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American Journal of Hospital Pharmacy May 1994
Comparative Study
Topics: Drug Incompatibility; Drug Stability; Humans; Melphalan
PubMed: 8042647
DOI: No ID Found -
Reproductive Toxicology (Elmsford, N.Y.) Oct 2022Melphalan significantly contributes to the increase in childhood cancer survival rate. It acts as a gonadotoxic agent and leads to testes damage, dysbalance in gonadal...
Melphalan significantly contributes to the increase in childhood cancer survival rate. It acts as a gonadotoxic agent and leads to testes damage, dysbalance in gonadal hormones, and impairment in the germ cell proliferation. Therefore, it might be a potent threat to male fertility in individuals who have undergone melphalan treatment during childhood cancer. However, the molecular mechanisms of melphalan-induced gonadal damage are not yet fully explored and they need to be investigated to determine the benefit-risk profile. In the present study, juvenile male SD rats were subjected to single and intermittent cycles of melphalan exposure in a dose-dependent (0.375, 0.75 and 1.5 mg/kg) manner. Methods of end-points evaluations were quantification of micronuclei formation in peripheral blood, sperm count, sperm motility and head morphology, sperm and testicular DNA damage, histological studies in testes, oxidative/nitrosative stress parameters. A single cycle of exposure at high dose (1.5 mg/kg) produced significant effect on micronuclei formation only after the first week of exposure, whereas failed to produce significant effect at the end of the sixth week. Intermittent cycles of exposure at the dose of 1.5 mg/kg produced significant alterations in all the parameters (micronuclei in peripheral blood, testes and epididymides weight and length, MDA, GSH and nitrite levels, sperm count and motility, sperm head morphology, testicular and sperm DNA damage, protein expression in testes and histological parameters). So, time of exposure as well as the amount of exposure (total dosage administered) is critical in determining the magnitude of the damage in germ cell risk assessment.
Topics: Animals; Germ Cells; Male; Melphalan; Nitrites; Oxidative Stress; Rats; Rats, Sprague-Dawley; Risk Assessment; Semen; Sperm Count; Sperm Motility; Spermatozoa; Testis
PubMed: 35961530
DOI: 10.1016/j.reprotox.2022.08.006 -
Cancer Treatment Reports Dec 1987Forty children with multiply relapsed cancers received iv melphalan at three doses: 30 mg/m2, 45 mg/m2, and 60 mg/m2. The hematologic toxicity was severe and protracted...
Forty children with multiply relapsed cancers received iv melphalan at three doses: 30 mg/m2, 45 mg/m2, and 60 mg/m2. The hematologic toxicity was severe and protracted at all dose levels, whether or not the bone marrow was involved with tumor. Of 39 evaluable patients, 37 had grade 3 or 4 hematologic toxicity. Nonhematologic toxic effects were infrequent and not severe. Two complete responses (Hodgkin's disease, rhabdomyosarcoma), eight partial responses, and 30 failures were seen. There appeared to be a very narrow margin between efficacy and toxicity. Further study of melphalan in pediatric tumors may be warranted in special circumstances: in higher doses (greater than 100 mg/m2) as cytoreduction therapy for specific cancers with marrow rescue, or as part of combination therapy in certain cancers (eg, lymphoma, sarcoma), possibly at doses of 20 to 30 mg/m2 every 4 weeks.
Topics: Child; Dose-Response Relationship, Drug; Humans; Melphalan; Neoplasms
PubMed: 3690538
DOI: No ID Found -
Scientific Reports Dec 2019Inter-individual differences in DNA adduct formation and repair influence the response to melphalan treatment, however, further clinical investigation of this...
Inter-individual differences in DNA adduct formation and repair influence the response to melphalan treatment, however, further clinical investigation of this variability requires a logistically feasible and reproducible bioassay. Our improved fluorescence-based QPCR-block assay is robust, has good precision, and improved throughput. It also incorporates direct PCR amplification from melphalan exposed PBMC using commercially available blood tubes and extraction kits to maximise the utility of this assay for future clinical studies. Using this assay we have demonstrated reproducible inter-individual differences in melphalan-induced QPCR-block across individual PBMC donors. As proof-of-principle we assessed nine healthy donors and found a 7.8 fold range in sensitivity following exposure of PBMC ex vivo. This likely reflects differences in melphalan transport into cells as well as differences in DNA adduct repair proficiency. This improved bioassay may be useful for assessment of these processes in patients about to receive melphalan treatment.
Topics: Antineoplastic Agents, Alkylating; DNA Damage; High-Throughput Screening Assays; Humans; Leukocytes, Mononuclear; Melphalan
PubMed: 31827154
DOI: 10.1038/s41598-019-55161-3 -
Bone Marrow Transplantation Dec 2018
Topics: Aged; Amyloidosis; Biomarkers; Female; Humans; Male; Melphalan; Middle Aged; Stem Cell Transplantation
PubMed: 29884854
DOI: 10.1038/s41409-018-0242-1 -
FEBS Letters Jan 1985In search of an affinity label of the opioid receptor, the nitrogen mustard melphalan, Mel, was built into the peptide chain of D-Ala2-Leu5-enkephalin (DALE) methyl...
In search of an affinity label of the opioid receptor, the nitrogen mustard melphalan, Mel, was built into the peptide chain of D-Ala2-Leu5-enkephalin (DALE) methyl ester in different positions. We report now that in contrast to the previous observations that an intact Tyr in position 1 is essential for opioid activity [(1980) Annu. Rev. Pharmacol. Toxicol. 20, 81-110], substitution of Tyr by Mel did not result in a loss of the binding affinity. Mel1, Leu5-enkephalin-OMe competed for the binding sites of [3H]naloxone as potently as DALE did; IC50 values for both compounds were 50 nM. Mel substitution has led to one order potency decrease in binding to the delta-sites. 0.5-1 microM of the compound irreversibly inactivates 50% of the binding sites of [3H]naloxone, and 5-10 microM of that of [3H]DALE. These results shed new light on the structural requirements established for opioid peptides. In addition, the new derivative can be used as an affinity label of the opioid receptor.
Topics: Animals; Binding, Competitive; Brain; Cell Membrane; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Kinetics; Melphalan; Naloxone; Rats; Receptors, Opioid
PubMed: 2981183
DOI: 10.1016/0014-5793(85)80197-6 -
Melanoma Research Dec 1994Isolated limb perfusion with melphalan is a long-standing treatment for melanoma but the clinical conditions have not been subjected to a systematic evaluation. In order...
Isolated limb perfusion with melphalan is a long-standing treatment for melanoma but the clinical conditions have not been subjected to a systematic evaluation. In order to establish optimal conditions for perfusion, three human melanoma cell lines were cultured with melphalan in vitro under conditions comparable to in vivo therapy. The most important findings were that: (a) 41.5 degrees C was synergistic for melphalan killing of three human melanoma cell lines; (b) prolonging the treatment time beyond 1 h had little additional toxicity; and (c) varying the initial pH of the culture medium had no effect. After 1 h of treatment, cells accumulated more melphalan at 41.5 degrees C than at 37 degrees C, relative to the extracellular concentration. A cell line (MM418) derived from a primary tumour was the most resistant of the three lines; pigmented or non-pigmented sublines were equally resistant. The A2058 line showed the lowest level of synergism with hyperthermia, and displayed a marked plateau at 10% of controls in the dose-response for survival, yet no melphalan-resistant subpopulation could be isolated. The implications of this work are that (a) enhanced cellular uptake of melphalan may account for hyperthermic synergism of melphalan; (b) varying conditions other than treatment time will be necessary to deal with the variation in resistance between tumours; and (c) repeated cycles of treatment may be needed for phenotypes such as A2058 where melphalan resistance appears to be based on an epigenetic mechanism.
Topics: Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Resistance; Drug Synergism; Extremities; Humans; Hyperthermia, Induced; Melanoma; Melphalan; Skin Neoplasms; Temperature; Tumor Cells, Cultured
PubMed: 7703715
DOI: 10.1097/00008390-199412000-00004 -
Drugs in R&D Sep 2015Melphalan is an alkylating agent frequently used in an intravenous formulation to treat hematologic malignancies and solid tumors in both adults and children. According...
Melphalan is an alkylating agent frequently used in an intravenous formulation to treat hematologic malignancies and solid tumors in both adults and children. According to the manufacturer, melphalan is stable in sterile 0.9% sodium chloride for 90 min at room temperature (RT). Several authors have studied the stability of different concentrations of melphalan; however, most were not adapted to the current manufacturing process applied in pharmaceutical centralized units. This study was conducted to determine the stability of melphalan in 0.9% sodium chloride solutions at concentrations used for intravenous injection in practice. Melphalan is commonly prepared in diluted solutions ranging from 2 to 4 mg/ml for the treatment of adult patients and at lower concentrations (down to 0.5 mg/ml) for pediatric use. Accordingly, these were the three concentrations chosen for this study. Melphalan concentrations were measured with high-performance thin-layer chromatography (HPTLC). At RT, admixtures prepared at 4 mg/ml were stable for up to 8 h without protection from light; however, at lower concentrations, such as 0.5 and 2 mg/ml, stability did not exceed 2 h. When refrigerated, melphalan was stable for 24 h at 2 mg/ml; however, at 0.5 and 4 mg/ml, the drug was not stable. Melphalan solutions present with limited stability at 0.5, 2, and 4 mg/ml and are not adapted for delayed administration in pharmaceutical centralized units. However, at 4 mg/ml and at RT, a stability of 8 h is very interesting in practice and allows sufficient time for preparation, pharmaceutical control, transport, and administration.
Topics: Drug Packaging; Drug Stability; Humans; Injections; Melphalan; Polyvinyl Chloride; Sodium Chloride
PubMed: 26178037
DOI: 10.1007/s40268-015-0098-4 -
Annals of Internal Medicine Jul 1984We administered melphalan by the intraperitoneal route to investigate its toxicity and pharmacokinetics. The drug was instilled with 2 litres of fluid and allowed to...
We administered melphalan by the intraperitoneal route to investigate its toxicity and pharmacokinetics. The drug was instilled with 2 litres of fluid and allowed to dwell in the peritoneal cavity for 4 hours. No local toxicity was detected by clinical examination, laboratory tests, or histologic examination. The intraperitoneal route allowed the dose to be increased to approximately three times the maximum dose tolerated intravenously before drug leaking into the systemic circulation produced dose-limiting myelosuppression. The peak peritoneal concentration averaged 93-fold greater than the plasma concentration, and total drug exposure for the peritoneal cavity averaged 63-fold greater than that for plasma. Tumor regressions were observed in patients with ovarian carcinoma and gastrointestinal adenocarcinomas. This study shows that from the pharmacologic point of view, if any portion of the tumor can be reached by intraperitoneal instillation, then there is a very strong rationale for the administration of melphalan by the intraperitoneal route, rather than the oral or intravenous route, for the treatment of tumors confined to the peritoneal cavity.
Topics: Adult; Aged; Ascites; Ascitic Fluid; Bone Marrow Diseases; Colonic Neoplasms; Female; Humans; Infusions, Parenteral; Kinetics; Laparotomy; Male; Melphalan; Middle Aged; Models, Biological; Neoplasms; Ovarian Neoplasms; Pancreatic Neoplasms; Peritoneal Cavity; Stomach Neoplasms
PubMed: 6732077
DOI: 10.7326/0003-4819-101-1-14 -
Recent Results in Cancer Research.... 1980We have studied the pharmacokinetics of orally administered chlorambucil and melphalan in patients with hematologic malignancies and solid tumors. With a standard oral... (Comparative Study)
Comparative Study
We have studied the pharmacokinetics of orally administered chlorambucil and melphalan in patients with hematologic malignancies and solid tumors. With a standard oral dose of 0.6 mg/kg, chlorambucil showed much more rapid systemic appearance than did melphalan and had a mean peak plasma concentration and area under the plasma disappearance curve which was 3-4 times greater than that observed in patients receiving melphalan. Melphalan had extremely variable systemic availability which was not observed with chlorambucil, and was not related to problems in tablet formulation. Chlorambucil undergoes extensive active metabolism to phenylacetic acid mustard, whereas melphalan undergoes rapid chemical degradation and has little, if any, active metabolism. On a pharmacokinetic basis, chlorambucil's greater in vitro stability, its more rapid and predictable systemic availability after oral dosing, and its extremely low urinary excretion make it a more predictable alkylating agent for clinical use than melphalan, especially for patients with reduced renal function.
Topics: Biotransformation; Chlorambucil; Humans; Kinetics; Melphalan
PubMed: 7444135
DOI: 10.1007/978-3-642-81488-4_16