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Clinical Therapeutics Apr 2022This study examined real-world treatment patterns with curative intent, adverse events, and health care resource utilization and costs in patients with relapsed or...
PURPOSE
This study examined real-world treatment patterns with curative intent, adverse events, and health care resource utilization and costs in patients with relapsed or refractory large B-cell lymphoma (LBCL) to understand the unmet medical need in the United States.
METHODS
Adult patients with ≥2 LBCL diagnoses between January 1, 2012, and March 31, 2019, were identified (index date was the date of the earliest LBCL diagnosis) from MarketScan® Commercial and Medicare Supplemental Databases. Patients had ≥1 claim for any LBCL treatment, ≥6 months of data before (baseline) and ≥12 months of data after (follow-up period) the index date, and no baseline LBCL diagnosis. Treatment patterns, adverse events, and all-cause and LBCL-related health care resource utilization and costs were examined. All patients had received first-line therapy of cyclophosphamide, doxorubicin, vincristine, and prednisone with or without rituximab; etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride with or without rituximab; or regimens with anthracycline and second-line therapy with stem cell transplant (SCT)-intended intensive therapy or platinum-based chemotherapy. Patients who received an SCT-intended second-line regimen or received an SCT regardless of second-line regimen were considered SCT eligible.
FINDINGS
A total of 188 patients met the criteria of eligibility for SCT. Among the 119 patients who received a second-line regimen intended for SCT, only 22.7% received an SCT. Patients eligible for SCT started first-line therapy within 1 month of their LBCL index date, and the mean duration of first-line therapy was 4.1 months. The mean gap in therapy between first- and second-line therapy was 6.6 months, and the mean duration of second-line therapy was 3.0 months. During the second-line therapy treatment window (mean duration with SCT, 12.4 months; mean duration without SCT, 4.8 months), the most common regimens for patients eligible for SCT were ifosfamide, carboplatin, and etoposide with or without rituximab and gemcitabine and oxaliplatin with or without rituximab; the top 4 most common treatment-related adverse events were febrile neutropenia (56.4%), anemia (49.5%), thrombocytopenia (42.6%), and nausea and vomiting (36.2%), which were similar regardless of receipt of SCT; mean (SD) per-patient-per-month all-cause costs were $46,174 ($49,057) for patients with SCT and $45,780 ($52,813) for patients without SCT.
IMPLICATIONS
Treatment patterns among patients with relapsed or refractory LBCL eligible for SCT were highly varied. Only 22.7% of patients who received an SCT-preparative regimen ultimately received SCT, which highlights the magnitude of unmet needs in this population. The occurrence of treatment-related adverse events was similar regardless of SCT status. Per-patient-per-month all-cause costs were also similar with upfront SCT costs averaged during a longer follow-up.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cost of Illness; Cyclophosphamide; Doxorubicin; Etoposide; Humans; Lymphoma, Large B-Cell, Diffuse; Medicare; Prednisone; Rituximab; United States; Vincristine
PubMed: 35241295
DOI: 10.1016/j.clinthera.2022.02.004 -
ACS Applied Materials & Interfaces Apr 2023Despite the enormous advancements in nanomedicine research, a limited number of nanoformulations are available on the market, and few have been translated to clinics. An...
Despite the enormous advancements in nanomedicine research, a limited number of nanoformulations are available on the market, and few have been translated to clinics. An easily scalable, sustainable, and cost-effective manufacturing strategy and long-term stability for storage are crucial for successful translation. Here, we report a system and method to instantly formulate NF achieved with a nanoscale polyelectrolyte coacervate-like system, consisting of anionic pseudopeptide poly(l-lysine isophthalamide) derivatives, polyethylenimine, and doxorubicin (Dox) via simple "mix-and-go" addition of precursor solutions in seconds. The coacervate-like nanosystem shows enhanced intracellular delivery of Dox to patient-derived multidrug-resistant (MDR) cells in 3D tumor spheroids. The results demonstrate the feasibility of an instant drug formulation using a coacervate-like nanosystem. We envisage that this technique can be widely utilized in the nanomedicine field to bypass the special requirement of large-scale production and elongated shelf life of nanomaterials.
Topics: Humans; Feasibility Studies; Doxorubicin; Neoplasms; Nanostructures; Drug Carriers; Nanoparticles; Cell Line, Tumor; Drug Delivery Systems
PubMed: 36976817
DOI: 10.1021/acsami.2c21586 -
European Journal of Pharmaceutical... Sep 2022To evaluate the bioequivalence of a hybrid pegylated liposomal doxorubicin (PLD) hydrochloride injection with reference product Caelyx®. (Randomized Controlled Trial)
Randomized Controlled Trial
Bioequivalence of a hybrid pegylated liposomal doxorubicin hydrochloride injection and Caelyx®: A single-dose, randomized, multicenter, open-label, two-period crossover study in patients with advanced ovarian cancer.
OBJECTIVE
To evaluate the bioequivalence of a hybrid pegylated liposomal doxorubicin (PLD) hydrochloride injection with reference product Caelyx®.
METHODS
This multicenter, open-label, balanced, randomized, two-treatment, two-period, two-sequence, single-dose, crossover, bioequivalence study was conducted in female patients aged ≥18 years and ≤75 years with ovarian cancer, whose disease progressed or recurred after platinum-based chemotherapy, and who were scheduled to start PLD therapy. Patients were intravenously infused drugs over 1 h at 50 mg/m dose two hours after breakfast on the first day of the chemotherapy cycle in period-I and crossed over to the other arm in period-II (day 29). Pharmacokinetic (PK) analyses were performed using two separate, validated liquid chromatography-mass spectrometry methods for encapsulated and unencapsulated doxorubicin.
RESULTS
Both the test and reference formulations were well-tolerated and safe. The pharmacokinetic analysis for both encapsulated and unencapsulated doxorubicin was conducted in 50 patients and PK parameters were found to be comparable between test and reference products. The geometric mean ratios (90% confidence interval) of hybrid PLD/Caelyx® were; maximum measured plasma concentration (C): 91.94-97.28%, area under the plasma concentration versus time from time 0 to t (AUC): 95.19-103.67% AUC from time 0 to ∞ (AUC): 95.13-103.66% for encapsulated doxorubicin and for unencapsulated doxorubicin C: 92.08-116.46% AUC: 91.91-108.28% AUC: 93.45-110.05%.
CONCLUSION
The PLD formulation was found to be bioequivalent to Caelyx®.
Topics: Adolescent; Adult; Area Under Curve; Cross-Over Studies; Doxorubicin; Female; Humans; Ovarian Neoplasms; Polyethylene Glycols; Tablets; Therapeutic Equivalency
PubMed: 35777616
DOI: 10.1016/j.ejps.2022.106248 -
International Journal of Nanomedicine 2020Synergistic treatment integrating photothermal therapy (PTT) and chemotherapy is a promising strategy for hepatocellular carcinoma (HCC). However, the most commonly used...
INTRODUCTION
Synergistic treatment integrating photothermal therapy (PTT) and chemotherapy is a promising strategy for hepatocellular carcinoma (HCC). However, the most commonly used photothermal agent, IR820, and chemotherapeutic drug, doxorubicin hydrochloride (DOX), are both hydrophilic molecules that suffer from the drawbacks of a short circulation time, rapid elimination and off-target effects.
METHODS AND RESULTS
Herein, a novel nanodrug that combined HCC-targeted IR820 and DOX was developed based on excipient-free co-assembly. First, lactosylated IR820 (LA-IR820) was designed to target HCC. Then, the LA-IR820/DOX nanodrug (LA-IR820/DOX ND) was purely self-assembled without excipient assistance. The physicochemical properties and the chemo-photothermal antitumour activity of the excipient-free LA-IR820/DOX ND were evaluated. More importantly, the obtained LA-IR820/DOX ND exhibited 100% drug loading, remarkable HCC targeting and excellent antitumour efficacy.
CONCLUSION
This excipient-free LA-IR820/DOX ND may be a promising candidate for the synchronous delivery and synergistic targeting of IR820 and DOX as a combined chemo-photothermal therapy.
Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Doxorubicin; Drug Delivery Systems; Drug Liberation; Drug Synergism; Humans; Indocyanine Green; Lactose; Liver Neoplasms; Mice; Nanoparticles
PubMed: 32606687
DOI: 10.2147/IJN.S247617 -
International Journal of Medical... 2022Omega-3 fatty acids from fish oil (FO) and selenium (Se) potentiate some conventional therapies and have anticancer immune potential. This study aims to determine...
Fish Oil and Selenium with Doxorubicin Modulates Expression of Fatty Acid Receptors and Selenoproteins, and Targets Multiple Anti-Cancer Signaling in Triple-negative Breast Cancer Tumors.
Omega-3 fatty acids from fish oil (FO) and selenium (Se) potentiate some conventional therapies and have anticancer immune potential. This study aims to determine whether FO/Se modulates G-protein-coupled polyunsaturated fatty acid receptors (GPR-40 and GPR-120) and selenoproteins (Sel-H, Sel-W, and GPx4), and increases the therapeutic effect of doxorubicin in a dose-dependent manner on triple-negative breast cancer (TNBC) mouse. Mice were randomized into 5 groups (n = 7/group) and treated with physiological saline (control), low-dose doxorubicin, and doxorubicin in combination with low, medium, or high doses of FO/Se. The expression of signaling molecules in tumors was determined by measuring either mRNA or protein expression. Compared with doxorubicin alone, combination treatment resulted in lower tumor sizes and fewer overall metastasis, lower GPR-40 mRNA levels, and higher expression of all selenoproteins. Doxorubicin-FO/Se combination treatment decreased expression of membrane EGFR and FGFR, down-regulated downstream PI3K/AKT/mTOR, MAPK/ERK, and JAK2/c-Src/STAT3 signaling, increased tumor suppressor PTEN/TSC1/TSC2 expression and P53 activation, and suppressed oncogenic transcription factor expression. Dose-dependent inhibition of proliferation index Ki-67, cell cycle, and stem-cell-related markers were observed. Decreased immune check-points PD-L1/CTLA-4/Foxp3/CD86 and increased PD-1/CD28/IL-2 expression was also found. These observations suggest that the nutritional supplements FO/Se increase the chemotherapeutic efficacy of doxorubicin against TNBC by modulating GPR-40 and selenoprotein and targeting multiple signaling pathways in tumor tissues.
Topics: Mice; Animals; Humans; Selenium; Triple Negative Breast Neoplasms; Fish Oils; Fatty Acids; Phosphatidylinositol 3-Kinases; Doxorubicin; RNA, Messenger
PubMed: 36483592
DOI: 10.7150/ijms.75848 -
Molecules (Basel, Switzerland) Jul 2020Recently, nanogels have been identified as innovative formulations for enlarging the application of hydrogels (HGs) in the area of drug delivery or in diagnostic...
Recently, nanogels have been identified as innovative formulations for enlarging the application of hydrogels (HGs) in the area of drug delivery or in diagnostic imaging. Nanogels are HGs-based aggregates with sizes in the range of nanometers and formulated in order to obtain injectable preparations. Regardless of the advantages offered by peptides in a hydrogel preparation, until now, only a few examples of peptide-based nanogels (PBNs) have been developed. Here, we describe the preparation of stable PBNs based on Fmoc-Phe-Phe-OH using three different methods, namely water/oil emulsion (W/O), top-down, and nanogelling in water. The effect of the hydrophilic-lipophilic balance (HLB) in the formulation was also evaluated in terms of size and stability. The resulting nanogels were found to encapsulate the anticancer drug doxorubicin, chosen as the model drug, with a drug loading comparable with those of the liposomes.
Topics: Doxorubicin; Drug Carriers; Drug Liberation; Emulsions; Hydrophobic and Hydrophilic Interactions; Molecular Structure; Nanogels; Peptides; Theranostic Nanomedicine
PubMed: 32751321
DOI: 10.3390/molecules25153455 -
Biomedicine & Pharmacotherapy =... Apr 2023Melanoma is a highly aggressive neoplasm with a high degree of malignancy and rapid acquisition of resistance by cancer cells.
BACKGROUND
Melanoma is a highly aggressive neoplasm with a high degree of malignancy and rapid acquisition of resistance by cancer cells.
METHODS
Biological studies of a series of isoxazole compounds with immunomodulatory properties were preceded by in silico analysis. The assay evaluated the viability of NHDF and A375 cell cultures after the administration of isoxazole compounds after a 24-hour incubation period in the MTT test. Analyzes of ROS and NO scavenging, P-glycoprotein activity, and properties were performed. The levels of Caspase 3 and Caspase 9 were measured using ELISA to assess which pathways induced apoptosis by the tested compounds. On the chip, the synergistic effect of doxorubicin and the most active compound from the MM9 series on cells of the A375 melanoma line was determined.
RESULTS
All tested N'-substituted derivatives of 5-amino-N,3-dimethyl-1,2-oxazole-4-carbohydrazide with immunomodulatory activity show multidirectional antitumor activity on A375 melanoma lines with an affinity for P-glycoprotein, induction of free radical formation and generation of DNA damage leading to the death of cancer cells, as well as formation of complexes with DNA Topoisomerase II. Most of the tested compounds show pro-apoptotic activity. The most active compound in the series induces apoptosis in three distinct pathways and acts synergistically with doxorubicin.
CONCLUSIONS
The most active compound with immunomodulatory properties showed multidirectional antitumor activity against cells of the A375 melanoma line and also had a synergistic pro-apoptotic effect with doxorubicin, which may result in a reduction of this cytostatic dose with increased effectiveness.
Topics: Humans; Immunomodulating Agents; Melanoma; Apoptosis; Doxorubicin; Isoxazoles; Cell Line, Tumor; Antineoplastic Agents; Cell Proliferation
PubMed: 36774726
DOI: 10.1016/j.biopha.2023.114374 -
Human & Experimental Toxicology 2022Osteosarcoma is the most frequent malignant bone malignancy and the current treatments are ineffective. Ivermectin, an anti-protozoal drug, has been shown to have...
BACKGROUND
Osteosarcoma is the most frequent malignant bone malignancy and the current treatments are ineffective. Ivermectin, an anti-protozoal drug, has been shown to have anti-cancer activity. This work investigated the potential of repurposing ivermectin to augment chemotherapy's efficacy in osteosarcoma.
METHODS
Proliferation, migration and apoptosis assays were performed in ivermectin-treated osteosarcoma cells. Combination studies were performed. Osteosarcoma xenograft mouse model was established to investigate the efficacy of ivermectin. Intracellular reactive oxygen species (ROS) and mitochondrial superoxide, membrane potential, ATP, 8-OHdG level, protein carbonylation and lipid peroxidation were determined after ivermectin treatment.
RESULTS
Ivermectin was effective and acted synergistically with doxorubicin in osteosarcoma cells regardless of cellular origin and genetic profiling. This was achieved through suppressing inhibiting growth and migration, and inducing caspase-dependent apoptosis. Ivermectin also significantly inhibited osteosarcoma growth in vivo and its combination with doxorubicin resulted in much greater efficacy than doxorubicin alone. Importantly, the effective dose of ivermectin was clinically feasible and did not cause significant toxicity in mice. Mechanistical analysis showed that ivermectin induced oxidative stress and damage, and mitochondrial dysfunction.
CONCLUSIONS
Our findings indicate that ivermectin has utility in treating patients with osteosarcoma, especially those resistant to chemotherapy.
Topics: Humans; Mice; Animals; Ivermectin; Cell Line, Tumor; Osteosarcoma; Doxorubicin; Bone Neoplasms
PubMed: 36503300
DOI: 10.1177/09603271221143693 -
Biomedicine & Pharmacotherapy =... Aug 2019Doxorubicin (DOX) is an effective chemotherapeutic drug. However, its clinical application may be hampered by dose-dependent cardiotoxicity. Alcohol metabolite and...
AIM
Doxorubicin (DOX) is an effective chemotherapeutic drug. However, its clinical application may be hampered by dose-dependent cardiotoxicity. Alcohol metabolite and doxorubicinol (DOXol) were the most prominent components in DOX-induced cardiotoxicity. It is necessary to elucidate the level of DOXol in heart in vivo and whether DOXol could cause toxicity at such a concentration.
METHODS
The pharmacokinetics and heart distribution of DOX and its second metabolite DOXol were determined in rats. Based on this concentration level in vivo, H9C2 cell was used to examine the cardiotoxicity of DOX and DOXol. Real-time cell viability was determined using the xCelligence system and the membrane-permeable of DOX, and DOXol was also assessed by determining the intracellular and extracellular concentrations.
RESULTS
Our data showed that DOX level was higher than DOXol level in heart tissue. DOX had a high level in intracellular H9C2 cell and was the primary cytotoxic agent. DOXol had a significantly low level in heart tissue and less cytotoxicity than that of DOX in H9C2. DOXol in heart could not diffuse from plasma but only form in the heart. DOXol could not enter cell as easy as DOX. The less cardiotoxicity of DOXol might be caused by the less intracellular concentration.
Topics: Animals; Cardiotoxicity; Cell Line; Cell Survival; Doxorubicin; Inhibitory Concentration 50; Male; Metabolome; Rats, Sprague-Dawley
PubMed: 31102935
DOI: 10.1016/j.biopha.2019.108964 -
Drug Design, Development and Therapy 2018Despite available therapies after initial systemic therapy, prognosis remains poor in relapsed or refractory soft tissue sarcomas (STS). The rational and clinical... (Review)
Review
Despite available therapies after initial systemic therapy, prognosis remains poor in relapsed or refractory soft tissue sarcomas (STS). The rational and clinical development of novel agents to improve outcomes in this area of high unmet need is desperately warranted. Aldoxorubicin is a prodrug of doxorubicin that binds to serum albumin immediately after administration through an acid-sensitive hydrazone linker and is subsequently transported to tumor tissues where the acidic environment cleaves the linker and facilitates delivery of a tumor-targeted drug payload. In clinical studies to date, there has been evidence of efficacy and mitigated cardiac toxicity. In this review, we comprehensively detail the clinical development of aldoxorubicin in STS to date. Specifically, we highlight available data on the pharmacokinetics and efficacy from Phase I, Phase II, and Phase III trials in advanced or metastatic STS. We conclude with considerations for future directions of investigation for this promising antitumor agent.
Topics: Antineoplastic Agents; Doxorubicin; Humans; Hydrazones; Sarcoma
PubMed: 29670334
DOI: 10.2147/DDDT.S140638