"In 2006, the U.S. Food and Drug Administration issued a caution about methadone, titled "Methadone Use for Pain Control May Result in Death." The FDA also revised the drugs package insert. The change deleted previous information about the usual adult dosage. The Charleston Gazette reported, "The old language about the usual adult dose was potentially deadly, according to pain specialists." Pharmacology
Methadone acts by binding to the µ-opioid receptor, but also has some affinity for the NMDA receptor, an ionotropic glutamate receptor. Methadone is metabolized by CYP3A4, CYP2B6, CYP2D6, and is a substrate, or in this case target, for the P-glycoprotein efflux protein, a protein which helps pump foreign substances out of cells, in the intestines and brain. The bioavailability and elimination half-life of methadone are subject to substantial interindividual variability. Its main route of administration is oral. Adverse effects include sedation, hypoventilation, constipation and miosis, in addition to tolerance, dependence and withdrawal difficulties. The withdrawal period can be much more prolonged than with other opioids, spanning anywhere from two weeks to several months. The metabolic half-life of methadone differs from its duration of action. The metabolic half-life is 8 to 59 hours (approximately 24 hours for opioid-tolerant people, and 55 hours in opioid-naive people), as opposed to a half-life of 1 to 5 hours for morphine. The length of the half-life of methadone allows for exhibition of respiratory depressant effects for an extended duration of time in opioid-naive people.
Germ cell tumor (GCT) is a neoplasm derived from germ cells. Germ-cell tumors can be cancerous or benign. Germ cells normally occur inside the gonads (ovary and testis). GCTs that originate outside the gonads may be birth defects resulting from errors during development of the embryo. Classification
GCTs are classified by their histology, regardless of location in the body. However, as more information about the genetics of these tumors become available, they may be classified based on specific gene mutations that characterize specific tumors. They are broadly divided in two classes:
The germinomatous or seminomatous germ-cell tumors (GGCT, SGCT) include only germinoma and its synonyms dysgerminoma and seminoma. The nongerminomatous or nonseminomatous germ-cell tumors (NGGCT, NSGCT) include all other germ-cell tumors, pure and mixed.The two classes reflect an important clinical difference. Compared to germinomatous tumors, nongerminomatous tumors tend to grow faster, have an earlier mean age at time of diagnosis (around 25 years versus 35 years, in the case of testicular cancers), and have a lower five-year survival rate. The survival rate for germinomatous tumors is higher in part because these tumors are very sensitive to radiation, and they also respond well to chemotherapy. The prognosis for nongerminomatous tumours has improved dramatically, however, due to the use of platinum-based chemotherapy regimens. Germinomatous
Nongerminomatous
Mixed
Mixed germ cell tumors occur in many forms. Among these, a common form is teratoma with endodermal sinus tumor. Teratocarcinoma refers to a germ cell tumor that is a mixture of teratoma with embryonal carcinoma, or with choriocarcinoma, or with both.