Details
| Stereochemistry | ACHIRAL |
| Molecular Formula | C9H18N6.ClH |
| Molecular Weight | 246.74 |
| Optical Activity | NONE |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
Cl.CN(C)C1=NC(=NC(=N1)N(C)C)N(C)C
InChI
InChIKey=AKAQBNIEQUSIJL-UHFFFAOYSA-N
InChI=1S/C9H18N6.ClH/c1-13(2)7-10-8(14(3)4)12-9(11-7)15(5)6;/h1-6H3;1H
DescriptionSources: http://www.drugbank.ca/drugs/DB00488Curator's Comment: Description was created based on several sources, including
http://www.rxlist.com/hexalen-drug/warnings-precautions.htm
http://www.survivorlibrary.com/library/anticancer-therapeutics.pdf#page=146
https://books.google.ru/books?hl=ru&lr=&id=VEibBwAAQBAJ&oi=fnd&pg=PP1&dq=Hexamethylmelamine+formaldehide&ots=-eXXGg_pDu&sig=H4nRJZrJvcJ4rK6AIQe68qCP_KI&redir_esc=y#v=onepage&q&f=false
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8456a8db-a7f6-4bc0-86be-e9c8c374140b
Sources: http://www.drugbank.ca/drugs/DB00488
Curator's Comment: Description was created based on several sources, including
http://www.rxlist.com/hexalen-drug/warnings-precautions.htm
http://www.survivorlibrary.com/library/anticancer-therapeutics.pdf#page=146
https://books.google.ru/books?hl=ru&lr=&id=VEibBwAAQBAJ&oi=fnd&pg=PP1&dq=Hexamethylmelamine+formaldehide&ots=-eXXGg_pDu&sig=H4nRJZrJvcJ4rK6AIQe68qCP_KI&redir_esc=y#v=onepage&q&f=false
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8456a8db-a7f6-4bc0-86be-e9c8c374140b
Altretamine is structurally similar to the alkylating agent triethylenemelamine (tretamine). Although Altretamine structurally resembles an alkylating agent, it has not been found to have alkylating activity in vitro. The precise mechanism of Altretamine cytotoxicity is unknown, although several proposals have been made. Altretamine requires N-demethylation in the liver to produce reactive intermediates (formaldehyde and/or iminium species) which covalently bind to DNA, resulting in DNA damage, or act as alkylating agents. Altretamine is used as a palliative treatment for persistent or recurrent ovarian cancer following treatment failure with a cisplatin- or alkylating agent-based combination. Side effects of Altretamine include nausea and vomiting, neurotoxicity (mood disorders, disorders of consciousness, ataxia, dizziness, vertigo), mild to moderate dose-related myelosuppression. Altretamine has been shown to be embryotoxic and teratogenic in rats and rabbits and may cause fetal damage when administered to a pregnant woman. Under the trade name Hexalen, Altretamine, is an antineoplastic agent. It is indicated for use as a single agent in the palliative treatment of patients with persistent or recurrent ovarian cancer following first-line therapy with a cisplatin and/or alkylating agent-based combination.
CNS Activity
Curator's Comment: Altretamine itself has poor CNS penetration. Its demethylated metabolites occur in high concentrations in cerebrospinal fluid and may be concentrated in the brain. Altretamine side effects include central neurotoxicity (rare) and peripheral neurotoxicity.
Additional resources:
https://books.google.ru/books?id=rRP-Wvc5uDgC&pg=PA89&lpg=PA89&dq=altretamine+blood+brain+barrier&source=bl&ots=V11TobJZil&sig=jAHs-S6mwG8qRRIHq1u185BIRuA&hl=ru&sa=X&sqi=2&ved=0ahUKEwiz1pfW5NbLAhUlAHMKHY-DDwgQ6AEITjAH#v=onepage&q=altretamine%20blood%20brain%20barrier&f=false
Approval Year
Targets
| Primary Target | Pharmacology | Condition | Potency |
|---|---|---|---|
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| Palliative | HEXALEN Approved UseINDICATIONS and USAGE HEXALEN® (altretamine) capsules is indicated for use as a single agent in the palliative treatment of patients with persistent or recurrent ovarian cancer following first-line therapy with a cisplatin and/or alkylating agent-based combination. Launch Date1990 |
Cmax
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
790 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/2515524 |
200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered: |
ALTRETAMINE plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE food status: FASTED |
AUC
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
1147 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/2515524 |
200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered: |
ALTRETAMINE plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE food status: FASTED |
T1/2
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
2.2 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/2515524 |
200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered: |
ALTRETAMINE plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE food status: FASTED |
Funbound
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
6% |
ALTRETAMINE plasma | Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN |
Doses
| Dose | Population | Adverse events |
|---|---|---|
260 mg/m2 1 times / day multiple, oral Recommended Dose: 260 mg/m2, 1 times / day Route: oral Route: multiple Dose: 260 mg/m2, 1 times / day Sources: |
unhealthy, 62.0 years (range: 33–81 years) n = 97 Health Status: unhealthy Condition: Epithelial Ovarian Cancer Age Group: 62.0 years (range: 33–81 years) Sex: F Population Size: 97 Sources: |
Other AEs: Granulocytopenia, Anxiety... Other AEs: Granulocytopenia (grade 4, 2 patients) Sources: Anxiety (grade 4, 1 patient) Depression (grade 4, 1 patient) Malaise (grade 3, 7%) Fatigue (grade 3, 7%) Lethargy (grade 3, 7%) Nausea (grade 3, 6%) Vomiting (grade 3, 3%) Paresthesia (grade 3, 1 patient) |
630 mg/m2 1 times / day multiple, parenteral MTD Dose: 630 mg/m2, 1 times / day Route: parenteral Route: multiple Dose: 630 mg/m2, 1 times / day Sources: |
unhealthy, adult |
|
850 mg/m2 single, parenteral MTD Dose: 850 mg/m2 Route: parenteral Route: single Dose: 850 mg/m2 Sources: |
unhealthy, adult |
AEs
| AE | Significance | Dose | Population |
|---|---|---|---|
| Paresthesia | grade 3, 1 patient | 260 mg/m2 1 times / day multiple, oral Recommended Dose: 260 mg/m2, 1 times / day Route: oral Route: multiple Dose: 260 mg/m2, 1 times / day Sources: |
unhealthy, 62.0 years (range: 33–81 years) n = 97 Health Status: unhealthy Condition: Epithelial Ovarian Cancer Age Group: 62.0 years (range: 33–81 years) Sex: F Population Size: 97 Sources: |
| Vomiting | grade 3, 3% | 260 mg/m2 1 times / day multiple, oral Recommended Dose: 260 mg/m2, 1 times / day Route: oral Route: multiple Dose: 260 mg/m2, 1 times / day Sources: |
unhealthy, 62.0 years (range: 33–81 years) n = 97 Health Status: unhealthy Condition: Epithelial Ovarian Cancer Age Group: 62.0 years (range: 33–81 years) Sex: F Population Size: 97 Sources: |
| Nausea | grade 3, 6% | 260 mg/m2 1 times / day multiple, oral Recommended Dose: 260 mg/m2, 1 times / day Route: oral Route: multiple Dose: 260 mg/m2, 1 times / day Sources: |
unhealthy, 62.0 years (range: 33–81 years) n = 97 Health Status: unhealthy Condition: Epithelial Ovarian Cancer Age Group: 62.0 years (range: 33–81 years) Sex: F Population Size: 97 Sources: |
| Fatigue | grade 3, 7% | 260 mg/m2 1 times / day multiple, oral Recommended Dose: 260 mg/m2, 1 times / day Route: oral Route: multiple Dose: 260 mg/m2, 1 times / day Sources: |
unhealthy, 62.0 years (range: 33–81 years) n = 97 Health Status: unhealthy Condition: Epithelial Ovarian Cancer Age Group: 62.0 years (range: 33–81 years) Sex: F Population Size: 97 Sources: |
| Lethargy | grade 3, 7% | 260 mg/m2 1 times / day multiple, oral Recommended Dose: 260 mg/m2, 1 times / day Route: oral Route: multiple Dose: 260 mg/m2, 1 times / day Sources: |
unhealthy, 62.0 years (range: 33–81 years) n = 97 Health Status: unhealthy Condition: Epithelial Ovarian Cancer Age Group: 62.0 years (range: 33–81 years) Sex: F Population Size: 97 Sources: |
| Malaise | grade 3, 7% | 260 mg/m2 1 times / day multiple, oral Recommended Dose: 260 mg/m2, 1 times / day Route: oral Route: multiple Dose: 260 mg/m2, 1 times / day Sources: |
unhealthy, 62.0 years (range: 33–81 years) n = 97 Health Status: unhealthy Condition: Epithelial Ovarian Cancer Age Group: 62.0 years (range: 33–81 years) Sex: F Population Size: 97 Sources: |
| Anxiety | grade 4, 1 patient | 260 mg/m2 1 times / day multiple, oral Recommended Dose: 260 mg/m2, 1 times / day Route: oral Route: multiple Dose: 260 mg/m2, 1 times / day Sources: |
unhealthy, 62.0 years (range: 33–81 years) n = 97 Health Status: unhealthy Condition: Epithelial Ovarian Cancer Age Group: 62.0 years (range: 33–81 years) Sex: F Population Size: 97 Sources: |
| Depression | grade 4, 1 patient | 260 mg/m2 1 times / day multiple, oral Recommended Dose: 260 mg/m2, 1 times / day Route: oral Route: multiple Dose: 260 mg/m2, 1 times / day Sources: |
unhealthy, 62.0 years (range: 33–81 years) n = 97 Health Status: unhealthy Condition: Epithelial Ovarian Cancer Age Group: 62.0 years (range: 33–81 years) Sex: F Population Size: 97 Sources: |
| Granulocytopenia | grade 4, 2 patients | 260 mg/m2 1 times / day multiple, oral Recommended Dose: 260 mg/m2, 1 times / day Route: oral Route: multiple Dose: 260 mg/m2, 1 times / day Sources: |
unhealthy, 62.0 years (range: 33–81 years) n = 97 Health Status: unhealthy Condition: Epithelial Ovarian Cancer Age Group: 62.0 years (range: 33–81 years) Sex: F Population Size: 97 Sources: |
PubMed
| Title | Date | PubMed |
|---|---|---|
| Hexamethylmelamine: an evaluation of its role in the treatment of ovarian cancer. | 1979 Apr 1 |
|
| Phase II evaluation of hexamethylmelamine in advanced breast cancer: a Southwest Oncology Group study. | 1979 Aug |
|
| Single-agent chemotherapy for recurrent carcinoma of the cervix. | 1980 |
|
| Hexamethylmelamine chemotherapy for disseminated endometrial cancer. | 1981 Sep |
|
| Orthostatic hypotension as a complication of hexamethylmelamine antidepressant interaction. | 1983 May |
|
| Randomised trial comparing two combination chemotherapy regimens (Hexa-CAF vs CHAP-5) in advanced ovarian carcinoma. | 1984 Sep 15 |
|
| Incidence of neuropathy in 395 patients with ovarian cancer treated with or without cisplatin. | 1990 Oct 15 |
|
| The w/w+ SMART is a useful tool for the evaluation of pesticides. | 1994 Jul |
|
| Clinical pharmacokinetics of altretamine. | 1995 Jun |
|
| A rapid and systematic review of the clinical effectiveness and cost-effectiveness of topotecan for ovarian cancer. | 2001 |
|
| Altretamine for the treatment of metastatic renal cell carcinoma. A Hoosier Oncology Group trial. | 2001 |
|
| Phase II study of vinorelbine in the treatment of platinum-resistant ovarian carcinoma. | 2001 Apr |
|
| A phase I study of paclitaxel and altretamine as second-line therapy to cisplatin regimens for ovarian cancer. | 2001 Aug |
|
| Phase II trial of oral altretamine for consolidation of clinical complete remission in women with stage III epithelial ovarian cancer: a Southwest Oncology Group trial (SWOG-9326). | 2001 Aug |
|
| Altretamine is an effective palliative therapy of patients with recurrent epithelial ovarian cancer. | 2001 Feb |
|
| Recent advances in the treatment of epithelial ovarian cancer. | 2001 Sep |
|
| A phase II study of mitomycin C, cisplatin and continuous infusion 5-fluorouracil (MCF) in the treatment of patients with carcinoma of unknown primary site. | 2002 Apr 22 |
|
| Solvent, emulsifier and drug concentration factors in poly(D,L-lactic acid) microspheres containing hexamethylmelamine. | 2002 Jan-Feb |
|
| Oral cancer treatment: developments in chemotherapy and beyond. | 2002 Oct 21 |
|
| Part II: chemotherapy for epithelial ovarian cancer-treatment of recurrent disease. | 2002 Sep |
|
| Altretamine (hexamethylmelamine) in the treatment of platinum-resistant ovarian cancer: a phase II study. | 2003 Feb |
|
| Outcome of ATP-based tumor chemosensitivity assay directed chemotherapy in heavily pre-treated recurrent ovarian carcinoma. | 2003 Jul 3 |
|
| Oral melphalan as a treatment for platinum-resistant ovarian cancer. | 2003 Jun 16 |
|
| Medication sheets for patients. Oral chemotherapy. | 2003 Nov-Dec |
|
| A phase II study of sequential carboplatin, paclitaxel and topotecan in patients with previously untreated advanced ovarian cancer. | 2004 Feb 23 |
|
| Oral altretamine used as salvage therapy in recurrent ovarian cancer. | 2004 Jan |
|
| Do CA125 response criteria overestimate tumour response in second-line treatment of epithelial ovarian carcinoma? | 2004 Jan 26 |
|
| Long-term follow-up of a phase II trial of oral altretamine for consolidation of clinical complete remission in women with stage III epithelial ovarian cancer in the Southwest Oncology Group. | 2004 Mar-Apr |
|
| Carboplatin, doxorubicin and etoposide in the treatment of tumours of unknown primary site. | 2004 May 17 |
|
| Recurrent ovarian cancer: how important is it to treat to disease progression? | 2004 Nov 15 |
|
| Emerging drugs for ovarian cancer. | 2005 May |
|
| Topotecan: weighing in when there are many options. | 2005 Oct |
|
| Better treatments improve survival of CHD patients. | 2005 Sep |
|
| Pretreatment CA-125 and risk of relapse in advanced ovarian cancer. | 2006 Mar 20 |
|
| Atom efficient cyclotrimerization of dimethylcyanamide catalyzed by aluminium amide: a combined experimental and theoretical investigation. | 2008 Aug 21 |
|
| Synergy of irofulven in combination with other DNA damaging agents: synergistic interaction with altretamine, alkylating, and platinum-derived agents in the MV522 lung tumor model. | 2008 Dec |
|
| Lessons from a time capsule: evolution, not revolution, in therapy for advanced non-small-cell lung cancer. | 2008 Jul 1 |
|
| Relationship between frailty and cognitive decline in older Mexican Americans. | 2008 Oct |
|
| Hexamethylmelamine as consolidation treatment for patients with advanced epithelial ovarian cancer in complete response after first-line chemotherapy. | 2009 Aug |
|
| Enhancing the efficacy of cisplatin in ovarian cancer treatment - could arsenic have a role. | 2009 Jan 14 |
|
| Liposomes incorporating sodium deoxycholate for hexamethylmelamine (HMM) oral delivery: development, characterization, and in vivo evaluation. | 2010 Apr |
|
| Cancer-drug associations: a complex system. | 2010 Apr 2 |
|
| Clinical trials and progress with paclitaxel in ovarian cancer. | 2010 Nov 19 |
Sample Use Guides
HEXALEN® (altretamine) capsules are administered orally. Doses are calculated on the basis of body surface area.
HEXALEN® (altretamine) capsules may be administered either for 14 or 21 consecutive days in a 28-day cycle at a dose of 260 mg/m²/day. The total daily dose should be given as 4 divided oral doses after meals and at bedtime.
Route of Administration:
Oral
In Vitro Use Guide
Curator's Comment: Hexamethylmelamine inhibited colony formation when incubated with A204 cells for 1 hour (short-term exposure) in the presence of the hepatic metabolizing system (S-9).
Long-term (10-day) exposure of Hexamethylmelamine (Altretamine) inhibited colony formation by human rhabdomyosarcoma cell line A204 by 70% at a concentration of 150 ug/ml.
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2975-00-0
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30FQ7QG6VM
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DTXSID80183901
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27305
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PARENT (SALT/SOLVATE)
SUBSTANCE RECORD
