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Journal of Pharmaceutical Sciences Mar 1985A stability-indicating high-performance liquid chromatographic assay has been used to investigate the stability of solutions of melphalan under conditions that pertain...
A stability-indicating high-performance liquid chromatographic assay has been used to investigate the stability of solutions of melphalan under conditions that pertain to setting up in vitro chemosensitivity assays. Melphalan (1 and 20 micrograms/mL) was found to be 30% more stable in 150 mM NaCl solution (normal saline) than in Dulbecco's phosphate-buffered saline. The drug stored at 20 micrograms/mL in normal saline at room temperature (21.5 degrees C) lost 5% of its activity (t0.95) in 1.5 h; at 5 degrees C the t0.95 was 20 h. From an Arrhenius plot of the results, the activation energy of the hydrolysis reaction in normal saline was 100.2 kJ/mol. Less than 5% of drug activity was lost when solutions of melphalan were (a) stored at -20 degrees C and -35 degrees C for 7 months, (b) frozen and thawed up to four times, or (c) filtered through various membranes. Drug degradation was not affected by storage-container material. The half-life of melphalan in a Roswell Park Memorial Institute medium containing 10% fetal bovine serum at 37 degrees C was 1.13 +/- 0.10 h; the presence of 0.3% agar had no effect. It is suggested that melphalan be handled at temperatures greater than 5 degrees C for a minimum of time, but solutions of the drug can be stored for at least 6 and possibly up to 12 months at -20 degrees C without significant deterioration taking place.
Topics: Drug Compounding; Drug Stability; Drug Storage; Filtration; Freezing; Half-Life; Melphalan; Temperature; Time Factors
PubMed: 4009450
DOI: 10.1002/jps.2600740329 -
Haematologica Nov 2007As new therapeutic options for multiple myeloma (MM) emerge, identification of biological markers which could predict clinical response to standard treatment with... (Clinical Trial)
Clinical Trial
BACKGROUND AND OBJECTIVES
As new therapeutic options for multiple myeloma (MM) emerge, identification of biological markers which could predict clinical response to standard treatment with high-dose melphalan (HDM) supported by autologous stem cell transplantation (ASCT) becomes more important.
DESIGN AND METHODS
Melphalan-induced damage formation and repair of monoadducts and interstrand cross-links in the p53 gene were studied in peripheral blood mononuclear cells obtained from 32 patients prior to therapy. The same studies were performed in the peripheral blood cells of these patients immediately after subsequent HDM administration. Clinical response and time to progression were correlated with molecular endpoints obtained in vitro.
RESULTS
Values for all molecular end-points examined in vitro were highly correlated with the respective in vivo results within individual patients. All in vitro end-points indicative of increased DNA damage and slower repair capacity were predictive of a favorable response to HDM; the area under the curve of total adducts (AUC-TA) had the highest predictive ability. Using the cut-off value of 736 adducts/10(6) nucleotides x h for the AUC-TA, the positive predictive value for clinical response to HDM was 100%. Moreover, patients with an AUC-TA equal to or higher than this cut-off value had significantly longer times to progression than had patients with an AUC-TA lower than the cut-off value (hazard ratio 0.19; 95% confidence intervals 0.06 to 0.60).
INTERPRETATION AND CONCLUSIONS
An in vitro assay to quantify melphalan-induced p53-specific damage formation/repair can be used to select those patients with MM who are more likely to benefit from HDM supported by ASCT.
Topics: Adult; Aged; DNA Damage; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Patient Selection; Predictive Value of Tests; Treatment Outcome
PubMed: 18024399
DOI: 10.3324/haematol.11435 -
European Journal of Cancer (Oxford,... 1992Levels of melphalan (L-phenylalanine mustard) were measured in the tissues of tumour-bearing limbs treated by isolated limb perfusion (ILP). 41 samples of melanoma...
Levels of melphalan (L-phenylalanine mustard) were measured in the tissues of tumour-bearing limbs treated by isolated limb perfusion (ILP). 41 samples of melanoma tissue, normal fat and skin were excised from 15 patients during ILP. A high performance liquid chromatography assay was used to measure melphalan concentrations. Levels of melphalan were higher in tumour than in fat (P < 0.01, Wilcoxon signed-ranks test), and not significantly different from levels in adjacent skin. In 2 cases there was significant regional toxicity in the treated limb, but this was not related to the levels of melphalan measured in the tissues of the limb. It is encouraging that the concentrations of melphalan which were achieved in large necrotic nodules by ILP were similar to those in well-perfused normal skin.
Topics: Adipose Tissue; Chemotherapy, Cancer, Regional Perfusion; Humans; Melanoma; Melphalan; Skin; Tissue Distribution
PubMed: 1389515
DOI: 10.1016/0959-8049(92)90009-q -
PloS One 2020Intravitreal melphalan injections are commonly used in the treatment for intraocular retinoblastoma. This study compares retinal toxicity and ocular survival between two... (Comparative Study)
Comparative Study
OBJECTIVE
Intravitreal melphalan injections are commonly used in the treatment for intraocular retinoblastoma. This study compares retinal toxicity and ocular survival between two formulations, with and without propylene glycol (Alkeran vs. Evomela, respectively).
METHODS
A retrospective cohort study of retinoblastoma patients who received intravitreal injections of Alkeran and Evomela at 30 μg from September 2012 to January 2019 at a single tertiary care center were enrolled. Retinal toxicity was measured using electroretinogram (ERG) and compared using a multivariate analysis of 338 injections in 101 eyes of 96 patients. Ocular survival of 163 eyes in 150 patients was compared across formulations using Cox proportional hazards model. Eyes were censored at the time a patient received a dose other than 30 μg.
RESULTS
Overall, ERG decline (mean, 95% CI) for each injection was -5.58 μV (-7.17, -3.99). No significant differences in ERG decrement were found between Alkeran (with alcohol) -5.52uV (-6.99, -4.05). and Evomela (without alcohol) -5.65uV (-8.31 to -2.98) formulations (p = 0.93). Ocular survival at 24 months was 93.6% (95% CI 86.2, 97.1) with alcohol and 91.7% (95% CI 53.9, 98.8) without alcohol. The hazard ratio (HR) for without vs with alcohol was 0.50 (95% CI 0.06 to 4.07); no significant difference in ocular survival was found between formulations (p = 0.52).
CONCLUSIONS AND RELEVANCE
No differences were found in retinal toxicity and ocular survival between 30 μg intravitreal injections of Alkeran or Evomela for intraocular retinoblastoma. Given the increased stability of Evomela, intravitreal treatment could be expanded to centers without the ability to supply Alkeran due to its shorter safety window; however, Alkeran is less expensive. For those with existing infrastructure, Alkeran is a comparable, cost-effective alternative.
Topics: Adolescent; Antineoplastic Agents, Alkylating; Child; Child, Preschool; Humans; Infant; Intravitreal Injections; Melphalan; Retina; Retinal Neoplasms; Retinoblastoma; Treatment Outcome
PubMed: 32609726
DOI: 10.1371/journal.pone.0235016 -
Bone Marrow Transplantation Apr 2019Autologous stem cell transplantation (ASCT) remains a mainstay in the treatment of multiple myeloma (MM). While the procedure is generally safe, toxicities associated...
Autologous stem cell transplantation (ASCT) remains a mainstay in the treatment of multiple myeloma (MM). While the procedure is generally safe, toxicities associated with high-dose melphalan conditioning are common and significantly affect patient quality of life. Recently, a propylene glycol-free melphalan formulation (PG-free MEL; Evomela®) was approved by the United States Food and Drug Administration as an ASCT-conditioning regimen for MM. PG-free MEL is more soluble and stable than propylene glycol-solubilized melphalan (PG-solubilized MEL; Alkeran®). As such, there is speculation that it could decrease toxicities and increase the efficacy of ASCT. We compared the outcomes of patients conditioned with PG-free MEL (n = 216) to PG-solubilized MEL (n = 200) at our institution. The baseline characteristics were similar between the two groups. After Day +0, there were no differences in terms of hospitalizations, neutropenic fevers, intravenous granisetron requirement, World Health Organization grade ≥ 2 oral/esophageal mucositis, intravenous fluid requirement, or narcotic requirement. However, PG-free MEL patients had a higher incidence of diarrhea, which was mostly C. difficile-negative (82% vs. 71%, P = 0.015*). Day + 100 hematologic responses and progression-free survival after ASCT were comparable. In summary, we demonstrate that switching to PG-free MEL did not significantly reduce short-term complications of ASCT or improve outcomes in MM.
Topics: Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Multiple Myeloma; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome
PubMed: 30116014
DOI: 10.1038/s41409-018-0302-6 -
PloS One 2022Percutaneous hepatic perfusion with melphalan (M-PHP) is increasingly used in patients with liver metastases from various primary tumors, yet data on colorectal liver...
PURPOSE
Percutaneous hepatic perfusion with melphalan (M-PHP) is increasingly used in patients with liver metastases from various primary tumors, yet data on colorectal liver metastases (CRLM) are limited. The aim of this study was to prospectively evaluate the efficacy and safety of M-PHP in patients with CRLM.
MATERIALS AND METHODS
Prospective, single-center, single-arm phase II study of M-PHP with hemofiltration in patients with unresectable CRLM. Proven, extrahepatic metastatic disease was one of the exclusion criteria. Primary outcomes were overall response rate (ORR) and best overall response (BOR). Secondary outcomes were overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety.
RESULTS
A total of 14 M-PHP procedures were performed in eight patients between March 2014 and December 2015. All patients (median age 56 years, ranging from 46 to 68) had received (extensive) systemic chemotherapy before entering the study. The ORR was 25.0%, with two out of eight patients showing partial response as BOR. Median OS was 17.3 months (ranging from 2.6 to 30.9) with a one-year OS of 50.0%. Median PFS and hPFS were 4.4 and 4.5 months, respectively. No serious adverse events occurred. Grade 3/4 hematologic adverse events were observed in the majority of patients, though all were transient and well-manageable.
CONCLUSION
M-PHP is a safe procedure with only limited efficacy in patients with unresectable CRLM who already showed progression of disease after receiving one or more systemic treatment regimens.
Topics: Aged; Colorectal Neoplasms; Extracorporeal Circulation; Female; Hemofiltration; Humans; Liver; Liver Neoplasms; Male; Melphalan; Middle Aged; Perfusion; Progression-Free Survival
PubMed: 35025911
DOI: 10.1371/journal.pone.0261939 -
European Journal of Clinical... Dec 2022To evaluate the accuracy of melphalan test dose pharmacokinetic (PK) predictions of the subsequent high dose (HDM) area under the concentration-versus-time curve (AUC)...
AIM
To evaluate the accuracy of melphalan test dose pharmacokinetic (PK) predictions of the subsequent high dose (HDM) area under the concentration-versus-time curve (AUC) and to identify sources of prediction error (PE).
METHODS
A prospective multicentre PK study was conducted in 40 myeloma patients of median age 60 (range:35-71) years using a 20 mg/m test dose administered 1-3 days prior to HDM (predominantly 180 mg/m). PK data were collected post the test and high doses to compare predicted versus actual AUCs determined using the trapezoidal rule. Test and high dose infusion concentration, volume and duration and the time from preparation to infusion were compared using the paired Wilcoxin rank sign test. The impact of Melphalan administration parameters on PE was evaluated using the Mann-Whitney test. The predictive capacity of a previously published population PK (PopPK) model was also examined.
RESULTS
Predicted HDM AUC was within 15% of the observed values in only 63% of patients when analysed using the trapezoidal rule and 70% of patients using PopPK. Test dose infusion concentration, volume, duration and time from preparation to infusion were significantly lower than for HDM (p < 0.005). Test dose administration within 15 min of reconstitution (n = 5) was associated with significantly lower PE than administration times of 16-60 min (n = 22), p < 0.05. Test and HDM infusion concentrations were lower in patients with large PE (> ± 15%), but the differences were not significant (p = 0.078, 0.228, respectively).
CONCLUSION
Test dose PK has the potential to predict subsequent HDM exposure to achieve a target AUC once melphalan administration parameters are optimised to account for stability issues in the formulation.
Topics: Humans; Middle Aged; Melphalan; Multiple Myeloma; Prospective Studies; Hematopoietic Stem Cell Transplantation; Area Under Curve
PubMed: 36205743
DOI: 10.1007/s00228-022-03396-x -
Cancer Chemotherapy and Pharmacology 1998The objective of the present study was to examine the relevance of collagenase in the antitumor action of a melphalan peptide (MHP) with a collagenase-cleavable...
PURPOSE
The objective of the present study was to examine the relevance of collagenase in the antitumor action of a melphalan peptide (MHP) with a collagenase-cleavable sequence. The question was addressed as to whether collagenase may act as an activator or a target in the antiproliferative mechanism of MHP.
METHODS
Melphalan was inserted into peptides representing the sequence Pro-Gln-Gly-Ile-Ala.Gly of the collagenase-cleavable site in collagens. Changes in growth and collagenase IV activities of HT-1080, HT-29, HT-168, and MCF-7 cell cultures were investigated.
RESULTS
The present investigations provide data indicating that Pro-Gln-Gly-Ile-Mel-Gly (melphalan hexapeptide, MHP) is a substrate for both bacterial and 72-kDa type IV collagenases and that in this way it can generate Ile-Mel-Gly (melphalan tripeptide, MTP) of higher cytotoxic potency. Indeed, the formation of MTP was detected in the conditioned medium of HT-1080, a collagenase IV-producing human fibrosarcoma. In a comparison of equimolar concentrations of melphalan and its two peptide derivatives (MHP and MTP), superior antiproliferative action of MTP was seen in HT-29, HT-1080, and HT-168 tumor cell cultures. However, the relatively modest cytostatic actions of MHP were increased when bacterial collagenase was added to the cell cultures. After melphalan treatment, reduced levels of both 92 and 72-kDa type IV collagenases were seen in the HT-1080 cell cultures. However, the reduction of collagenase activity and the cell counts did not run parallel in the MTP- or MHP-treated cultures; indeed, collagenase activity related to cell numbers showed an elevated level.
CONCLUSIONS
As the conversion of MHP to the more toxic MTP was detected in the presence of collagenases, it is possible that collagenase-directed activation of prodrugs may be a promising approach for the development of more selective cytostatic drugs against malignant tumors with high collagenase activities.
Topics: Antineoplastic Agents, Alkylating; Cell Division; Collagenases; Drug Design; Humans; In Vitro Techniques; Melphalan; Peptide Fragments; Prodrugs; Substrate Specificity; Tumor Cells, Cultured
PubMed: 9488598
DOI: 10.1007/s002800050742 -
International Journal of Biological... Dec 2019Melphalan (MEL) is an effective chemotherapeutic agent for treatment of retinoblastoma (Rb) which is the most common childhood malignancy. However, the inherent...
Melphalan (MEL) is an effective chemotherapeutic agent for treatment of retinoblastoma (Rb) which is the most common childhood malignancy. However, the inherent cardiopulmonary toxicity and hazardous integration limit its therapeutic effect on RB. N-Acetylheparosan (AH), a natural heparin-like polysaccharide in mammals with long circulation effect and good biocompatibility, was linked by d-α-tocopherol acid succinate (VES) via and cystamine (CYS) to synthesize reduction-responsive N-acetylheparosan-CYS-Vitamin E succinate (AHV) copolymers. In addition, CYS was replaced by adipic acid dihydrazide (ADH) to obtain a control of non-reduction-responsive polymers N-acetylheparosan-ADH-Vitamin E succinate (ADV). MEL-loaded AHV micelles (MEL/AHV) as well as ADV micelles (MEL/ADV) were prepared with small particle size and high drug loading content. In vitro drug release showed that MEL/AHV micelles presented obvious reduction-triggered release behavior compared with MEL/ADV. In vitro antitumor effects were investigated using WERI-Rb-1 retinoblastoma cells. Cytotoxicity experiments showed that the IC of MEL/AHV was significantly lower than that of free MEL and MEL/ADV, suggesting that MEL/AHV enhanced the cytotoxicity against retinoblastoma cells. Furthermore, MEL/AHV micelles were more easily uptaken by multiple pathways compared with MEL/ADV and free MEL. Therefore, MEL/AHV might be a potential delivery system for enhanced delivery of melphalan to Rb cells.
Topics: Antineoplastic Agents, Alkylating; Cell Line, Tumor; Cell Survival; Drug Liberation; Humans; Magnetic Resonance Spectroscopy; Melphalan; Micelles; Models, Biological; Polymers; Retinoblastoma
PubMed: 31521654
DOI: 10.1016/j.ijbiomac.2019.09.085 -
Transplantation Proceedings Feb 1989
Review
Topics: Bone Marrow Transplantation; Combined Modality Therapy; Graft vs Host Disease; Humans; Leukemia; Melphalan; Whole-Body Irradiation
PubMed: 2650403
DOI: No ID Found