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International Journal of Pharmaceutics Nov 1999The objective of this work was to evaluate the potential of using (SBE)(7m)-beta-CD and HP-beta-CD as enabling excipients to improve on the current melphalan injectable... (Comparative Study)
Comparative Study
The objective of this work was to evaluate the potential of using (SBE)(7m)-beta-CD and HP-beta-CD as enabling excipients to improve on the current melphalan injectable formulation. Melphalan is an anti-neoplastic agent formulated for parenteral use as a sterile, non-pyrogenic, freeze-dried powder. It is marketed by Glaxo-Wellcome as ALKERAN((R)) for Injection (Alkeran). A major concern with melphalan therapy, other than its intrinsic cytotoxicity and biocompatibility, arises from its marginal aqueous solubility and chemical stability; thus, co-solvents are used in the current two-vial formulation. Because of the two-vial system, the product is also inconvenient to use. Two approaches to improve melphalan's formulation utilizing cyclodextrins, including the use of aqueous (SBE)(7m)-beta-CD or HP-beta-CD solutions as the reconstitution diluents, and/or the use of (SBE)(7m)-beta-CD as a freeze-drying excipient in a melphalan formulation, are presented. Results showed that, when the cyclodextrins were used as diluents, the use of organic co-solvents can be eliminated and the shelf-life of the reconstituted melphalan greatly enhanced. When the freeze-dried melphalan/(SBE)(7m)-beta-CD formulation was prepared, the formulation was found to be stable; and a simplified one-vial delivery system was achieved. In conclusion, the parenterally safe beta-cyclodextrins derivatives can provide promising alternatives and improved formulations for melphalan injectable and perhaps similar problematic drugs.
Topics: 2-Hydroxypropyl-beta-cyclodextrin; Antineoplastic Agents, Alkylating; Chemistry, Pharmaceutical; Chlorides; Cyclodextrins; Drug Compounding; Drug Stability; Excipients; Freeze Drying; Injections, Intravenous; Kinetics; Melphalan; Solvents; Time Factors; beta-Cyclodextrins
PubMed: 10536251
DOI: 10.1016/s0378-5173(99)00255-0 -
European Journal of Cancer Aug 1977
Clinical Trial Comparative Study Randomized Controlled Trial
Topics: Cyclophosphamide; Drug Resistance; Female; Humans; Melphalan; Ovarian Neoplasms; Risk; Thrombocytopenia; Thrombophlebitis
PubMed: 908343
DOI: 10.1016/0014-2964(77)90136-0 -
Chemical & Pharmaceutical Bulletin Mar 2010A series of spin-labeled melphalan and chlorambucil derivatives, coupling the alkylating agents with 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) radicals, were...
A series of spin-labeled melphalan and chlorambucil derivatives, coupling the alkylating agents with 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) radicals, were synthesized, characterized, and their biological properties in vitro were evaluated. These compounds showed much higher cytotoxic activity against human leukemia cell line K562 in vitro than their parent compounds.
Topics: Cell Line, Tumor; Cell Proliferation; Cell Survival; Chlorambucil; Cyclic N-Oxides; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Free Radicals; Humans; Hydrolysis; Kinetics; Melphalan; Structure-Activity Relationship
PubMed: 20190437
DOI: 10.1248/cpb.58.332 -
Cancer Chemotherapy and Pharmacology Nov 2021Melphalan is a bifunctional alkylating agent that elicits its cytotoxic activity by rapidly forming an initial DNA monoadduct, which then produces an inter-strand...
PURPOSE
Melphalan is a bifunctional alkylating agent that elicits its cytotoxic activity by rapidly forming an initial DNA monoadduct, which then produces an inter-strand crosslink. Most studies exploring the role of inherited differences in DNA repair and melphalan outcomes focus on inter-strand crosslink repair, however, monoadduct repair likely plays a key role since it minimises the ultimate production of these crosslinks. The purpose of this systematic review was to assess evidence of an association between variation in monoadduct repair pathways and melphalan response.
METHODS
A literature search was undertaken using Medline, Embase, Scopus and PubMed databases. Duplicates were removed and only full-text articles were included. To be included for critique in this systematic review, articles were assessed for relevance using strict inclusion/exclusion criteria.
RESULTS
Fourteen studies were identified that involved patients treated with melphalan, however, in 3, only a minority of the cohort received melphalan. Across the remaining 11 studies, 61 genes/proteins in DNA monoadduct repair pathways were assessed. Both germline SNP (CDKN1A, ERCC1, ERCC2, ERCC4, ERCC6, EXO1, MLH1, MNAT1, MUTYH, PARP4, PCNA, POLE, POLR1G, RAD23B, RFC1, RFC3, RPA1, RPA3, TREX1, UNG, XPC, XRCC1) and somatic expression (CDKN1A, PARP1, PCNA, MGMT, RECQL, RFC5) were associated with melphalan outcomes in ≥ 1 study.
CONCLUSION
It appears that inherited germline differences in monoadduct repair genes may be a risk factor for poor outcomes. However, the diversity of study design, patient cohorts, genes assessed and lack of replication, preclude any meta-analysis. Further prospective studies are required to validate these findings.
Topics: Antineoplastic Agents, Alkylating; DNA Adducts; DNA Repair; Gene Expression Regulation, Neoplastic; Humans; Melphalan; Neoplasms; Pharmacogenomic Variants; Progression-Free Survival; Treatment Outcome
PubMed: 34347127
DOI: 10.1007/s00280-021-04340-z -
Journal of Surgical Oncology Apr 2006In patients with unresectable lung cancer or pulmonary metastases, isolated lung perfusion (ILP) has been described as an alternative method to deliver high-dose...
BACKGROUND
In patients with unresectable lung cancer or pulmonary metastases, isolated lung perfusion (ILP) has been described as an alternative method to deliver high-dose chemotherapy to the lungs, thereby minimizing systemic toxicity. Pharmacokinetics of ILP have not been extensively investigated. Therefore, we studied the feasibility of ILP with melphalan in a pig model with emphasis on pharmacokinetics and acute lung damage.
METHODS
Five pigs underwent ILP with melphalan. Blood and tissue samples were obtained for determination of melphalan levels. Tissue biopsies were taken for microscopic evaluation of lung damage.
RESULTS
During ILP, no hemodynamic effects of importance were noted. No systemic leakage of melphalan was observed in any of the animals. Compared with normal lung tissue, microscopic examination of lung tissue after perfusion without melphalan showed pulmonary edema. Directly after melphalan perfusion additional hemorrhagic areas were seen; however, electron microscopy displayed no irreversible endothelial damage.
CONCLUSION
This study on pigs proved to be a well reproducible model for ILP with melphalan. Pharmacokinetics show a safety profile with no systemic toxicity, which could justify further patient studies, necessary to determine its effect on pulmonary metastases in humans, especially in case of adjuvant therapy after surgical resection or in unresectable disease.
Topics: Animals; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Lung Neoplasms; Melphalan; Swine
PubMed: 16550578
DOI: 10.1002/jso.20498 -
British Journal of Cancer Jan 1982A group of 12 children with advanced neuroblastoma (7 Stage IV and 5 Stage III), selected by their initial response to chemotherapy with pulsed...
A group of 12 children with advanced neuroblastoma (7 Stage IV and 5 Stage III), selected by their initial response to chemotherapy with pulsed cyclophosphamide/vincristine/Adriamycin (CVA), were given consolidation therapy with high-dose melphalan (140 mg/m2) and then surgical removal of residual disease. Twenty-two high-dose melphalan procedures were combined with autologous marrow grafting to offset myelotoxicity and were well tolerated. In each of 2 additional children, procedures carried out without marrow autografting led to serious marrow and mucosal toxicity. There were no treatment-related deaths. In 7/11 patients with evaluable computerized tomographic (CT) scans there was a decrease in maximum diameter of the primary tumour after melphalan. Complete response was achieved in 6 patients, of whom 3 are well and have no evidence of disease at 35, 33 and 18 months from completion of all treatment; however, although survival (median 23 months) of all 12 autografted patients is longer than that of 28 comparable children treated between 1970-77 with conventional chemotherapy (median 14 months) the difference is not statistically significant. High-dose melphalan is a safe and tolerable treatment in children when combined with autologous marrow grafting, but further study is required to determine whether the procedure can improve prognosis for patients with advanced neuroblastoma.
Topics: Adolescent; Bone Marrow Transplantation; Child; Child, Preschool; Drug Administration Schedule; Humans; Melphalan; Neuroblastoma; Tomography, X-Ray Computed
PubMed: 7037033
DOI: 10.1038/bjc.1982.11 -
Cancer Chemotherapy and Pharmacology 1982Nine patients with myeloma were studied over 13 oral administrations of 10 mg melphalan and 5-10 mg prednisolone. Plasma melphalan concentrations were estimated by...
Nine patients with myeloma were studied over 13 oral administrations of 10 mg melphalan and 5-10 mg prednisolone. Plasma melphalan concentrations were estimated by high-pressure liquid chromatography, prednisolone concentrations by quantitative thin-layer chromatography. The mean plasma half-life of unchanged melphalan was 0.9 +/- 0.5 (SD) h. The 'lag-time' before melphalan was detected in the plasma varied from 1 to 4 h, the mean peak concentration was 96 +/- 21 ng/ml, and the mean area under the plasma concentration by time curve was 160 +/- 78 ng h/ml. This variability was consistent with observations made elsewhere following much higher oral doses of melphalan and illustrates the relatively wide interindividual variability of absorption. Observations made in the same subjects on two separate occasions showed lower variability. The melphalan elimination rate was not significantly affected by moderate impairment of creatinine clearance (to 31 ml/min). Absorption of prednisolone in five of these patients was apparently normal and unaffected by concurrent administration of melphalan.
Topics: Adult; Aged; Female; Humans; Intestinal Absorption; Kinetics; Male; Melphalan; Middle Aged; Multiple Myeloma; Prednisolone
PubMed: 7139852
DOI: 10.1007/BF00296764 -
Rapid Communications in Mass... Mar 2016Melphalan is a frequently used chemotherapeutical agent for the treatment of myeloma, breast cancer, ovarian cancer and sarcoma of soft tissue. A good knowledge of the...
RATIONALE
Melphalan is a frequently used chemotherapeutical agent for the treatment of myeloma, breast cancer, ovarian cancer and sarcoma of soft tissue. A good knowledge of the reactivity of the drug toward the different amino acids, e.g. covalent adduct formation, is crucial for the understanding of its activity and side effects during cancer treatment.
METHODS
The reactivity of melphalan and sites of adduct formation were studied by in vitro incubation of melphalan with free amino acids and glutathione as a model peptide. The formed covalent adducts were investigated using ultra-performance liquid chromatography tandem mass spectrometry (UPLC/MS/MS) using a triple-quadrupole instrument. Accurate mass measurements for the confirmation of characteristic product ions were performed on a quadrupole time-of-flight (QTOF) mass spectrometer.
RESULTS
The incubation of melphalan with different classes of amino acids resulted in the formation of adducts on the amino and carboxyl termini, as well as adduct formation in the reactive side chains of Cys, Met, Tyr, His, Lys, Asp and Glu. All these melphalan adducts could be identified by their characteristic collision-induced dissociation (CID) product ion patterns.
CONCLUSIONS
The present study demonstrates the reactivity of melphalan towards the functional groups of amino acids. The different alkylation site products show distinctive fragmentation patterns, which enable a fast identification of the different melphalan adducts. This study is a first important step towards a better understanding of the adduct formation in more complex molecules, e.g. peptides and proteins.
Topics: Amino Acids; Chromatography, Liquid; DNA Adducts; Melphalan; Models, Chemical; Peptides; Tandem Mass Spectrometry
PubMed: 26864525
DOI: 10.1002/rcm.7489 -
Cancer Chemotherapy and Pharmacology 1986Fifteen patients receiving oral melphalan (4.2-5.3 mg/m2) for a variety of neoplastic disorders were studied. Ten patients received the drug on separate occasions, with... (Comparative Study)
Comparative Study
Fifteen patients receiving oral melphalan (4.2-5.3 mg/m2) for a variety of neoplastic disorders were studied. Ten patients received the drug on separate occasions, with and without a standardized breakfast. Eight of these patients also received an IV bolus dose (5 mg/m2) to determine bioavailability. Serial melphalan plasma samples were taken over 5 h after administration and assayed by high-performance liquid chromatography. The median area under the curve (AUC) when taken fasting was 179 (range 95-336) ng X h X ml-1, and when taken with food, 122 (47-227) ng X h X ml-1, the median reduction being 39% (P less than 0.01). In one patient, who died before completing the study, the drug was not detectable at all after being taken with food. In the eight patients who were also given IV melphalan, the median terminal melphalan half-life (57 min, range 38-71) was no different from its oral half-life [55 (27-104) min fasting; 55 (30-72) min with food] (P greater than 0.1). In these patients bioavailability was 85% (26-96)% when the drug was taken fasting and 58% (7-99)% when taken with food (P less than 0.025). Median clearance following IV administration was 362 ml/min/m2 (range 104-694). It was found that the melphalan level in a single plasma sample drawn 1.5 h after administration was highly predictive of oral melphalan AUC (rs = 0.915, P less than 0.1). This study suggests that to ensure optimum absorption of the drug, melphalan should not be taken with food.
Topics: Absorption; Administration, Oral; Aged; Biological Availability; Chromatography, High Pressure Liquid; Fasting; Female; Food; Humans; Injections, Intravenous; Kinetics; Male; Melphalan; Middle Aged; Neoplasms
PubMed: 3948305
DOI: 10.1007/BF00256176 -
British Journal of Cancer 1997The effects of the diatomic radical, nitric oxide (NO), on melphalan-induced cytotoxicity in Chinese hamster V79 and human MCF-7 breast cancer cells were studied using...
The effects of the diatomic radical, nitric oxide (NO), on melphalan-induced cytotoxicity in Chinese hamster V79 and human MCF-7 breast cancer cells were studied using clonogenic assays. NO delivered by the NO-releasing agent (C2H5)2N[N(O)NO]- Na+ (DEA/NO; 1 mM) resulted in enhancement of melphalan-mediated toxicity in Chinese hamster V79 lung fibroblasts and human breast cancer (MCF-7) cells by 3.6- and 4.3-fold, respectively, at the IC50 level. Nitrite/nitrate and diethylamine, the ultimate end products of DEA/NO decomposition, had little effect on melphalan cytotoxicity, which suggests that NO was responsible for the sensitization. Whereas maximal sensitization of melphalan cytotoxicity by DEA/NO was observed for simultaneous exposure of DEA/NO and melphalan, cells pretreated with DEA/NO were sensitized to melphalan for several hours after NO exposure. Reversing the order of treatment also resulted in a time-dependent enhancement in melphalan cytotoxicity. To explore possible mechanisms of NO enhancement of melphalan cytotoxicity, the effects of DEA/NO on three factors that might influence melphalan toxicity were examined, namely NO-mediated cell cycle perturbations, intracellular glutathione (GSH) levels and melphalan uptake. NO pretreatment resulted in a delayed entry into S phase and a G2/M block for both V79 and MCF-7 cells; however, cell cycle redistribution for V79 cells occurred after the cells returned to a level of cell survival, consistent with treatment with melphalan alone. After 15 min exposure of V79 cells to DEA/NO (1 mM), GSH levels were reduced to 40% of control values; however, GSH levels recovered fully after 1 h and were elevated 2 h after DEA/NO incubation. In contrast, DEA/NO (1 mM) incubation did not reduce GSH levels significantly in MCF-7 cells (approximately 10%). Melphalan uptake was increased by 33% after DEA/NO exposure in V79 cells. From these results enhancement of melphalan cytotoxicity mediated by NO appears to be complex and may involve several pathways, including possibly alteration of the repair of melphalan-induced lesions. Our observations may give insights for improving tumour kill with melphalan using either exogenous or possibly endogenous sources of NO.
Topics: Animals; Buthionine Sulfoximine; Cricetinae; DNA Repair; Drug Synergism; Glutathione; Humans; Melphalan; Nitric Oxide; Tumor Cells, Cultured
PubMed: 9252199
DOI: 10.1038/bjc.1997.386