Medicinal Chemistry - Fusion of Traditional and Western Medicine

Perhaps nothing epitomizes the fusion of traditional and western medicine more than predictive, preventive, personalized and participatory (P4) medicine. It takes not just a holistic but also a quantitative and mathematical approach to practicing medicine. Personalized medicine is designed for the specific genetic, epigenetic and environmental properties of patients and their diseased cells. Diagnoses, treatments and cures are improving for diseases caused by a single gene (Mendelian). As the costs of genotyping with microarrays and complete DNA sequencing continue to drop, new collaborative projects become possible. Biomarkers are being discovered through advanced genomic, proteomic, metabolomic and imaging technologies. This has a very high priority because they can improve the diagnosis of a disease, define subsets of patients and use appropriate therapies for them. Clinical trials are being modernized by automation and improved data management. Instead of just making the medicine specific for the DNA that a person is born with, it can be made specific for the mutated DNA that is in a type of cancer or other disease. This is being done by developing monoclonal antibodies, which will bind to receptors that are specific for a particular type of cancer. Some of them are even parts of FDA-approved medications. Most can’t kill cells by themselves, but they can still bind to cancer-specific antigens and deliver drugs that are covalently attached to the monoclonal antibody. Even treatments for diseases that are caused by many factors (genetic and environmental) are benefiting from P4 medicine.

Inflammation can be a cause or a symptom of many diseases. When controlled, it is also an important part of maintaining good health. Reactive oxygen substances (ROS) are produced as part of normal, healthy aerobic metabolism, such as electron transport in the mitochondria of cells. Many foods, spices, herbs and dietary supplements contain antioxidants that can destroy ROS and help to prevent diseases. Some important dietary antioxidants include vitamins A and E, oleic acid, polyunsaturated fats, omega-3 fats, resveratrol and polyphenols. Inflammation is a significant factor in many diseases, including arthritis, cancer, diabetes, heart disease, stroke, Alzheimer´s disease, hormonal diseases, osteoporosis, inflammatory bowel disease, pelvic inflammatory disease, and many others. Smoldering inflammation is a relatively low level of inflammation that occurs in obesity, type-2 diabetes, asthma, and atherosclerosis. In many cases, these diseases of inflammation can be prevented by avoiding obesity, trans fats and saturated fats that are in the typical fast food diet that many people in the USA consume. Instead, unsaturated fats are much better. Omega-3 fats can be taken as dietary supplements such as fish oil and flaxseed oil. They are also present in fatty fish, such as salmon. Omega-3 fats are also very important in the brain, where they play an important role in cognitive function and behavior. Inflammation plays an important role in all stages of atherosclerosis and cardiovascular disease. Inflammation is also an important factor in stroke.

Heart disease is the biggest killer in the world. Its major cause is obesity or metabolic syndrome, which can also lead to diabetes and stroke - the third leading killer (after cancer) and the most frequent cause of disability in the world. All of these involve imbalances in energy metabolism. Early symptoms of metabolic syndrome include excessive weight, high blood pressure, elevated blood glucose and elevated levels of lipids, especially low density lipoprotein (LDL). People who have one or more of these symptoms are at a higher risk of developing heart disease, stroke and type-2 diabetes. Childhood obesity is such a big problem that it will probably mean that this generation will be the first to have a shorter life expectancy than their parents. Ischemic strokes need to be treated as soon as possible, so it is very important to get a stroke victim to a hospital as soon as possible, so the blockage can be removed and blood can begin to flow properly. Drugs such as aspirin, clopidrogel and dipyridamole can be given to prevent the formation of more clots by preventing blood platelets from aggregating. If the patient can get to a hospital soon enough, tPA, or tissue plasminogen activator, can be given. When blood flow to the heart is interrupted, it causes a myocardial infarction, or heart attack. The most common cause is a blockage in the coronary artery that is usually caused by the rupture of an atherosclerotic plaque.

Cancer is the rapid, unregulated and pathological growth (proliferation) of abnormal cells. Even when cancers occur in the same part of the body, they can be very different diseases. When tumors become malignant, their threat depends on their ability to modify surrounding cells to form new blood vessels (angiogenesis) and other supporting cells. The typical American diet that leads to obesity can make people more susceptible to cancer. The human papilloma virus, hepatitis B and T cell leukemia virus type 1 can cause cancer of the cervix, liver and leukocytes (leukemia). Tyrosine kinases regulate many cellular processes which can contribute to cancer development and progression. KRAS is the oncoprotein that is most commonly activated in human cancer [1]. RAS is one of the most commonly mutated genes in human cancers. Oncogenes code for oncoproteins, which are upregulated in cancer. Another important oncogene is PI3K, which codes for the enzyme PI3K (phosphoinositide 3-kinase). The enzyme PTEN (phosphatase and tensin homolog) catalyzes the opposite reaction, so it is a tumor suppressor and the gene coding for it is downregulated in cancer. Human epidermal growth factor (hEGF, or HER), vascular endothelial growth factor, or VEGF, and the PI3K/Akt/mTOR (mammalian target of rapamycin) survival pathway are all important therapeutic targets in many cancers [1]. Cancer stem cells could be good targets for new drugs that will prevent the recurrence and metastasis of tumors. Also, induced pluripotent stem cells could be used to screen drugs to see if they will be effective in treating each individual patient.

The endocrine system consists of cells, glands and tissues that secrete hormones into the bloodstream that affect physiological and behavioral function and activities [1]. This is in contrast to the exocrine system that secretes substances into ducts. The hypothalamus connects the nervous and endocrine systems to each other through the pituitary gland, or hypophysis. It helps control body temperature, hunger, parenting and attachment behavior, thirst, fatigue, sleep, circadian rhythms and other activities of the autonomic nervous system. Darkness causes the pineal gland to secrete N-acetyl-5-methoxytryptamine, which is better known as melatonin. Melatonin is part of the system that regulates the sleep-wake cycle. It causes drowsiness and lowers the body temperature. The anterior lobe of the pituitary gland secretes growth hormone (GH), beta-endorphin, luteinizing hormone (LH), follicle stimulating hormone (FSH), melanocyte stimulating hormone (MSH), adrenocorticotropic hormone (ACTH), thyroid stimulating hormone (TSH) and prolactin (PRL). The posterior lobe stores vasopressin, also known as antidiuretic hormone (ADH) and oxytocin (OXT). The thyroid gland helps control how fast a body uses energy and makes proteins as well as influencing the sensitivity of the body to other hormones. It does this by producing T3 and T4, which are made from tyrosine and iodine. The stomach, duodenum, liver, pancreas and kidneys all secrete hormones. The kidneys secrete renin, erythropoietin, calcitrol and thrombopoietin. They regulate pH, electrolytes and blood pressure. The adrenal glands produce hormones in response to stress by synthesizing corticosteroids such as cortisol and catecholamines, such as adrenaline (epinephrine) and noradrenaline (norepinephrine). They also produce androgens in their innermost cortical layer. The adrenal glands affect kidney function by secreting aldosterone. The testes, ovarian follicle and corpus luteum are in the endocrine system, as are the placenta and uterus when a woman is pregnant. The testes secrete androgens (mostly testosterone), estradiol and inhibin. They stimulate or control the development and maintenance of male characteristics by binding to androgen receptors. This includes the activity of the male sex organs and development of male secondary sex characteristics. Androgens are also the original anabolic steroids and the precursor of all estrogens. The endocrine system also regulates the concentration of Ca2+. The parathyroid gland secretes the parathyroid hormone (PTH), which stimulates Ca2+ release from bones, stimulates osteoclasts and Ca2+ reabsorption in the kidneys. Calcium regulation also occurs in the skin, which secretes the prehormone calcidiol (25-hydroxyvitamin D3), the inactive form of vitamin D. The major endocrine systems are the TRH-TSH-Y3/T4, the GnRH LH/FSH-sex hormones, the CRH-ACTH-cortisol, the renin-angiotensin-aldosterone system and the leptin vs insulin system. The TRH-TSH-Y3/T4 system is also called [1].

The fertility cycle in women is controlled by a cascade of events, which are initiated by protein and steroid hormones. These hormones create signals between the hypothalamus, the pituitary gland and the ovaries. Oral contraceptives contain an estrogen-like drug, ethinyl estradiol. It is combined with any of a number of progestin derivatives. Progestin-only pills are available for women who are breast feeding and those who are not able to tolerate estrogens. There is also an emergency contraceptive to prevent pregnancy after unprotected intercourse, called Plan B. One form consists of two pills, each containing 0.75 mg of levonorgestrel. Mifepristone is a synthetic steroid that is used for the termination of pregnancy up to the 49th day of gestation. It has been tested as a morning after pill to prevent pregnancy when taken within 12 hours of unprotected intercourse. It is also used in combination with another drug called Gemeprost to terminate pregnancies between weeks 13 and 24. In the USA, levonorgestrel is the preferred emergency contraceptive. It can prevent a pregnancy up to 72 hrs after unprotected sex or contraceptive failure. Oxytocin and prostaglandin E2 are also available to induce labor by stimulating uterine contractions. Some women take hormone replacement therapy, in which a low dose of one or more estrogens (conjugated equine estrogens) and a progestin are given. Another approach is to increase the consumption of soybeans and foods made from soybeans (such as soy milk).

The first year of life is critical in brain development, for the total brain volume doubles, as measured by MRI. This is when the brain is most susceptible to damage by genetic defects and environmental insults. It is also the time in which therapeutic intervention can have its maximum effect. A principal component of the nervous system is the neuron. Neurons are arranged in networks and circuits. The normal human brain has many local regions, or centers, and many pathways between them. The autonomic nervous system is organized into three divisions: the sympathetic, parasympathetic and enteric [1]. These maintenance activities are usually performed without conscious control or sensation. The sympathetic and parasympathetic nervous systems work to maintain a type of balance. They have opposite effects on the body. The sympathetic division is used in actions requiring quick responses. The parasympathetic division is used in actions that do not require immediate reaction [1]. Messages are sent to and from neurons in the form of primary messengers, called neurotransmitters. L-DOPA is used to treat Parkinson’s disease, which affects about 1% of the population over 65. Alzheimer’s disease (AD) is the most common neurodegenerative disease. Phenobarbital, carbamazepine, valproic acid and its sodium salt, gabapentin, ethosuximide, lamotrigrine, and tiagabine are anti-epileptics. Diazepam, buspirone, b-blockers, tricyclic antidepressants and monoamine oxidase inhibitors treat anxiety disorders. Currently the first-line treatment is either SSRIs or SNRIs. The four main classes of antidepressant drugs are MAOIs, TCAs, SSRIs and SNRIs.

The immune system recognizes and defends us against internal threats caused by invading organisms and pathogens. The innate immune system recognizes bacteria, fungi and other organisms, breaks them down, identifies a characteristic protein on them (an antigen) and attaches it to the surface of specific cells, which present it to the adaptive immune system for destruction. The adaptive or acquired immune system is activated after being stimulated by the innate system. The adaptive immune response is initiated by specific interactions between antigen-bound, mature dendritic cells and naïve CD4+ T cells in the lymph nodes. The adaptive or acquired immune system acts once it is stimulated by the innate system. The five families of immune cells are: phagocytes, granulocytes, natural killer (NK) cells, lymphocytic Tcells and lymphocytic B-cells. The four major classes of immune system mediators are chemotactic agents, cytokines, C-reactive protein and antibodies. A fifth class of immune network mediators are the small molecules, including neurotransmitters, such as L-DOPA and catecholamines. Risk factors for autoimmune diseases include exposure to man-made chemicals. Benlysta (belimumab) is approved for treating lupus erythematosus. AIDS is caused by the retrovirus HIV. Currently, a mixture, or cocktail of antiretroviral drugs are given in what is often called highly active antiretroviral therapy, or HAART. Microbes in the intestines and lungs (acquired from the environment) keep rare invariant natural killer immune cells from triggering autoimmune diseases.

Infectious diseases can be caused by worms, protozoa, fungi, bacteria, viruses and even proteins (prions). Organisms, viruses and prions can be classified by their infectivity, or their ability to enter, survive and multiply in a host. There are seven classes of viruses, based on their DNA or RNA. By number, 90% of the cells in the human body are bacteria. Even though our lives depend on symbiotic bacteria, it is important that they stay in their proper places in our human bodies, or ecosystems. By the mid-1980s strains of S. aureus emerged which were resistant to common antibiotics. Multicellular parasites include four species of Schistosoma, a flatworm that causes schistosomiasis, which is second in importance only to malaria, with hundreds of millions infected worldwide. In addition to schistosomiasis, helminths can cause ascariasis, dracunculiasis, elephantiasis, hookworm, lymphatic filiaruasis, onchocersiasis, and trichuriasis.

An extremely important part of disease prevention is vaccination, which improves the immune response to a particular disease. Vaccines save lives and prevent deadly diseases that used to take millions of lives, especially the lives of infants. Vaccines can be made from dead or inactive organisms or viruses. Vaccines can also contain “live” attenuated viruses. The tetanus and diphtheria vaccines contain inactivated toxic compounds. Children should be vaccinated against hepatitis B, hepatitis A, diphtheria, tetanus, pertussis, polio, Pneumococcus, measles, mumps, rubella, rotavirus, human papilloma virus (HPV), Meningococcus, Orthomyxoviridae (flu virus) and varicella (chicken pox).

The five major food groups: cereals, vegetables, fruits, dairy, meat (and meat substitutes), and fats, oils and sweets. A lack of folic acid causes birth defects, such as spina bifida, which leaves the victim severely disabled. Folic acid is also found in multi-vitamin supplements, and these are recommended for pregnant women. It is better to eat many types of fish, than to eat red meat. If at all possible, mother’s should be encouraged to breast feed their babies. The best-selling, most interesting and controversial dietary supplements are multi-vitamins. The American Medical Association (AMA) does not recommend them. Instead, the AMA recommends getting your vitamins and minerals from a healthy, balanced diet. The National Institutes of Health maintains several pages on their website that have fact sheets on many dietary supplements. The NIH has an office of dietary supplements. It provides information on the use and safety, nutrient requirements, database resources, news and research. However, it is the FDA that has regulatory responsibility for dietary supplements, as dictated by the dietary supplement health and education act, or DSHEA, passed in 1994. The DSHEA indicated that the dietary supplement manufacturer is responsible for ensuring that a dietary supplement is safe before it is marketed, but the FDA is responsible for taking action against any unsafe dietary supplement product after it reaches the market [1]. The popular dietary supplement, açaí, will make you gain weight – not lose weight. Another supplement, myo-inositol, may help prevent lung cancer in smokers.

Many new phenomena emerge at higher levels of organization. For example, it is possible that the virus causes the flu in birds or pigs will mutate to a form that can easily infect and kill people. In addition, as the global climate continues to change, several tropical diseases could appear as cooler regions warm up as the habitats of the carriers of tropical diseases like dengue and yellow fevers spread. It is also possible that the poliovirus or smallpox virus could re-emerge, even though they have been almost eradicated. On the other hand, scientists are creating new, genetically altered life forms, in which some consider an emergent solution, while others consider genetic engineering to be a terrible problem. Scientists use genetic modification (GM), biotechnology, gene splicing and recombinant DNA technology. At the same time, nanotechnology has the potential to turn relatively inactive molecules into potent drugs. Stem cell technology may aslo be able to provide many medical benefits. More recently, there has been a shortage of some important prescription drugs. This can continue to happen if a major producer has problems in manufacturing and has to stop production for a while, or if there is not enough profit to be made and they shut down production. As a result, patients may experience unacceptable delays in receiving 210 different medicines for cancer, anesthesia Parkinson’s disease, schizophrenia, osteoporosis and organ failure. Finally, the ebola virus has emerged as a new problem, so therapies and vaccines are being developed.

To sustain life and good health, it is essential that cells and tissues can communicate with each other. Organelles within cells, cells within tissues, tissues within our body, and all of the bodies in a society must sense their internal and external environments and respond appropriately to changes. Hormones, neurotransmitters and cytokines can act as primary messengers. Secondary messengers include is Ca2+, IP3 and diacyl glycerol (produced by the hydrolysis of phosphoinositides), arachidonic acid (produced by the hydrolysis of phospholipids that have arachidonoyl on carbon number 2 of the glycerol backbone), ceramide, eicosanoids, lysophosphatidic acid, NO (nitric oxide), cAMP and cGMP. The IP3 receptor, or IP3R is a membrane-bound complex of glycoproteins. It is a Ca2+ channel that is activated by IP3, which is a secondary intracellular messenger. Inter- and intracellular communication can be thought of as a network that contains many items (nodes) that have anywhere from one to thousands of connections. The most widely connected nodes are called hubs. Probably the major genetic hub in human and many other mammalian cells is the gene TP53 which codes for the protein p53. About 50% of all human cancers have one or more mutations in p53 that alter DNA transcription.

Systems biology is essential for P4 medicine, as are autopoiesis, network theory and the concept of emergent properties. That is, the basic, fundamental unit of life is the cell, not the atoms and molecules in the cell. Many new properties emerge when atoms, molecules and ions are organized in a living cell. The functions of a cell do not depend on just the properties of the individual molecules, but also on how these molecules interact. Autopoiesis means self-production. It is a network of production processes, in which the function of each component is to participate in the production or transformation of itself and the other components in the network. The production processes are circular. Life is a cyclic process that produces the components of a living system. Based on the autopoietic theory of life, the biosphere of Earth is often thought of as a living system. Bacteria can be thought of as the catalysts that maintain the atmosphere in its present state, far from equilibrium, but stable, like homeostasis in a cell, organ or organism. Networks permeate living systems. Living systems and the internet are examples of a type of network called a scale-free network. These networks are dominated by a few well-connected nodes, called hubs. Most nodes in the network have a few connections, but a small number of nodes have a seemingly unlimited number of connections. In the scale-free network that is in living cells, there are many levels of organization. Each of them can be viewed as a network. There is a network of genes, a metabolic network, a regulatory network and a cellular network.