We have studied the disposition and elimination of melphalan after intravenous administration in 9 patients with cancer. High-pressure liquid chromatography and (14)C-melphalan were used to assay drug concentration in plasma and urine. Composite plasma t1/2alpha was 7.7 +/- 3.3 and t1/2beta was 108 +/- 20.8 min for 8 of the patients. The mean 24-hr urinary excretion of melphalan was 13.0 +/- 5.4% of the administered dose. In 2 patients, 80% to 100% of the measured (14)C counts in plasma and urine samples at each study interval, up to 24 hr after drug administration, could be accounted for by the sum of parent compound, monohydroxy and dihydroxy products, and methanol nonextractable radioactivity (i.e., protein-bound activity). These data and evidence of rapid disappearance from plasma at 37 degrees /C/ in vitro suggest that spontaneous degradation, and not enzymatic metabolism, is the major determinant of the t1/2 of melphalan in vivo.
Melphalan is apparently eliminated from plasma by spontaneous hydrolysis, froming the monohydroxy and dihydroxy derivatives of the drug; no other metabolites have been identified in humans.
Melphalan is not actively metabolised, it spontaneously degrades to mono and dihydroxy products.
Route of Elimination: The 24-hour urinary excretion of parent drug in these patients was 10% Њ± 4.5%, suggesting that renal clearance is not a major route of elimination of parent drug.
Half Life: 1.5 (±0.83) hours
IDENTIFICATION AND USE: Melphalan is an alkylating agent that is a white to buff odorless powder at room temperature. Melphalan is used as a drug to treat cancer and other medical conditions, including ovarian cancer, malignant melanoma, multiple myeloma, breast cancer, advanced prostate cancer, testicular cancer, chronic myelogenous leukemia, osteogenic sarcoma, polycythemia vera, amyloidosis, and scleromyxedema (a rare skin disease). It is also used as an insect chemosterilant. HUMAN EXPOSURE AND TOXICITY: Epidemiological studies found that patients treated with melphalan for breast cancer, ovarian cancer, and bone-marrow cancer (multiple myeloma) had an increased risk of leukemia. The risk of leukemia increased with increasing dose of melphalan but was not affected by co-exposure to radiation therapy. Melphalan produces chromatid-type aberrations in peripheral blood lymphocytes taken from cancer patients. ANIMAL STUDIES: There is sufficient evidence for the carcinogenicity of melphalan from studies in experimental animals. When administered by intraperitoneal injection, melphalan caused cancer of lymphatic tissue (lymphosarcoma) in male mice, lung tumors in mice of both sexes, and cancer of the abdominal cavity (sarcoma of the peritoneum) in rats of both sexes. Melphalan produces structural aberrations of chromatid and chromosome types in bone marrow cells of treated rats.
Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases (primarily at the N-7 position of guanine and to a lesser extent, at the N-3 position of adenine), forming monoadducts and resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations.
Mild and transient elevations in serum aminotransferase levels are uncommon with standard doses of melphalan, but occur more commonly with high dose intravenous regimens. The enzyme elevations are usually mild and asymptomatic and do not require dose modification. Clinically apparent liver disease has not been reported with standard doses of melphalan in chemotherapeutic regimens. However, use of high doses of melphalan in preparation for hematopoietic cell (bone marrow and stem cell) transplantation or in local-regional therapy has been associated with sinusoidal obstruction syndrome that can be severe, leading to acute liver failure and death. Onset of sinusoidal obstruction syndrome is usually within 1 to 3 weeks of the myeloablative or high dose therapy, and is characterized by the onset of abdominal pain, hepatomegaly, weight gain and ascites followed by jaundice. The pattern of serum enzyme elevations is usually hepatocellular, with marked increases in serum aminotransferase and lactic dehydrogenase levels and minimal increase in alkaline phosphatase. The severity of injury varies considerably. In mild forms there is serum enzyme elevations without jaundice and with few or no symptoms. In severe instances, there are elevations in prothrombin time and progressive jaundice and hepatic failure. Immunoallergic and autoimmune features are uncommon. The fatality rate is high. Liver biopsy shows centrolobular necrosis and congestion with occlusion of small veins and red cells in sinusoids.
Melphalan has also been used in the regional therapy of nonresectable cancers in a limb, solid organ or even the liver. In isolated, hyperthermic hepatic perfusion with chemotherapeutic agents, the liver is isolated surgically and perfused with melphalan, with or without tumor necrosis factor (or other antineoplastic agents). The perfusion typically lasts for at least 1 hour and results in a high rate of tumor regression, but with a high rate of hepatotoxicity. At least 80% of patients develop significant serum aminotransferase elevations (5 to 20 times ULN) and two-thirds develop jaundice transiently. The liver injury can be severe and even fatal if complicated by severe sinusoidal obstruction syndrome, direct cytotoxicity or hyperthermia or ischemic injury.
Finally, melphalan is a cytotoxic and immunosuppressive agent and has been linked to rare instances of reactivation of hepatitis B which can be severe and even fatal. Reactivation typically occurs in patients with inactive hepatitits B with HBsAg, but no HBeAg and no or only low levels of HBV DNA in serum before treatment. Reactivation is marked by sudden rise in HBV DNA levels and subsequent increases in ALT and, in severe instances, jaundice and signs of hepatic failure. Reactivation can also occur in patients who are HBsAg and HBV DNA negative, but have anti-HBc in serum with or without anti-HBs, a serologic pattern suggestive of recovery from hepatitis B. In this situation, referred to as “reverse seroconversion”, HBV DNA levels arise followed by HBsAg and serum enzyme elevations. Reverse seroconversion tends to be severe. Most cases of reactivation of hepatitis B attributed to cytotoxic alkylating agents such as melphalan have occurred in patients who are also receiving high doses of corticosteroids, which on their own can lead to reactivation. The combination of the two immunosuppressive agents is probably more likely to cause reactivation than either alone.
Likelihood score: B[H] (likely cause of clinically apparent liver injury when used in high doses).
The 24-hour urinary excretion of parent drug in these patients was 10% ± 4.5%, suggesting that renal clearance is not a major route of elimination of parent drug.
来源:DrugBank
吸收、分配和排泄
分布容积
0.5 升/千克
0.5 L/kg
来源:DrugBank
吸收、分配和排泄
GI肠道对吸收美法仑是不完全的且极其多变。
Absorption melphalan from the GI tract is incomplete and extremely variable.
After admin of (3)H-labeled melphalan to Walker carcinoma-bearing rats, radioactivity was found in liver, spleen, kidney, intestine and Walker carcinoma and to lesser extent in bone marrow, muscle, skin, testis and brain, but not in DNA fraction of any of these tissues. Approx 25% of admin radioactivity was excreted in urine during 1st 48 hr.
[EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
申请人：GILEAD APOLLO LLC
公开号：WO2017075056A1
公开（公告）日：2017-05-04
The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.
Heterocyclic derivatives for the treatment of cancer and other proliferative diseases
申请人：——
公开号：US20020143182A1
公开（公告）日：2002-10-03
The invention relates to certain heterocyclic compounds useful for the treatment of cancer and other diseases, having the Formula (I):
1
wherein:
(a) m is an integer 0 or 1;
(b) R
12
is an alkyl, a substituted alkyl, a cycloalkyl, a substituted cycloalkyl, a heterocyclic, a substituted heterocyclic, a heteroaryl, a substituted heteroaryl, an aryl or a substituted aryl residue;
(c) Ar
3
is an aryl, a substituted aryl, a heteroaryl or a substituted heteroaryl residue;
(d) Ar
4
is an aryl, a substituted aryl, a heteroaryl or a substituted heteroaryl residue;
(e) R
5
is hydrogen, hydroxy, alkyl or substituted alkyl;
(f) - - - - - represents a bond present or absent; and
(g) W, X, Y and Z are independently or together C(O)—, C(S), S, O, or NH; or a pharmaceutically acceptable salt thereof.
[EN] COMPOUNDS AND COMPOSITIONS COMPRISING CDK INHIBITORS AND METHODS FOR THE TREATMENT OF CANCER<br/>[FR] COMPOSÉS ET COMPOSITIONS COMPRENANT DES INHIBITEURS DES CDK ET MÉTHODES DE TRAITEMENT DU CANCER
申请人：UNIV GEORGIA STATE RES FOUND
公开号：WO2010129858A1
公开（公告）日：2010-11-11
Disclosed herein are compounds suitable for use as antitumor agents, methods for treating cancer wherein the disclosed compounds are used in making a medicament for the treatment of cancer, methods for treating a tumor comprising, administering to a subject a composition comprising one or more of the disclosed cytotoxic agents, and methods for preparing the disclosed antitumor agents.
The present invention provides a cobalamin-drug conjugate suitable for the treatment of tumor related diseases. Cobalamin is indirectly covalently bound to an anti-tumor drug via a cleavable linker and one or more optional spacers. Cobalamin is covalently bound to a first spacer or the cleavable linker via the 5′-OH of the cobalamin ribose ring. The drug is bound to a second spacer of the cleavable linker via an existing or added functional group on the drug. After administration, the conjugate forms a complex with transcobalamin (any of its isoforms). The complex then binds to a receptor on a cell membrane and is taken up into the cell. Once in the cell, an intracellular enzyme cleaves the conjugate thereby releasing the drug. Depending upon the structure of the conjugate, a particular class or type of intracellular enzyme affects the cleavage. Due to the high demand for cobalamin in growing cells, tumor cells typically take up a higher percentage of the conjugate than do normal non-growing cells. The conjugate of the invention advantageously provides a reduced systemic toxicity and enhanced efficacy as compared to a corresponding free drug.
[EN] 2-QUINOLONE DERIVED INHIBITORS OF BCL6<br/>[FR] INHIBITEURS DE BCL6 DÉRIVÉS DE 2-QUINOLONE
申请人：CANCER RESEARCH TECH LTD
公开号：WO2018215798A1
公开（公告）日：2018-11-29
The present invention relates to compounds of formula I that function as inhibitors of BCL6(B- cell lymphoma 6) activity: Formula I wherein X1, X2, X3, R1, R2, R3, R4 and R5 are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer,as well as other diseases or conditions in which BCL6 activity is implicated.
