GLOSSARY OF TERMS

• ADME/Tox is a study of the absorption, distribution, metabolism, excretion, and toxicological profile of a drug that is required by the FDA before human clinical trials.

• Agonists are chemical entities either produced endogenously by the body, found in natural products, or synthesized to bind to a specific receptor that initiates a signaling process that ultimately leads to the molecular events associated with the activation of the receptor. There are three classes of agonists – full, partial, or inverse.

• Antagonists have the opposite effects of agonists by occupying the receptor site and blocking its response. The best-known example is naloxone which reverses the sedation and respiratory depression that is caused by opioids.

• Aromatase inhibitors are drugs that inhibit the enzyme that is responsible for the conversion of androgens into estrogen to deprive estrogen receptor-positive breast cancer cells of estrogen. They are primarily used in post-menopausal women who are at increased risk of breast cancer. They are different than selective estrogen receptor modulators (see below) that also produce symptoms of menopause.

• Branded generics are off-patent drugs that have been given proprietary names that are sold by a generic drug manufacturer that may compete with brand-name drugs sold by the original manufacturer.

• Cannabidiol is found in the botanical class of cannabis Sativa which is devoid of psychoactive properties. It is commonly extracted from the hemp plant and then purified for medicinal purposes. It can also be synthesized in a pure form. It is classified as an antagonist for the CB1 and CB2 receptors by causing conformational changes in them that prevent the activity of THC as well as endocannabinoids.

• Cannabis is a natural product containing 540 chemical substances including 113 different cannabinoids including tetrahydrocannabinol(THC) which is psychoactive and cannabidiol which is non-psychoactive.

• The CB1 receptor is an endocannabinoid type 1 receptor that is found primarily in the central nervous system that is activated by specialized fatty acids known as endocannabinoids that do not produce any psychotropic effects that are associated with cannabis. CB1 receptor expression is also found in the periphery to varying degrees.

• The CB2 receptor is an endocannabinoid type 2 receptor that is found primarily in the immune system and is also activated by specialized fatty acids known as endocannabinoids. The CB2 receptors are also found in specialized immune cells found in the brain. It is also expressed by other peripheral tissues including the vaginal tissue which has the highest expression second only to that found in the esophagus. Both receptors share about 88% of their amino acid sequences and the difference is enough to prevent any ligand that targets the CB2 receptors from producing psychotropic effects.

• Clinical Trials are required by the FDA to establish the safety and efficacy of a drug before it is marketed.

Phase 1 – is a small study involving at least 25 individuals to establish safety

Phase 1b – a limited study of a specified cohort of patients to study efficacy.

Phase 2 – an efficacy-based study based on a larger cohort of patients.

Phase 3 – an efficacy-based trial with an even larger cohort of patients to determine if the new treatment is better than the standard treatment.

• Dyspareunia is painful sexual intercourse.

• Dysuria is painful urination usually associated with urinary tract infections.

• The Endocannabinoid system (ECS) is a  complex signaling network that involves the central nervous system and the immune system that is identified by the expression of specialized receptors and endogenous ligands that are activated on-demand by neuroexcitation and immune activation respectively. The receptors are also activated by cannabis, the natural product that led to the naming of the system. After the ECS was identified, numerous synthetic compounds and hybrid natural products have been developed that selectively mimic or antagonize the receptors for various medical indications.

• Estrogen Replacement Therapy (ERT) is also known as hormone replacement therapy, ERT is a medication that contains estrogen for the treatment of estrogen deficiency that is associated with the symptoms of menopause. The primary source of pharmaceutical-grade estrogen is obtained from the urine of pregnant mares.

• Ethical drugs are drugs that require a doctor’s prescription.

• Federal Drug Administration (FDA) is a government agency responsible for the approval of all drugs with specific, defined indications.

• Full agonists bind and activate their cognate receptors to produce a maximum response in the system.

• Genitourinary syndrome of menopause (GSM)  is a condition that is associated with menopause which is the result of declining estrogen levels that ultimately results in vaginal atrophy, or thinning of the vaginal epithelium. The symptoms include itching, burning, vaginal dryness, painful sexual intercourse, and recurrent urinary tract infections due to a change in the vaginal microbiome. Until now the only treatment has been ERT.

• Genomics refers to the interaction of all the genes in an organism as it relates to its growth, development, and its maintenance.  In the context of drug development, genomics provides a tool to predict the up or down-regulation of genes responsible for the desired or undesired outcome.

• Genetics is the study of single genes and how they are transmitted from one generation to the next. The genetic code refers to the program that is responsible for making the proteins that identify the features of a particular organism.

• Glycogen is a form of glucose that is stored in different body tissues such as the liver and muscle. It is also expressed by the vaginal tissue of pre-menopausal women.

• Inverse agonists bind to the same receptor as agonists or partial agonists and produce the opposite effects.

• Investigational New Drug application (IND)  is the first step in the process of obtaining approval for the continuation of a new drug entity.

• Ligand is a naturally occurring or synthetic compound that binds and activates an enzyme or protein receptor.

• Menopause is a condition that is identified by irregular menses that is caused by the decline and eventual termination of estrogen production that ends with the cessation of menses. This is a gradual process that may begin late in the third decade of a woman’s life and is usually complete by the time she reaches her mid-to-late-50s.

• The microbiome is a collection of microorganisms, bacteria, fungi, and viruses, that is uniquely associated with a particular organ system of an organism with functions specific to its environment, i.e. alimentary, reproductive, airway and skin.

• The National Institutes of Health (NIH) is the country’s leading government-funded research institution that is also responsible for the review and funding of extramural research grants to other government and non-governmental entities. 

• Non-psychoactive, as it pertains to the development of ligands for the ECS, there are no mind-altering effects.

• Over-the-counter drugs are sold without a prescription many of which may have been name-brand ethical drugs but are considered safe and essential and do not require a physician’s input.

• Partial agonists interact with their cognate receptors to initiate an alternative signaling pathway based on a complex set of events related to conformational changes in the receptor or its internalization. This may result in an ‘always on’ status of the signaling process likened to a dimmer switch stuck in the middle.

• Psychoactive is any drug or natural product that alters a sense of perception and emotions that has been described by many as a feeling of euphoria. The use of cannabis may cause acute anxiety and panic attacks in others.

• An R21 grant is a special grant awarded by the NIH to researchers with a research hypothesis for which little or no data is available. In essence, it is an exploratory grant for novel ideas.

• Selective estrogen receptor modulators (SERMS) bind to estrogen receptors and can mimic or block the effect of estrogen and lower the risk of breast cancer. The most common side effects are the symptoms associated with GSM.

• Tetrahydrocannabinol (THC) is the major cannabinoid found in cannabis that is responsible for the psychotropic effects that it produces when used either for recreational or medicinal purposes.

• Transepithelial resistance refers to the use of a voltmeter to measure the resistance of an electrical current that is passed through in vitro epithelial tissues. It is an indirect measurement of the strength and integrity of a tissue when it is challenged or treated with a substance or drug.

• The vaginal maturation index is a method of quantifying the bioactivity of estrogen on vaginal tissue that can be obtained by using a vaginal swab.