1299), 4.00 ± 0.08 µM (A549) and 3.51 ± 0.05 µM (NCI-H1437). Furthermore, our results showed that 4b and 4c could effectively inhibit proliferation, colony formation and cell migration in a concentration-dependent manner, as well as induce apoptosis in H1299 cells. In addition, 4b and 4c exerted its anti-tumor effects by inducing cell apoptosis, upregulating the expression of cleaved-caspase 3 and cleaved-PARP and downregulating the protein levels of Bcl-2. Based on these results, it is suggested that 4b and 4c be developed as potential new drugs for lung cancer treatment.


Subject(s)
Antineoplastic Agents , Lung Neoplasms , Humans , Gefitinib/pharmacology , Cell Proliferation , Cell Line, Tumor , Lung Neoplasms/drug therapy , Apoptosis , Triazoles/pharmacology , Triazoles/therapeutic use , Antineoplastic Agents/chemistry , Drug Screening Assays, Antitumor , Structure-Activity Relationship
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