Digoxin, a cardiac glycoside similar to digitoxin, is used to treat congestive heart failure and supraventricular arrhythmias due to reentry mechanisms, and to control ventricular rate in the treatment of chronic atrial fibrillation. Digoxin inhibits the Na-K-ATPase membrane pump, resulting in an increase in intracellular sodium. The sodium calcium exchanger (NCX) in turn tries to extrude the sodium and in so doing, pumps in more calcium. Increased intracellular concentrations of calcium may promote activation of contractile proteins (e.g., actin, myosin). Digoxin also acts on the electrical activity of the heart, increasing the slope of phase 4 depolarization, shortening the action potential duration, and decreasing the maximal diastolic potential.

Sodium is the primary cation (positive ion) in extracellular fluids in animals and humans. Sodium ions are necessary for regulation of blood and body fluids, transmission of nerve impulses, heart activity, and certain metabolic functions. Physiologically, it exists as an ion in the body. Sodium is needed by animals, which maintain high concentrations in their blood and extracellular fluids, but the ion is not needed by plants. The human requirement for sodium in the diet is less than 500 mg per day, which is typically less than a tenth as much as many diets "seasoned to taste. " Most people consume far more sodium than is physiologically needed. For certain people with salt-sensitive blood pressure, this extra intake may cause a negative effect on health.

Clogestone Acetate (AY-11440) is a steroidal progestin that was synthesized in 1964 and was investigated as a progestin-only contraceptive but was never marketed.

Oleandrin is a toxic cardiac glycoside found in oleander (Nerium oleander L.). Along with neandrin it is primarily responsible for the toxicity of the sap of oleander. Oleandrin has been used for many years in China and Russia for its properties as a cardiac glycoside, for both suicidal and therapeutic purposes as in treatment of cardiac insufficiency. Because of its properties as a cardiac glycoside, oleandrin interferes in some essential processes within the cell, the most important of these being the inhibition of the Na-K ATPase. This protein enables the cell to exchange the cations Na+ and K+ between the intercellular and extracellular spaces by which, for instance, electronic signaling is made possible in nerve cells. Oleandrin binds to specific amino acids in the protein, causing it to lose its function. After depolarization of the cell in which Na+ flows into the cell, the Na+ cannot be transported back into the extracellular membrane, causing the sodium gradient to disappear. This gradient is the driving force for other transport proteins, such as the sodium-calcium exchanger, which plays an important role in cardiomyocytes. To make muscle contraction possible, a calcium influx from the extracellular fluid into the cell is crucial. After the muscle contraction, the calcium is normally pumped out of the cell and exchanged for sodium. When the sodium gradient is depleted, calcium cannot be pumped back and, as a consequence, accumulates in the cardiomyocyte. As a result of the high calcium concentration, actin and myosin filaments will bind stronger, unable to relax properly to make a new contraction possible. This may result in cardiac arrhythmias, in the worst case decreasing cardiac output and causing a shortage in oxygen supply in vital tissues. Apart from being a potent toxic compound, it may also be used in therapeutic ways. Both oleandrin and oleandrigenin, as well as their relatives, may be able to inhibit proliferation of tumor cells and stimulate their apoptosis as a result of the high concentration of intracellular calcium. In addition, it inhibits excretion of fibroblast growth factor 2 through membrane interaction and through inhibition of the Na,K-ATPase pump. However, there are no results from clinical testing on humans that support any use as a cancer treatment. Oleandrin has been reported to be lethal, but exact dosages are not fully documented. The fatal blood concentration of oleandrin has been estimated for humans to be approximately 20 ng/ml in decreased blood by extrapolation of intoxication symptoms. Symptoms present in poisoned animals include bloody diarrhea and colic, the latter especially in horses. Because the leaf itself is quite bitter, only starving animals will be likely to eat the plant. The lethal dosage for animals is estimated to be about 0.5 mg/kg.

Isoquercetin is a flavonoid, derivative of quercetin. It was isolated from various plant species including Ammothamnus Lehmanii, Caragana alaica, Cicer baldshuanicum, C. macroconthum, C. pungens, Euphorbia cyparissias, E. helioscapia, E. lathyris, E. lucida, E. purporata and others. It demonstrated radical scavenging activity, inhibitory effects on Na+/K+-ATPase and positive inotropic activity. It is protein disulfide isomerase (PDI) inhibitor. As a PDI inhibitor, this agent blocks PDI-mediated platelet activation, and fibrin generation, which prevents thrombus formation after vascular injury. Isoquercetin inhibited the replication of both influenza A and B viruses at the lowest effective concentration. Isoquercetin activates the ERK1/2-Nrf2 pathway and protects against cerebral ischemia-reperfusion injury in vivo and in vitro. It is being investigated for prevention of thromboembolism in selected cancer patients and as an anti-fatigue agent in kidney cancer patients treated with sunitinib.

Valtrate is a principle compound isolated from Valeriana jatamansi Jones, which is a Traditional Chinese Medicine used to treat various mood disorders. Valtrate at a high dose has been found to have sedative properties by inhibiting spontaneous motion and increasing the sleeping number induced by pentobarbital sodium in mice. In rats valtrate exhibits anxiolytic-like profiles in the elevated plus maze test and the open field test. Valtrate attenuated HPA axis activity by reducing the corticosterone level. Valtrate also possesses anti-breast cancer activities via cell cycle arrest, apoptosis, and inhibition of cell migration, thus supporting valtrate as a potential antitumor agent.

The monoterpene perillyl alcohol (POH) is a naturally occurring compound derived from citrus fruits, mint, and herbs. It exhibited chemotherapeutic potential against various malignant tumors in preclinical models and was being tested in clinical trials in patients with refractory advanced cancers. POH was formulated in soft gelatine capsules and orally administered to cancer patients several times a day on a continuous basis. However, such clinical trials in humans yielded disappointing results, also because of the large number of capsules that had to be swallowed caused hard-to-tolerate intestinal side effects, causing many patients to withdraw from treatment due to unrelenting nausea, fatigue, and vomiting. The clinical trials in Brazil have explored intranasal POH delivery as an alternative to circumvent the toxic limitations of oral administration. In these trials, patients with recurrent malignant gliomas were given comparatively small doses of POH via simple inhalation through the nose. Results from these studies showed, that this type of long-term, daily chemotherapy was well tolerated and effective. The precise mechanism of action is still undetermined, but it is known, that perillyl alcohol plays an important role in the process of hepatoma cell invasion and migration via decreasing the activity of Notch signaling pathway and increasing E-cadherin expression regulated by Snail. Another possible mechanism is included inhibition of Na/K-ATPase (NKA). The NKA α1 subunit is known to be superexpresses in glioblastoma cells (GBM) and POH acts in signaling cascades associated with NKA can control cell proliferation and/or cellular death.

Arenobufagin, a representative natural bufadienolide compound, is the major active component extracted from toad venom. Arenobufagin is a part of Chinese medicine Chan'su. It possesses significant antineoplastic activity in vitro. Antineoplastic activity of arenobufagin was tested using cell lines from different cancers: breast cancer, hepatocellular carcinoma, prostatic cancer, etc. Arenobufagin acts by intercalating with DNA and disrupting the cell cycle. Also it was shown to inhibit PI3K/Akt/mTOR pathway (in hepatocellular carcinoma cells) and inhibit Na, K-ATPase.

Actein is tetracyclic triterpenoid compound isolated from the rhizome of Cimicifuga foetida L. In North America, the cimicifuga species had a long medicinal history, mainly used to treat diarrhea, sore throat, and rheumatism. Actein inhibits the activity of the Na,K-ATPase, which affects calcium metabolism. The primary target of actein may relate to calcium metabolism since this agent altered the expression of several genes related to calcium. Although actein was shown to exhibit other pathological functions, such as prevention of oxidative damage to osteoblast and regulation of lipid disorder, the major role of actein is played on its anticancer activity, particularly in breast cancer.

Digitoxigenin is a cardenolide and aglycone constituent of digitoxin, an extract from the foxglove plant, D. purpurea. It elicits cardiac contraction and cardiotonic effects by inhibiting the Na+/K+ ATPase via binding at the digitalis receptor site with nanomolar potency. Digitoxigenin is highly cytotoxic, inhibiting Na+/K+ ATPase-dependent protein synthesis, and has been examined for use as an antitumor compound.