Lonidamine is a derivative of the indazole-3-carboxylic acid, with limited antineoplastic activity as a single agent but with exceptional potential in modulating the activities of conventional chemotherapeutic agents such as N-mustard alkylating agents and anthracyclines as well as hyperthermia, radiation therapy and photodynamic therapy. The most critical property of Lonidamine is its selective activity against a broad range of tumors with little to no effect on normal tissues provided that doses are below a threshold level of ~400 mg/m^2 (oral or i.v. doses). Selective effects of Lonidamine on tumors compared to other potential targets probably result from the dependence of most tumors on glycolytic metabolism, but the exact mechanism of specificity is still not fully known. Current evidence indicates that Lonidamine inhibits lactate export by the proton-linked monocarboxylate transporter(s) (MCT) and pyruvate uptake into mitochondria via the mitochondrial pyruvate carrier (MPC), whereas inhibition of respiration involves both diminished mitochondrial uptake of pyruvate via the MPC as well as inhibition of the mitochondrial electron-transport chain at Complex II and perhaps also Complex I, in both instances at the ubiquinone reduction step. There is also evidence that the drug may indirectly inhibit hexokinase as well as possibly other glycolytic and pentose shunt enzymes as a result of cytosolic acidification. Key problems that remain to be addressed are the production of Lonidamine under GMP conditions since Angelini Pharmaceuticals in Rome, Italy, the sole commercial source of this drug, stopped producing it in 2006. In addition, utilization of Lonidamine in the US requires IND approval by the FDA, which has previously been granted for a number of clinical trials. Finally, even though LND is a potent enhancer of the activity of a number of potent anti-cancer agents, potentially less toxic (and patentable) “targeted-tumor agents” are replacing traditional chemotherapy. Another problem remaining to be addressed is the limited solubility of Lonidamine at neutral pH. Oral delivery has led to variable results; more soluble derivatives that can be administered by the intravenous administration are needed to accurately control the dosing schedules.

Tofisopam (marketed under brand names Emandaxin and Grandaxin) is a 2,3-benzodiazepine derivative that is marketed in several European countries as the anxiolytic drug. Tofisopam does not bind to the benzodiazepine binding site of the gamma-aminobutyric acid receptor. One study has shown that tofisopam acts as an isoenzyme-selective inhibitor of phosphodiesterases (PDEs) with the highest affinity to PDE-4A1 followed by PDE-10A1, PDE-3, and PDE-2A3. Like other benzodiazepines, tofisopam possesses anxiolytic properties but unlike other benzodiazepines, it does not have anticonvulsant, sedative, skeletal muscle relaxant, motor skill-impairing or amnestic properties. While it may not be an anticonvulsant in and of itself, it has been shown to enhance the anticonvulsant action of classical 1,4-benzodiazepines such as diazepam (but not sodium valproate, carbamazepine, phenobarbital, or phenytoin). Tofisopam is not approved for sale in the United States or Canada. However, Vela Pharmaceuticals of New Jersey is developing the D-enantiomer (dextofisopam) as a treatment for irritable bowel syndrome, with moderate efficacy demonstrated in clinical trials so far.

Alfatradiol (17a-estradiol, Ell-Cranell® alpha) is a stereoisomer of the female hormone 17b-estradiol. It inhibits the conversion of testosterone to the metabolite dihydrotestosterone (DHT) by suppressing 5a-reductase activity. In addition, by inhibiting 17b-dehydrogenase, it impedes the conversion process of androstenedione to testosterone, resulting in a reduction in the syntheses of testosterone and DHT. It also accelerates the conversion of testosterone to estradiol by stimulating aromatase, decreasing the level of testosterone and leading to a reduction in DHT. In addition, alfatradiol (17a-estradiol) has been reported to stimulate the generation of hair follicular matrix cells.

Menbutone is a choleretic compound which is used in veterinary medicine at a dose rate up to 10 mg/kg bw by parenteral (intravenous or intramuscular) route in bovine, ovine, caprine, porcine, and equine species. Menbutone stimulates the digestive tract by increasing excretion of bile, gastric acid, and pancreatic juices by two to five times baseline. It is marketed for veterinary use in Europe under several brand names.

Bambuterol is an active precursor of the selective beta2-adrenergic agonist terbutaline. Bambuterol is the bis-N,N-dimethyl-carbamate of terbutaline. Bambuterol is a remarkably selective and potent inhibitor of cholinesterase. BAMBEC (Bambuterol hydrochloride) oral solution or tablets are indicated for the management of asthma, bronchospasm and/or reversible airways obstruction.

Xamoterol (ICI 118,587) is a partial agonist of beta1-adrenoceptors. Xamoterol acts on the cardiac beta 1-adrenergic receptor, modifies the response of the heart to variations in sympathetic activity. At rest, it produces modest improvements in cardiac contractility, relaxation, and filling without increase in myocardial oxygen demand. The improvements are maintained during exercise although the attendant tachycardia is attenuated. The beneficial effects of xamoterol on both systolic and diastolic function suggested that it would be effective in patients with mild-to-moderate heart failure, and this was demonstrated in small placebo-controlled studies where effort tolerance and symptoms were improved. Xamoterol produced improvements in exercise capacity, clinical signs, symptoms and quality of life with a low incidence of adverse experiences. Xamoterol is effective as monotherapy in heart failure.

Tetrandrine, isolated from the root of Stephania tetrandra S Moore, is a traditional Chinese clinical agent for silicosis, autoimmune disorders, inflammatory pulmonary diseases, cardiovascular diseases and hypertension. Tetrandrine is a potent MDR-reversing agent and is an ABCB1/ABCC1 inhibitor. Tetrandrine (CBT-1) is being developed by CBA Pharma, as an adjunctive therapy to chemotherapy in various cancer types with multiple drug resistance (MDR), including acute myelogenous leukemia , Breast, Non-Hodgkin’s Lymphoma, Hodgkin’s disease, Non-Small Cell Lung Cancer, Multiple Myeloma, Gallbladder, Pancreatic, Gastrointestinal Tract, Small Cell Lung Cancer, Bladder, Head & Neck, and Sarcoma.

Rilmenidine (brand names Albarel, Hyperium, Iterium and Tenaxum) is an imidazoline derivative used for the treatment of hypertension. Rilmenidine, an oxazoline compound with antihypertensive properties, acts on both medullary and peripheral vasomotor structures. Rilmenidine shows greater selectivity for imidazoline receptors than for cerebral alpha2-adrenergic receptors, distinguishing it from reference alpha2-agonists. Rilmenidine is as effective in monotherapy as all other first line classes of drugs, including diuretics, beta-blockers, angiotensin converting enzyme (ACE) inhibitors, and calcium antagonists. It is well tolerated and can be taken in combination for greater efficacy. Sedation and dry mouth are not prominent side effects and withdrawal hypertension is not seen when treatment is stopped abruptly. In addition to a reduction in blood pressure, Rilmenidine has been shown to improve glucose tolerance, lipid risk factors, and insulin sensitivity.

Melperone is an antipsychotic drug which is used in Europe for the treatment of sleep disorders, agitation and confusion states. The exact mechanism of melperone action is unknown.

Evocalcet (MT-4580, KHK7580) is an allosteric calcium-sensing receptor agonist. Evocalcet directly acts on calcium receptors on parathyroid cells to suppress synthesis and secretion of parathyroid hormone (PTH), and it consequently decreases serum PTH and serum calcium. ORKEDIA® TABLETS (generic name: evocalcet, code name: KHK7580) has been listed on the National Health Insurance (NHI) Drug Price List and launched for the treatment of secondary hyperparathyroidism in patients on maintenance dialysis in Japan.