-
Cancer Research Sep 2023Nanoparticles (NP) spanning diverse materials and properties have the potential to encapsulate and to protect a wide range of therapeutic cargos to increase...
UNLABELLED
Nanoparticles (NP) spanning diverse materials and properties have the potential to encapsulate and to protect a wide range of therapeutic cargos to increase bioavailability, to prevent undesired degradation, and to mitigate toxicity. Fulvestrant, a selective estrogen receptor degrader, is commonly used for treating patients with estrogen receptor (ER)-positive breast cancer, but its broad and continual application is limited by poor solubility, invasive muscle administration, and drug resistance. Here, we developed an active targeting motif-modified, intravenously injectable, hydrophilic NP that encapsulates fulvestrant to facilitate its delivery via the bloodstream to tumors, improving bioavailability and systemic tolerability. In addition, the NP was coloaded with abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), to prevent the development of drug resistance associated with long-term fulvestrant treatment. Targeting peptide modifications on the NP surface assisted in the site-specific release of the drugs to ensure specific toxicity in the tumor tissues and to spare normal tissue. The NP formulation (PPFA-cRGD) exhibited efficient tumor cell killing in both in vitro organoid models and in vivo orthotopic ER-positive breast cancer models without apparent adverse effects, as verified in mouse and Bama miniature pig models. This NP-based therapeutic provides an opportunity for continual and extensive clinical application of fulvestrant, thus indicating its promise as a treatment option for patients with ER-positive breast cancer.
SIGNIFICANCE
A smart nanomedicine encapsulating fulvestrant to improve its half-life, bioavailability, and tumor-targeting and coloaded with CDK4/6 inhibitor abemaciclib to block resistance is a safe and effective therapy for ER-positive breast cancer.
Topics: Animals; Mice; Swine; Fulvestrant; Receptors, Estrogen; Aminopyridines; Neoplasms; Drug Resistance, Neoplasm; Cell Line, Tumor
PubMed: 37326467
DOI: 10.1158/0008-5472.CAN-22-3559 -
The Annals of Pharmacotherapy Aug 2023This article reviews clinical trials to assess the efficacy, safety, and clinical application of once-daily roflumilast 0.3% cream for the treatment of plaque psoriasis. (Review)
Review
OBJECTIVE
This article reviews clinical trials to assess the efficacy, safety, and clinical application of once-daily roflumilast 0.3% cream for the treatment of plaque psoriasis.
DATA SOURCES
A systematic review of the literature was performed using the terms OR OR in MEDLINE (PubMed) and EMBASE databases between January 2012 and October 2022. Bibliographies and the ClinicalTrials.gov website were also searched to identify further studies.
STUDY SELECTION AND DATA EXTRACTION
Studies written in English and relevant to pharmacology, clinical trials, and safety were considered for inclusion.
DATA SYNTHESIS
In two 8-week phase III clinical trials, disease severity as assessed by a score of "clear" or "almost clear" and a 2-point improvement on Investigator Global Assessment (IGA) was 42.4% and 37.5% at week 8 in DERMIS-1 and DERMIS-2, respectively, compared to 6.1% and 6.9% in the control groups. In the 52-week phase III trial, treatment success rates for plaque psoriasis and intertriginous psoriasis were similar to the 8-week data with 45% of patients in the treatment group were evaluated as an IGA of "clear" or "almost clear" at week 52.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON TO EXISTING DRUGS
Roflumilast is a new US Food and Drug Administration (FDA)-approved topical phosphodiesterase inhibitor that shows promise for the treatment of mild-severe plaque psoriasis. It is an effective and safe topical nonsteroidal alternative to currently available topical corticosteroids, but there are currently no comparative studies with other psoriasis treatments.
CONCLUSION
Roflumilast is effective and safe for the treatment of plaque psoriasis and intertriginous psoriasis. Future trials should compare its efficacy and tolerability with that of the older, clinically established topical corticosteroids. Prohibitive factors may include limited patient adherence to topical treatments and cost.
Topics: Humans; Adrenal Cortex Hormones; Aminopyridines; Dermatologic Agents; Immunoglobulin A; Psoriasis; Severity of Illness Index; Treatment Outcome; Clinical Trials as Topic
PubMed: 36420929
DOI: 10.1177/10600280221137750 -
Nature Communications Jun 2023The interplay of positive and negative interactions between drug-sensitive and resistant cells influences the effectiveness of treatment in heterogeneous cancer cell...
The interplay of positive and negative interactions between drug-sensitive and resistant cells influences the effectiveness of treatment in heterogeneous cancer cell populations. Here, we study interactions between estrogen receptor-positive breast cancer cell lineages that are sensitive and resistant to ribociclib-induced cyclin-dependent kinase 4 and 6 (CDK4/6) inhibition. In mono- and coculture, we find that sensitive cells grow and compete more effectively in the absence of treatment. During treatment with ribociclib, sensitive cells survive and proliferate better when grown together with resistant cells than when grown in monoculture, termed facilitation in ecology. Molecular, protein, and genomic analyses show that resistant cells increase metabolism and production of estradiol, a highly active estrogen metabolite, and increase estrogen signaling in sensitive cells to promote facilitation in coculture. Adding estradiol in monoculture provides sensitive cells with increased resistance to therapy and cancels facilitation in coculture. Under partial inhibition of estrogen signaling through low-dose endocrine therapy, estradiol supplied by resistant cells facilitates sensitive cell growth. However, a more complete blockade of estrogen signaling, through higher-dose endocrine therapy, diminished the facilitative growth of sensitive cells. Mathematical modeling quantifies the strength of competition and facilitation during CDK4/6 inhibition and predicts that blocking facilitation has the potential to control both resistant and sensitive cancer cell populations and inhibit the emergence of a refractory population during cell cycle therapy.
Topics: Humans; Neoplasms; Aminopyridines; Estrogens; Estradiol
PubMed: 37386030
DOI: 10.1038/s41467-023-39242-6 -
Journal of Drugs in Dermatology : JDD Jul 2019Background: Impetigo, a bacterial infection that is highly contagious, involves the superficial skin. Topical treatment for impetigo includes amongst other bacitracin,... (Review)
Review
Background: Impetigo, a bacterial infection that is highly contagious, involves the superficial skin. Topical treatment for impetigo includes amongst other bacitracin, gentamycin, mupirocin, retapamulin, and more recently, ozenoxacin 1% cream. For more severe conditions systemic antibiotics are prescribed and may be combined with a topical treatment. The current review explored the challenges in treating impetigo in pediatric and adult populations and examined the role of ozenoxacin 1% cream as a safe and effective treatment option. Methods: We performed PubMed and Google Scholar searches of the English-language literature (2010-2018) using the terms impetigo, bullous impetigo, non-bullous impetigo, antimicrobial and antibiotic resistance, mupirocin, retapamulin, and ozenoxacin. The selected publications were manually reviewed for additional resources. Results: Although guidelines were updated regularly, the recommended treatments have not changed much since 2014. Emerging antimicrobial resistance is a growing concern in dermatology and pediatrics. Impetigo therapy choices should consider the resistance pattern of S. aureus. Ozenoxacin 1% cream is a prescription medicine for topical treatment of impetigo in adults and children 2 months or older. Ozenoxacin has a low probability of selecting spontaneous resistant mutants in quinolone-susceptible or quinolone-resistant bacterial strains and has shown to be active against MRSA isolates. Ozenoxacin 1% cream has potent bactericidal activity and was shown to be effective and safe for the treatment of impetigo in two well-controlled Phase 3 trials. Conclusions: Resistance patterns in a wide range of pathogens against oral or topical antibiotics and antiseptics used for the treatment of dermatological conditions, such as impetigo have been observed. When making treatment decisions for impetigo MRSA and other antimicrobial resistance has to be taken into account. Ozenoxacin 1% cream offers a potent bactericidal activity and has demonstrated clinical efficacy and safety. Combined with its favorable features, such as a low dosing frequency and a 5 days treatment regimen, ozenoxacin 1% cream is an important option for the treatment of impetigo for pediatric and adult populations. J Drugs Dermatol. 2019;18(7):655-661.
Topics: Aminopyridines; Anti-Bacterial Agents; Antimicrobial Stewardship; Clinical Decision-Making; Drug Resistance, Bacterial; Humans; Impetigo; Mutation; Patient Selection; Practice Guidelines as Topic; Quinolones; Skin Cream; Staphylococcus aureus; Treatment Outcome
PubMed: 31334625
DOI: No ID Found -
Clinical Cancer Research : An Official... Jan 2024Brain metastases are associated with high morbidity and are often resistant to immune checkpoint inhibitors. We evaluated whether CDK4/6 inhibitor (CDKi) abemaciclib can...
PURPOSE
Brain metastases are associated with high morbidity and are often resistant to immune checkpoint inhibitors. We evaluated whether CDK4/6 inhibitor (CDKi) abemaciclib can sensitize intracranial tumors to programmed cell death protein 1 (PD-1) inhibition in mouse models of melanoma and breast cancer brain metastasis.
EXPERIMENTAL DESIGN
Treatment response was evaluated in vivo using immunocompetent mouse models of brain metastasis bearing concurrent intracranial and extracranial tumors. Treatment effect on intracranial and extracranial tumor-immune microenvironments (TIME) was evaluated using immunofluorescence, multiplex immunoassays, high-parameter flow cytometry, and T-cell receptor profiling. Mice with humanized immune systems were evaluated using flow cytometry to study the effect of CDKi on human T-cell development.
RESULTS
We found that combining abemaciclib with PD-1 inhibition reduced tumor burden and improved overall survival in mice. The TIME, which differed on the basis of anatomic location of tumors, was altered with CDKi and PD-1 inhibition in an organ-specific manner. Combination abemaciclib and anti-PD-1 treatment increased recruitment and expansion of CD8+ effector T-cell subsets, depleted CD4+ regulatory T (Treg) cells, and reduced levels of immunosuppressive cytokines in intracranial tumors. In immunodeficient mice engrafted with human immune systems, abemaciclib treatment supported development and maintenance of CD8+ T cells and depleted Treg cells.
CONCLUSIONS
Our results highlight the distinct properties of intracranial and extracranial tumors and support clinical investigation of combination CDK4/6 and PD-1 inhibition in patients with brain metastases. See related commentary by Margolin, p. 257.
Topics: Humans; Mice; Animals; Programmed Cell Death 1 Receptor; Brain Neoplasms; Aminopyridines; Benzimidazoles; CD8-Positive T-Lymphocytes; Tumor Microenvironment; Cyclin-Dependent Kinase 4
PubMed: 37611074
DOI: 10.1158/1078-0432.CCR-23-0433 -
Actas Dermo-sifiliograficas Mar 2024Oral roflumilast is a phosphodiesterase-4 inhibitor approved for the prevention of exacerbations of chronic obstructive pulmonary disease and chronic bronchitis. In... (Review)
Review
Oral roflumilast is a phosphodiesterase-4 inhibitor approved for the prevention of exacerbations of chronic obstructive pulmonary disease and chronic bronchitis. In dermatology, topical roflumilast is authorized by the US Food and Drug Administration for the treatment of plaque psoriasis and mild to moderate seborrheic dermatitis. Several studies have described the off-label use of roflumilast in dermatology, including a randomized controlled trial showing its usefulness in the treatment of psoriasis; case reports and small series have also reported successful outcomes in hidradenitis suppurativa, recurrent oral aphthosis, nummular eczema, lichen planus, and Behçet disease. Roflumilast has a favorable safety profile, similar to that of apremilast, and it is considerably cheaper than new generation drugs and even some conventional immunosuppressants. We review the pharmacokinetics and pharmacodynamics of topical and oral roflumilast and discuss potential adverse effects and both approved and off-label uses in dermatology. Roflumilast is a promising agent to consider.
Topics: Humans; Dermatology; Pulmonary Disease, Chronic Obstructive; Aminopyridines; Psoriasis; Randomized Controlled Trials as Topic; Benzamides; Cyclopropanes
PubMed: 37709133
DOI: 10.1016/j.ad.2023.09.005 -
Leukemia Research Nov 2022Enasidenib was approved by the Food and Drug Administration in 2017 for the treatment of patients with relapsed or refractory (RR) acute myeloid leukemia (AML) with an...
Enasidenib was approved by the Food and Drug Administration in 2017 for the treatment of patients with relapsed or refractory (RR) acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation. Given limited data in clinical practice, this study assessed real-world clinical outcomes and healthcare resource use in patients with RR AML. Physicians performed chart abstraction of patients with RR IDH2-mutated AML treated with enasidenib (between 1/2018 and 6/2019) or other first-line (1 L) RR therapy (between 1/2016 and 7/2017). Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method, and adjusted risk of progression and death were estimated by multivariable Cox proportional hazard models. Among 124 patients treated with enasidenib and 76 patients treated with other 1 L RR therapy, overall response rate was higher among patients treated with enasidenib vs. other 1 L RR therapies (77% vs. 52%, p < 0.01). After a median follow-up of 9 and 6 months, median PFS was 8 months in enasidenib-treated patients and 5 months in patients receiving other 1 L RR therapy, respectively (adjusted HR=0.36, 95% CI: 0.23-0.57, p < 0.01). Median OS was 11 and 6 months in enasidenib-treated patients and patients receiving other 1 L RR therapy, respectively (adjusted HR=0.37, 95% CI: 0.22-0.60, p < 0.01). Fewer enasidenib-treated patients were hospitalized during 1 L RR therapy vs. those receiving other therapies (14% vs. 46%, p < 0.01). Results from this real-world study confirm the effectiveness of enasidenib among patients with IDH2-mutated RR AML and demonstrate that hospitalizations were significantly lower vs. other 1 L RR treatment in clinical practice.
Topics: Humans; Isocitrate Dehydrogenase; Leukemia, Myeloid, Acute; Aminopyridines; Triazines; Mutation
PubMed: 36108427
DOI: 10.1016/j.leukres.2022.106946 -
BMC Neuroscience Jul 2023Several phosphodiesterase 4 (PDE4) inhibitors have emerged as potential therapeutics for central nervous system (CNS) diseases. This study investigated the...
BACKGROUND
Several phosphodiesterase 4 (PDE4) inhibitors have emerged as potential therapeutics for central nervous system (CNS) diseases. This study investigated the pharmacological effects of two selective PDE4 inhibitors, roflumilast and zatolmilast, against lipopolysaccharide-induced neuroinflammation.
RESULTS
In BV-2 cells, the PDE4 inhibitor roflumilast reduced the production of nitric oxide and tumor necrosis factor-α (TNF-α) by inhibiting NF-κB phosphorylation. Moreover, mice administered roflumilast had significantly reduced TNF-α, interleukin-1β (IL-1β), and IL-6 levels in plasma and brain tissues. By contrast, zatolmilast, a PDE4D inhibitor, showed no anti-neuroinflammatory effects in vitro or in vivo. Next, in vitro and in vivo pharmacokinetic studies of these compounds in the brain were performed. The apparent permeability coefficients of 3 µM roflumilast and zatolmilast were high (> 23 × 10 cm/s) and moderate (3.72-7.18 × 10 cm/s), respectively, and increased in a concentration-dependent manner in the MDR1-MDCK monolayer. The efflux ratios were < 1.92, suggesting that these compounds are not P-glycoprotein substrates. Following oral administration, both roflumilast and zatolmilast were slowly absorbed and eliminated, with time-to-peak drug concentrations of 2-2.3 h and terminal half-lives of 7-20 h. Assessment of their brain dispositions revealed the unbound brain-to-plasma partition coefficients of roflumilast and zatolmilast to be 0.17 and 0.18, respectively.
CONCLUSIONS
These findings suggest that roflumilast, but not zatolmilast, has the potential for use as a therapeutic agent against neuroinflammatory diseases.
Topics: Mice; Animals; Phosphodiesterase 4 Inhibitors; Neuroinflammatory Diseases; Lipopolysaccharides; Tumor Necrosis Factor-alpha; Aminopyridines; Cyclopropanes
PubMed: 37525115
DOI: 10.1186/s12868-023-00810-7 -
Anticancer Research Dec 2023Breast cancer (BC) is a common malignancy in women, with hormone receptor (HR)-positive subtype responsible for approximately 70% of cases. Currently, patients with... (Review)
Review
Breast cancer (BC) is a common malignancy in women, with hormone receptor (HR)-positive subtype responsible for approximately 70% of cases. Currently, patients with metastatic HR-positive BC rely on endocrine therapy and cyclin-dependent kinase (CDK)-4/6 inhibitors for treatment. Currently, approved CDK4/6 inhibitors include palbociclib, ribociclib, and abemaciclib. However, clinical evidence of CDK-4/6 inhibitor resistance is emerging, suggesting that the gap in the knowledge of its resistance mechanism requires further investigation. This review discusses the mechanisms of CDK4/6 inhibitor resistance in BC, including both intrinsic and extrinsic mechanisms. We also discuss possible alternative strategies to overcome CDK4/6 inhibitor resistance in future clinical applications.
Topics: Humans; Female; Breast Neoplasms; Protein Kinase Inhibitors; Aminopyridines; Cyclin-Dependent Kinase Inhibitor Proteins; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6
PubMed: 38030174
DOI: 10.21873/anticanres.16732 -
The Oncologist Oct 2022Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4 and 6) are approved for the treatment of subsets of patients with hormone receptor positive (HR+)... (Review)
Review
Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4 and 6) are approved for the treatment of subsets of patients with hormone receptor positive (HR+) breast cancer (BC). In metastatic disease, strategies involving endocrine therapy combined with CDK4 and 6 inhibitors (CDK4 and 6i) improve clinical outcomes in HR+ BCs. CDK4 and 6i prevent retinoblastoma tumor suppressor protein phosphorylation, thereby blocking the transcription of E2F target genes, which in turn inhibits both mitogen and estrogen-mediated cell proliferation. In this review, we summarize preclinical data pertaining to the use of CDK4 and 6i in BC, with a particular focus on several of the unique chemical, pharmacologic, and mechanistic properties of abemaciclib. As research efforts elucidate the novel mechanisms underlying abemaciclib activity, potential new applications are being identified. For example, preclinical studies have demonstrated abemaciclib can exert antitumor activity against multiple tumor types and can cross the blood-brain barrier. Abemaciclib has also demonstrated distinct activity as a monotherapeutic in the treatment of BC. Accordingly, we also discuss how a greater understanding of mechanisms related to CDK4 and 6 blockade highlight abemaciclib's unique in-class properties, and could pave new avenues for enhancing its therapeutic efficacy.
Topics: Aminopyridines; Benzimidazoles; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Estrogens; Female; Humans; Mitogens; Protein Kinase Inhibitors; Tumor Suppressor Proteins
PubMed: 35917168
DOI: 10.1093/oncolo/oyac138