-
Dermatology and Therapy Dec 2022Chlormethine (CL) gel is a skin-directed therapy approved for treatment of stage IA/IB mycosis fungoides-type cutaneous T-cell lymphoma (MF-CTCL) in the USA. MF-CTCL has...
Maintenance and Concomitant Therapy Use with Chlormethine Gel Among Patients with Stage IA/IB Mycosis Fungoides-Type Cutaneous T-Cell Lymphoma (MF-CTCL): A Real-World Evidence Study.
INTRODUCTION
Chlormethine (CL) gel is a skin-directed therapy approved for treatment of stage IA/IB mycosis fungoides-type cutaneous T-cell lymphoma (MF-CTCL) in the USA. MF-CTCL has a chronic clinical course, requiring long-term maintenance therapy with one or more therapies. This analysis describes real-world patterns of maintenance therapy and use of concomitant therapy with CL gel among patients with stage IA/IB MF-CTCL.
METHODS
In a US-based registry, MF-CTCL patients treated with CL gel were enrolled between 3/2015 and 10/2018 across 46 centers and followed for up to 2 years. Patient demographics, clinical characteristics, CL gel treatment patterns, concomitant treatments, clinical response, and adverse events (AEs) were collected from medical records. Descriptive statistics are reported.
RESULTS
Of the 206 patients with stage IA/IB MF-CTCL, 58.7% were male, and average age was 60.7 years with 4.6 years since diagnosis. Topical steroids, phototherapy, and topical retinoids were used concomitantly with CL gel in 62.6%, 26.2%, and 6.3% of patients, respectively. Most concomitant therapies (up to 85%) were started before CL gel initiation and, in about half of the cases (up to 57%), were used concurrently for ≥ 12 months. Overall, 158 (76.7%) patients experienced partial response (PR) and 144 continued with maintenance therapy. After achieving PR, most patients (74.3%) kept the same maintenance therapy schedule, most commonly once daily. Of patients who had any skin-related AE (31.6%) or skin-related AEs associated with CL gel (28.2%), nearly half experienced CL gel treatment interruption and ~40% had a dosing reduction. The observed real-world treatment patterns were concordant with National Comprehensive Cancer Network (NCCN) guidelines.
CONCLUSION
The study results suggest that continuing CL gel maintenance therapy and combining treatments with CL gel are common practice in the real-world setting, with most maintained on a stable dosing schedule. Careful management of AEs may help patients maintain long-term optimal dosing with less treatment interruptions and dosing reductions.
PubMed: 36284059
DOI: 10.1007/s13555-022-00831-w -
European Journal of Medicinal Chemistry Dec 2022The incidence of various types of cancers is increasing every year. Among these, leukemia is extremely common, and thus, developing novel drugs to combat leukemia is...
The incidence of various types of cancers is increasing every year. Among these, leukemia is extremely common, and thus, developing novel drugs to combat leukemia is crucial. In this study, we designed and synthesized several hybrids and obtained a new lead molecule 5a, with a strong therapeutic effect on leukemia. The results indicated that most hybrids effectively inhibited the growth of leukemia cells, HCT-116, and A549 cancer cells with an IC of <10 μM. Among these hybrids, 5a and 4h showed significant anticancer activity against CCRF-CEM, with IC values of 0.895 μM and 0.555 μM, respectively. Particularly, 5a had lower toxicity to L02 than chlorambucil (CLB) and doxorubicin (Dox), and the high selectivity was also reflected in the normal human B lymphoblast cell line (IM9). Upon investigating the mechanism of action, we found that 5a downregulated Bcl-2 and caused DNA double-stranded breaks (DSBs) to induce several genotoxic stress responses. The results of the flow cytometry assay showed that 5a was a non-specific molecule in the cell cycle. Furthermore, 5a did not affect total ROS levels but significantly improved the activity of glutathione peroxidase (GPx). Preliminary studies showed that nitrogen mustard exerted an efficient effect, and 5a can combine the advantages of artemisinin and nitrogen mustard and exhibit effects superior to either. This study showed that 5a should be further investigated as a therapeutic compound against leukemia.
Topics: Humans; Mechlorethamine; Glutathione Peroxidase; Artemisinins; Leukemia; DNA Damage; Neoplasms; Cell Line, Tumor; Apoptosis; Antineoplastic Agents
PubMed: 36240546
DOI: 10.1016/j.ejmech.2022.114783 -
International Journal of Molecular... Sep 2022Ocular surface exposure to nitrogen mustard (NM) leads to severe ocular toxicity which includes the separation of epithelial and stromal layers, loss of endothelial...
Ocular surface exposure to nitrogen mustard (NM) leads to severe ocular toxicity which includes the separation of epithelial and stromal layers, loss of endothelial cells, cell death, and severe loss of tissue function. No definitive treatment for mustard gas-induced ocular surface disorders is currently available. The research was conducted to investigate the therapeutic potential of mesenchymal stem cell-conditioned media (MSC-CM) in NM-induced corneal wounds. NM was added to different types of corneal cells, the ocular surface of porcine, and the ocular surface of mice, followed by MSC-CM treatment. NM significantly induced apoptotic cell death, cellular ROS (Reactive oxygen species), and reduced cell viability, metabolic gene expression, and mitochondrial function, and, in turn, delayed wound healing. The application of MSC-CM post NM exposure partially restored mitochondrial function and decreased intracellular ROS generation which promoted cell survival. MSC-CM therapy enhanced wound healing process. MSC-CM inhibited NM-induced apoptotic cell death in murine and porcine corneal tissue. The application of MSC-CM following a chemical insult led to significant improvements in the preservation of corneal structure and wound healing. In vitro, ex vivo, and in vivo results suggest that MSC-CM can potentially provide targeted therapy for the treatment of chemical eye injuries, including mustard gas keratopathy (MGK) which presents with significant loss of vision alongside numerous corneal pathologies.
Topics: Animals; Corneal Injuries; Culture Media, Conditioned; Endothelial Cells; Mechlorethamine; Mesenchymal Stem Cells; Mice; Mustard Gas; Reactive Oxygen Species; Stem Cell Factor; Swine; Wound Healing
PubMed: 36232805
DOI: 10.3390/ijms231911510 -
Dermatology and Therapy Nov 2022The DNA-alkylating agent chlormethine (CL, or mechlorethamine) is approved in several countries worldwide as a 0.016% w/w topical CL gel formulation, to treat mycosis...
INTRODUCTION
The DNA-alkylating agent chlormethine (CL, or mechlorethamine) is approved in several countries worldwide as a 0.016% w/w topical CL gel formulation, to treat mycosis fungoides cutaneous T-cell lymphoma, with a positive benefit/risk ratio.
METHODS
Release profiles of CL from the gel and a compounded ointment-based 0.016% CL formulation were compared via in vitro release testing (IVRT), utilizing static diffusion cells, a pseudo-infinite dose, and polytetrafluoroethylene membranes, over 5 h. The percutaneous absorption profile of CL gel in ex vivo human skin was also examined, using in vitro permeation testing (IVPT) with flow-through diffusion cells, dermatomed skin (epidermis plus dermis) and epidermal membranes, a finite dose, over 24 h.
RESULTS
In IVRT experiments, the mean ± SD CL release rate was significantly higher for the gel versus the ointment (5.70 ± 0.73 versus 2.38 ± 1.03 μg/cm/√h); the formulations were inequivalent per the US Food and Drug Administration scale-up and postapproval changes for nonsterile semisolid dosage forms (FDA SUPAC-SS) criteria. Mean IVPT cumulative CL (gel) permeating through epidermal membrane was higher than for dermatomed skin (4.6% versus 2.5% of applied dose). Mean residual CL on the epidermal membrane surface was 1.3% of the applied dose.
CONCLUSIONS
CL gel (0.016%) and ointment were inequivalent, with an optimized release profile, suggesting minimal passage of CL gel through human epidermal tissue to the dermis.
PubMed: 36229764
DOI: 10.1007/s13555-022-00813-y -
Toxicology and Applied Pharmacology Dec 2022Nitrogen mustard (NM) is a cytotoxic vesicant known to cause acute lung injury which progresses to fibrosis. Alveolar Type II cells are primarily responsible for...
Nitrogen mustard (NM) is a cytotoxic vesicant known to cause acute lung injury which progresses to fibrosis. Alveolar Type II cells are primarily responsible for surfactant production; they also play a key role in lung repair following injury. Herein, we assessed the effects of NM on Type II cell activity. Male Wistar rats were administered NM (0.125 mg/kg) or PBS control intratracheally. Type II cells, lung tissue and BAL were collected 3 d later. NM exposure resulted in double strand DNA breaks in Type II cells, as assessed by expression of γH2AX; this was associated with decreased expression of the DNA repair protein, PARP1. Expression of HO-1 was upregulated and nitrotyrosine residues were noted in Type II cells after NM exposure indicating oxidative stress. NM also caused alterations in Type II cell energy metabolism; thus, both glycolysis and oxidative phosphorylation were reduced; there was also a shift from a reliance on oxidative phosphorylation to glycolysis for ATP production. This was associated with increased expression of pro-apoptotic proteins activated caspase-3 and -9, and decreases in survival proteins, β-catenin, Nur77, HMGB1 and SOCS2. Intracellular signaling molecules important in Type II cell activity including PI3K, Akt2, phospho-p38 MAPK and phospho-ERK were reduced after NM exposure. This was correlated with dysregulation of surfactant protein production and impaired pulmonary functioning. These data demonstrate that Type II cells are targets of NM-induced DNA damage and oxidative stress. Impaired functioning of these cells may contribute to pulmonary toxicity caused by mustards.
Topics: Rats; Male; Animals; Mechlorethamine; Rats, Wistar; Acute Lung Injury; Alveolar Epithelial Cells; Oxidative Stress; Energy Metabolism; Surface-Active Agents
PubMed: 36174670
DOI: 10.1016/j.taap.2022.116257 -
Toxicology and Applied Pharmacology Nov 2022Nitrogen mustard (NM) is a cytotoxic vesicant known to cause acute lung injury which progresses to fibrosis; this is associated with a sequential accumulation of pro-...
Nitrogen mustard (NM) is a cytotoxic vesicant known to cause acute lung injury which progresses to fibrosis; this is associated with a sequential accumulation of pro- and anti-inflammatory macrophages in the lung which have been implicated in NM toxicity. Farnesoid X receptor (FXR) is a nuclear receptor involved in regulating lipid homeostasis and inflammation. In these studies, we analyzed the role of FXR in inflammatory macrophage activation, lung injury and oxidative stress following NM exposure. Wild-type (WT) and FXR mice were treated intratracheally with PBS (control) or NM (0.08 mg/kg). Bronchoalveolar lavage fluid (BAL) and lung tissue were collected 3, 14 and 28 d later. NM caused progressive histopathologic alterations in the lung including inflammatory cell infiltration and alveolar wall thickening and increases in protein and cells in BAL; oxidative stress was also noted, as reflected by upregulation of heme oxygenase-1. These changes were more prominent in male FXR mice. Flow cytometric analysis revealed that loss of FXR resulted in increases in proinflammatory macrophages at 3 d post NM; this correlated with upregulation of COX-2 and ARL11, markers of macrophage activation. Markers of anti-inflammatory macrophage activation, CD163 and STAT6, were also upregulated after NM; this response was exacerbated in FXR mice at 14 d post-NM. These findings demonstrate that FXR plays a role in limiting macrophage inflammatory responses important in lung injury and oxidative stress. Maintaining or enhancing FXR function may represent a useful strategy in the development of countermeasures to treat mustard lung toxicity.
Topics: Acute Lung Injury; Animals; Cyclooxygenase 2; Heme Oxygenase-1; Irritants; Lipids; Lung; Macrophage Activation; Male; Mechlorethamine; Mice
PubMed: 35998709
DOI: 10.1016/j.taap.2022.116208 -
Experimental Eye Research Oct 2022Sulfur mustard (SM) is a notorious, bifunctional alkylating vesicant that was first used in warfare during World War I in 1917 and since then has been deployed in... (Review)
Review
Sulfur mustard (SM) is a notorious, bifunctional alkylating vesicant that was first used in warfare during World War I in 1917 and since then has been deployed in numerous skirmishes with its most recent documented use being during the Middle Eastern conflicts. Apart from its use in combat and terrorist activities, continual threat of accidental exposure from old stockpiles and improperly discarded munitions is ever present, especially to the innocent and unassuming civilian populations. SM can cause devastating injuries, depending on the dosage of SM exposure, route of exposure, as well as the physiological conditions of the individuals exposed. The most common routes of exposure are ocular, dermal, and exposure to the lungs and respiratory tissues through inhalation. Eyes are the most susceptible organ to SM-induced toxicities owing to their high moisture content and rapidly dividing cells. Additionally, ocular injury causes the most expeditious disablement of individuals even upon whole-body exposures. Therefore, it is imperative to understand the mechanisms underlying SM-induced ocular toxicity and design therapeutic interventions to prevent/mitigate ocular injuries. Ocular SM exposure may cause a wide range of symptoms such as inflammation, lacrimation, itching, dryness, photophobia, edema of the cornea/sclera/retina/iris, conjunctivitis, degradation of the corneal layer, fusion of two or more ocular layers, neovascularization, fibrosis, and temporary or permanent structural damage to one or more ocular layers. These symptoms may lead to vision impairments, resulting in partial or complete blindness that may be permanent. The highly toxic and exceedingly notorious nature of SM makes it a highly regulated chemical, requiring very expensive licensing, security, and safety requirements; thus, the more easily accessible analogue, nitrogen mustard (NM) that mimics SM-induced toxicity and injuries is employed in plethora of studies conducted in different animal models and culture systems. This review provides a comprehensive account of the injuries and symptoms that occur upon ocular SM exposures in human patients as well as studies in animal (in vivo, ex vivo) and cell (in vitro) models of SM and NM ocular exposures. Special emphasis has been laid on highlighting the strengths and lacunae in the research as well as the possible unexplored avenues of mechanisms underlying mustard-induced ocular injury that can be explored in future research endeavors. Furthermore, development of therapeutic interventions and targets of interest in the ocular system exposed to SM and NM, based on studies in human patients as well as in vivo, ex vivo, and in vitro models has been discussed in great depth, providing a valuable knowledge database to delineate pathways associated with vesicant-induced toxicity, and strategies/diagnostic tools against SM-induced toxicity.
Topics: Animals; Chemical Warfare Agents; Cornea; Eye Injuries; Humans; Irritants; Mechlorethamine; Mustard Gas
PubMed: 35961426
DOI: 10.1016/j.exer.2022.109209 -
Clinical Lymphoma, Myeloma & Leukemia Nov 2022Chemotherapy for classic Hodgkin lymphoma (cHL) patients on hemodialysis (HD) is an extremely challenging situation because pharmacokinetic and pharmacodynamic studies... (Review)
Review
Chemotherapy for classic Hodgkin lymphoma (cHL) patients on hemodialysis (HD) is an extremely challenging situation because pharmacokinetic and pharmacodynamic studies of most chemotherapeutics are lacking for the HD patient, and the small amount of evidence available comes mostly from case reports and small case series. In this review, we provide recommendations based on treatment experience of cHL patients on HD in the literature. HD patients undergoing chemotherapy are at risk of overdose and toxicities because many drugs are significantly eliminated by the kidneys, and at the same time, are at risk of undertreatment because many drugs are removed by HD. Therefore, dose modifications and timing of drug administration in relation to HD sessions must be carefully planned according to the distinct traits of each chemotherapeutic. We carried out an exhaustive literature review of reports of actual administrations of chemotherapeutics to cHL on HD, and also extrapolated data from reports of the same chemotherapeutics that were administered to HD patients with malignancies other than cHL. We summarized the information found in the literature, and provide practical and balanced recommendations concerning dose modifications and optimal timing of drug administration in relation to HD sessions for each chemotherapeutic. Chemotherapy regimens and individual chemotherapeutics studied in this review include ABVD (doxorubicin + bleomycin + vinblastine + dacarbazine), BEACOPP (bleomycin + etoposide + doxorubicin + cyclophosphamide + vincristine + procarbazine + prednisolone), MOPP (mechlorethamine + vincristine + procarbazine + prednisolone), gemcitabine, vinorelbine, brentuximab vedotin, and PD-1 inhibitors (nivolumab and pembrolizumab).
Topics: Humans; Hodgkin Disease; Vinblastine; Vincristine; Antineoplastic Combined Chemotherapy Protocols; Etoposide; Brentuximab Vedotin; Mechlorethamine; Procarbazine; Vinorelbine; Nivolumab; Immune Checkpoint Inhibitors; Bleomycin; Dacarbazine; Doxorubicin; Cyclophosphamide; Prednisolone; Renal Dialysis
PubMed: 35948477
DOI: 10.1016/j.clml.2022.07.008 -
Journal of Molecular Modeling Jul 2022In the present research, the adsorption and release of chlormethine (CM) drug on the BO nanocage have been reported in the water media and gas phase at GGA/PBE/DNP...
In the present research, the adsorption and release of chlormethine (CM) drug on the BO nanocage have been reported in the water media and gas phase at GGA/PBE/DNP computational level. The interaction between BO nanocage and CM drug shows that adsorptions of the chlormethine on BO nanocage for the most stable complexes are - 1.47 to - 1.36 eV in the gas phase and water media, respectively. The CM adsorption caused a notable change in the band gap (E) and work function (Φ) of the BO nanocage in the studied complexes. The binding of chlormethine to BO also significantly increased the polarity of the drug carrier, which is a desirable property for drug delivery in biological environments. CM drugs can be released from the nanocage in the presence of an external electric field along the X-axis direction. The present study results show that the BO nanocage is a possible carrier for delivering chlormethine drugs.
Topics: Antineoplastic Agents; Drug Carriers; Drug Delivery Systems; Mechlorethamine; Water
PubMed: 35900596
DOI: 10.1007/s00894-022-05224-6 -
Advances in Therapy Sep 2022Mycosis fungoides (MF) is a rare disease and is the most common form of cutaneous T cell lymphoma. Topical chlormethine (CL) gel is the first cytotoxic chemotherapy gel... (Review)
Review
Mycosis fungoides (MF) is a rare disease and is the most common form of cutaneous T cell lymphoma. Topical chlormethine (CL) gel is the first cytotoxic chemotherapy gel that was specifically developed for treatment of MF. In this review, we provide an overview of all available data on the use of CL gel for treatment of patients with MF. On the basis of the current data collected, CL gel is highly effective, with good response rates observed both in clinical trial and real-world settings. While the gel is approved for monotherapy, it is also used in combination with concomitant skin-directed or systemic therapies in clinical practice. Responses to CL gel treatment can be rapid, but they also frequently occur with a delayed onset of up to 6 months. This indicates that continued treatment with CL gel is important. CL gel has a manageable safety profile, with most adverse events being mild and skin related. Contact dermatitis is one of the more common skin-related adverse events to occur with CL gel treatment that can potentially lead to treatment discontinuation. The data from the literature indicate that patients being treated with CL gel should be monitored carefully, and that dermatitis must be managed effectively to allow patients to continue treatment and achieve the best possible response to treatment.
Topics: Clinical Trials as Topic; Gels; Humans; Lymphoma, T-Cell, Cutaneous; Mechlorethamine; Mycosis Fungoides; Skin Neoplasms
PubMed: 35852707
DOI: 10.1007/s12325-022-02219-w