Oxitriptyline, a tricyclic antidepressant that has never been marketed

Antineoplaston A10 is a piperidinedione antineoplaston with potential antineoplastic activity. Antineoplaston A10 was originally isolated from human urine but is now synthetically derived. This agent intercalates into DNA, resulting in cell cycle arrest in G1 phase, reduction of mitosis, and decreased protein synthesis. Antineoplaston A10 may also inhibit ras-oncogene expression and activate tumor suppressor gene p53, leading to cell differentiation and apoptosis. Antineoplaston A10 has been used in trials studying the treatment of glioma, sarcoma, lymphoma, lung cancer, liver cancer, and kidney cancer, among others.

Picropodophyllin (also known as picropodophyllotoxin (PPP)), an orally active insulin-like growth factor 1 receptor (IGF1R) inhibitor that exhibits no activity at the insulin receptor, FGFR, PDGFR or EGFR. Picropodophyllin possesses antineoplastic activity. PPP is currently tested as an orally administrated single agent treatment in an open-label combined Phase I/II clinical study in advanced cancer patients with solid tumors which progress in spite of several lines of treatment. In addition, it effectively inhibits rhambodmyosarcomas tumor proliferation and metastasis in vitro and in an animal model.

Porfiromycin is an N-methyl derivative of the antineoplastic antibiotic mitomycin-C initially isolated from Streptomyces ardus. Upon administration, the drug undergoes chemical or enzymatic reduction, followed by spontaneous loss of the tertiary methoxy (hydroxyl) group and formation of an aromatic indole system. Thus activated, porfiromycin generates oxygen radicals and alkylates DNA, producing interstrand cross-links and single-strand breaks at guanosine residues. Porfiromycin was tested in phase III for head and neck carcinoma, however, its development was terminated.

Repromicin is a compound that was reported in the literature in the 1990’s. Repromicin derivatives were found to have potent antibacterial activity against the Gram-negative pathogen Pasteurella multocida and Pasteurella heamolytica (in vitro and in vivo). Subcutaneous administration (single dose) in animals was found to control induced pasteurellosis (in swine) and induced respiratory disease (in cattle).

Inocoterone acetate (USAN) (also known as RU-38882, RU-882) is the acetate ester of inocoterone a steroid-like nonsteroidal antiandrogen (NSAA) that was developed for topical administration to treat acne but was never marketed. Inocoterone acetate is actually not a silent antagonist of the androgen receptor but rather a weak partial agonist, similarly to steroidal antiandrogens like cyproterone acetate. In this double-blind study of 126 male subjects with acne, a topical solution of the antiandrogen inocoterone produced a modest but statistically significant reduction in the number of inflammatory acne lesions.

Piponulfan is neutral, difunctional alkylating derivative of piperazine. This agent was studied for their antineoplastic activity. Piposulfan has been found to be active against the following mouse tumors: sarcoma 180, carcinoma 755, and leukemia 1210. In patients with polycythemia piposulfan produced a response rate similar to that seen with pipobroman, busulfan, and triethylene melamine. However, piposulfan produces noticeably less toxicity than standard recommended doses of either busulfan or triethylene melamine. Various degrees of therapeutie remissions were seen in patients with malignant lymphomas, acute and chronic leukemia, multiple myeloma, adenocarcinomas, epidermoid carcinomas, and various types of sarcomas. The most common adverse reactions to piposulfan involved the hematopoietic (bone marrow depression) and gastrointestinal organs.

Pentamorphone was developed as a highly potent opioid with rapid onset and short duration of action that has been reported to produce analgesia with limited depression of ventilation. Pentamorphone participated in a clinical trial for the management of postoperative pain. However, no acute cardiorespiratory changes were observed. The drug was ineffective for treating acute postoperative pain after major surgery. In addition, was shown that pentamorphone, 10 micrograms/kg, does not seem to offer any significant advantage over opioids currently used for anesthesia in patients undergoing elective coronary artery bypass grafting (CABG). That is why its further development was discontinued.

Docebenone (AA-861) is a potent, selective and orally active 5-LO (5-lipoxygenase) inhibitor. T. vaginalis-derived secretory products (TvSP)-induced IL-8 production was efficiently inhibited when trichomonads were pretreated with docebenone. Docebenone increased [Ca(2+)](i) in Madin Darby canine kidney cells by releasing Ca(2+) from multiple internal stores in a manner independent of the formation of inositol-1,4,5-trisphosphate, followed by Ca(2+) entry from external medium. In animal model, it was shown that docebenone may prove useful in the treatment of acute pancreatitis. Docebenone showed a dose-dependent inhibition of slow reacting substance of anaphylaxis (SRS-A) release, with no effect on histamine release from passively sensitized guinea pig, monkey (M. irus) and human lung fragments. It markedly suppresses biosynthesis of the leukotrienes. This drug inhibits the release of histamine as well as SRS-A from lung fragments of anaphylactic monkey (M. mulatta) and in the Ca ionophore-stimulated rat peritoneal cavity. AA-861 suppressed the anaphylactically-induced airway resistance in mepyramine- and cimetidine-treated guinea pigs. These results suggest that AA-861 may be clinically effective for treating allergy-related asthma by modulating the 5-lipoxygenase pathway and that an inhibitory mechanism of histamine release by AA-861 may be present in some species. Docebenone has shown anti-inflammatory effects in several animal models following local dosing: phorbol ester-induced oedema and neutrophil influx in mouse skin, arachidonate-induced plasma extravasation in rabbit skin, the pleural reversed passive Arthus reaction in rats.