Valproic acid (VPA; valproate; di-n-propylacetic acid, DPA; 2-propylpentanoic acid, or 2-propylvaleric acid) was first synthesized in 1882, by Burton. FDA approved valproic acid for the treatment of manic episodes associated with bipolar disorder, for the monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures and adjunctive therapy in patients with multiple seizure types that include absence seizures and for the prophylaxis of migraine headaches. The mechanisms of VPA which seem to be of clinical importance in the treatment of epilepsy include increased gamma-aminobutyric acid (GABA)-ergic activity, reduction in excitatory neurotransmission, and modification of monoamines. Recently, it was discovered that the VPA is a class I selective histone deacetylase inhibitor. This activity can be distinguished from its therapeutically exploited antiepileptic activity.

Amitriptyline is a derivative of dibenzocycloheptadiene and a tricyclic antidepressant (TCA) and is mainly used to treat symptoms of depression. It works on the central nervous system (CNS) by inhibiting the membrane pump mechanism responsible for uptake of norepinephrine and serotonin in adrenergic and serotonergic neurons. Amitriptyline has been frequently used as an active comparator in clinical trials on newer antidepressants. It is rarely used as a first-line antidepressant nowadays due to its high degree of toxicity in overdose and generally poorer tolerability than the newer antidepressants.

Dexamethasone is an anti-inflammatory agent that is FDA approved for the treatment of many conditions, including rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive lung disease, croup, brain swelling and others. Dexamethasone is a glucocorticoid agonist. Unbound dexamethasone crosses cell membranes and binds with high affinity to specific cytoplasmic glucocorticoid receptors. Adverse reactions are: Glaucoma with optic nerve damage, visual acuity and field defects; cataract formation; secondary ocular infection following suppression of host response; and perforation of the globe may occur; muscle weakness; osteoporosis and others. Aminoglutethimide may diminish adrenal suppression by corticosteroids. Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance.

Estradiol benzoate is the synthetic benzoate ester of estradiol, a steroid sex hormone vital to the maintenance of fertility and secondary sexual characteristics in females. As the primary, most potent estrogen hormone produced by the ovaries, estradiol binds to and activates specific nuclear receptors. This agent exhibits mild anabolic and metabolic properties, and increases blood coagulability. Although estradiol benzoate is not approved by the FDA for use in humans in the United States, it is approved for veterinary use as a subdermal implant both alone (CELERIN®) and in combination with the anabolic steroid trenbolone acetate (SYNOVEX® Plus).

Morphine-6-glucuronide is a pharmacologically active metabolite of morphine that is being developed by CeNeS Pharmaceuticals as an alternative to morphine for the management of postoperative pain. Compared to morphine, Morphine-6-glucuronide has been reported to have6 and 86 times lower affinity for the human mu and kappa opioid receptors, respectively, and similar affinity for the delta opioid receptor. Morphine-6-glucuronide is was studied in phase III clinical trials for postoperative pain management. Unfortunately, Morphine-6-glucuronide failed to demonstrate superior safety compared to Morphine and further development was discontinued. Morphine-6-glucuronide accumulates after administration of morphine to patients with renal insufficiency, and analgesia can be obtained with lower doses of morphine compared to patients with normal renal function. More importantly, the dose should be reduced to avoid serious side-effects, although the simulations in this review did not account for side-effects.

Clofibrate is a fibric acid derivative used to lower cholesterol and triglyceride (fat-like substances) levels in the blood. This may help prevent medical problems caused by such substances clogging the blood vessels. However, this treatment was discontinued in 2002 due to adverse effects. Clofibrate is an agonist of the PPAR-α receptor in muscle, liver, and other tissues. This agonism ultimately leads to modification in gene expression resulting in increased beta-oxidation, decreased triglyceride secretion, increased HDL, and increased lipoprotein lipase activity. Clofibrate increased the activity of extrahepatic lipoprotein lipase (LL), thereby increasing lipoprotein triglyceride lipolysis, inhibited the synthesis, and increases the clearance of apolipoprotein B, a carrier molecule for VLDL. In addition, clofibrate was investigated as a novel therapy agent in multiple myeloma and it shown the promising results.

Uridine 5'-triphosphate (UTP, INS316) is a naturally occurring agonist for P2Y(2) receptors on the apical surface of ciliated respiratory epithelium. INS316, being developed by Inspire Pharmaceuticals, is a short-acting, aerosolized uridine 5-triphosphate (UTP) solution used as a diagnostic aid for lung cancer. INS316 appears to improve sputum expectoration mediated through the P2Y2 receptor, a nucleotide receptor expressed in human airway epithelial cells and some other tissues. UTP binding to the P2Y2 receptor triggers signal transduction that leads to chloride ion secretion, thereby resulting in mucociliary clearance of airway. UTP stimulates salt and water transport and cilia beat frequency in human airway epithelium in vitro. Single, inhaled doses of UTP stimulate mucociliary clearance in conscious, intubated sheep and in patients with mild chronic bronchitis (smokers and former smokers), suggesting that UTP may be useful for obtaining deep-lung sputum specimens suitable for diagnostic purposes. A single dose of INS316 safely improves the ability of patients with mild chronic bronchitis to expectorate a deep-lung sputum specimen suitable for cytologic evaluation.