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The Use of Engineered Microbes as Medical Agents by Geoff Graham Chapter 2- The Desirability of Concentrating Drugs at Their Targets Why Are There So Many Dangerous Medicines? 2.1 Introduction to Chapter 2 2.1.1. How this Chapter Fits into the Overall Book 2.1.2. The Contents of this Chapter 2.2 The Problems of Oral Drug Administration 2.3 The Right Signal but the Wrong Place: The Traffic Cop Metaphor 2.4 The Liver Is Particularly Vulnerable 2.5 Candidates for Concentration at the Target 2.5.1 Monoclonal Antibodies 2.5.1.1 Monoclonal antibodies as medicines 2.5.1.2 How monoclonal antibodies act against their targets 2.5.1.3 Cancer as a target of monoclonal antibodies 2.5.1.4 Autoimmune disease as a target of monoclonal antibodies 2.5.1.5 Four specific examples 2.5.1.6 Natalizumab 2.5.1.7 Abciximab 2.5.1.8 Adalimumab 2.5.1.9 Bevacizumab 2.5.2 Nitric Oxide 2.5.3 Leptin 2.5.4 Growth Hormone 2.5.5 Insulin-Like Growth Factor-1 2.5.6 Somatostatin 2.5.7 Lithium 2.5.8 Other Candidates for Local Administration 2.6 Access to Blood Vessels from Lymphatic Vessels 2.7 Sharpening the Focus with Two Molecules 2.8 Research Benefits of Concentration at the Target 2.9 The Consequences of Restricted Location for Drug Characteristics 2.10 Analysis of 50 Withdrawn Drugs - General Remarks 2.11 Drugs That Would Benefit from Spatial Restriction 2.11.1 Liver Toxicity 2.11.2 Growth Factors in the Blood 2.11.3 Changes in Heart Rhythm 2.11.4 Other Reasons 2.12 Drugs That Would Not Benefit from Spatial Restriction 2.12.1 Addiction and Abuse 2.12.2 Damage Is at Intended Target 2.12.3 Other Reasons 2.1 Introduction to the Chapter 2.1.1. How this Chapter Fits into the Overall Book This e-book proposes almost 100 medical tests and therapies based on genetically modified microbes. The most valuable of the proposed therapies, but also the most difficult, is Repnumi rejuvenation, rejuvenation of the whole human body by replacement of nuclei and mitochondria in individual cells. I believe that progress toward Repnumi rejuvenation will be quickest if the path to it includes multiple intermediate rewards (or goals), each worth striving for. In general, the abilities gained in pursuit of easier goals will accelerate progress toward the more difficult goals. In this chapter, I argue that the ability to concentrate medicines at specific places in the body is one worthwhile intermediate goal. Repnumi rejuvenation would require moving differentiated nuclei, as well as mitochondria, to precise locations within the body. The nuclei and mitochondria would be carried by some cellular or multicellular construct whose characteristics are discussed in subsequent chapters. Although we mostly lack the ability to concentrate substances in chosen locations of the body, there is good reason to think that we can acquire such an ability. This would produce important benefits that would materialize much sooner than Repnumi rejuvenation will, and yet is a necessary prerequisite to Repnumi. This chapter explores the benefits of concentrating conventional medicines at their site of action. Non-conventional medicines, such as those based on engineered microbes, are discussed in subsequent chapters. With the exception of a few topics (see below) discussion of the methods of concentration is also deferred. 2.1.2. The Contents of this Chapter This chapter begins by discussing the problems that doctors face when they administer medicines orally. I conclude that targeting of medicines to specific locations will probably bypass the oral route, and instead involve injection of medicines into blood or lymph. This chapter then discusses two special problems that occur when medicines are NOT concentrated at their site of action. The first problem is that because many medicines mimic or inhibit short-range chemical signals between cells, and because specific signals are reused in many different tissues, diffused medicines may disrupt signaling in tissues other than their target tissues. The second problem is that because the liver is the main organ for removing foreign substances from the body, and because the removal process may increase the toxicity of foreign substances, the liver is especially vulnerable to poisoning by diffused medicines. This chapter then examines several important medicines or medicine classes and the potential advantages of concentrating them at their site of action. The medicines or classes are monoclonal antibodies, nitric oxide, leptin hormone, growth hormone, insulin-like growth factor 1, somatostatin, lithium, prostaglandins, and endothelin-1. Although this chapter (Chapter 2) mostly avoids the question of how medicines might be concentrated at chosen targets, it discusses two special issues. The first issue is the advantages that might result from accessing blood vessels via lymphatic vessels. The second issue is the possibility of sharpening a medicine’s effective concentration by dividing the medicine into two diffusible interacting components. Restriction of a drug to its target organ might reveal the unsuspected involvement of distant organs in the drug’s mechanism of action. As just one example, a drug that seemed to benefit arthritic joints might actually affect the bone marrow and immune system. This chapter discusses this possibility in more detail. In my experience, it is easy to convince biologists that concentrating medicines at their targets is desirable. The advantages seem intuitively clear. In this chapter I go beyond simply making the case for this idea, and try to assess how much we would benefit. I analyze 50 drugs that have been withdrawn from the market, asking which ones would be improved by targeting to their desired site or sites of action. My answer (see below) is that about 70% of them would be substantially improved. The ability of doctors to concentrate drugs at their targets would probably also change the nature of the drugs used. This is particularly true if the concentration process required that the drugs be manufactured in situ by living cells. This chapter explores that issue. Again, discussion of the methods by which medical agents might be concentrated at their targets is mostly left to subsequent chapters. This chapter merely discusses the advantages and disadvantages. 2.2 The Problems of Oral Drug Administration Oral administration is the easiest, most natural, and most pleasant method of delivering drugs. However, it also suffers from a dosing problem known as the “first pass effect” The first pass effect is the partial (or total) inactivation of an oral drug before it reaches the general circulation. Before they reach the general circulation, oral drugs are susceptible to enzymes and chemical conditions within the gastrointestinal lumen, to the action of intestinal bacteria, to the actions of enzymes within the intestinal walls and to the enzymes of the liver. This last is because materials absorbed through the gastrointestinal wall enter the hepatic portal system; they pass through the hepatic portal vein and into the liver before they enter the general circulation. Notable drugs that experience a significant first-pass effect are imipramine, morphine, propranolol, buprenorphine, diazepam, midazolam, demerol, cimetidine, and lidocaine { }. It is the liver’s job to chemically modify foreign substances so they can be more easily cleared from the body. Sometimes, it modifies so much of an oral drug that only a small fraction of the drug reaches the general circulation. This is dangerous because small variations between patients or within a single patient from time to time, can lead to large changes in a drug’s effective dose. For example, a decrease in the first pass effect from 90% to 70% in a patient would increase the effective dose of a medicine by three-fold. Because of the problem of the first pass effect, methods that avoid it are often used to administer drugs. These methods include rectal suppositories, intravenous injection, intramuscular injection, inhalational aerosols, and sublingual administration. http://en.w ikipedia.org/wiki/First_pass_effect, SR Methods to concentrate drugs at targets within the body would very likely involve injection into either the blood or the lymphatic system, and would avoid the first pass effect. These possibilities are explored in subsequent chapters. 2.3 The Right Signal but the Wrong Place: The Traffic Cop Metaphor Medicines can be divided into at least three classes: vaccines, poisons, and modifiers of chemical communication. This subchapter describes a danger of not spatially restricting the third class of medicine, the modifiers of chemical communication. Vaccines are a very successful class of medicine. The vaccines and the immunological changes caused by vaccines presumably should pervade the entire body except for a few immunologically privileged areas. On this issue, there is little to discuss. Many other medicines are poisons. These include antibiotics that kill bacteria, drugs that impede viruses, agents that kill eukaryotic parasites, and toxins that kill cancer cells. In general, concentrating these agents near the targeted cells is desirable, especially in the case of anti-cancer toxins. Again, there is little to discuss. A third class of medicines―a very large and important class―consists of agents that alter chemical communications within the body. These agents may block chemical communications, or they may mimic it. Many disease states―such as cancer, heart disease, diabetic retinopathy, and skeletal muscle wastage―are made worse by inappropriate chemical signals from other parts of the body, but benefit from appropriate chemical signals. The body contains many chemical messengers that could be medically useful if applied in concentrated form to the right tisssue at the right time (see examples below). Most of the body’s chemical messengers act at short range―they are made near the site where they will act―and are re-used in different tissues. This creates the possibility of deleterious cross-talk between tissues, but the body is largely protected from this by the fact that the messengers are made in small amounts and are short-lived. Drug researchers hoping to manipulate the body’s chemical signals are stymied by their labile nature. To circumvent this lability, drug researchers must create chemical analogs of natural messengers that will not break down before they can act. These analogs generally turn out to be very unbiological molecules. The above pharmacological strategy frequently succeeds, but it creates two serious problems. The first problem is that there is often, as one would expect, unwanted biological activity at tissues other than the target tissue. The second problem is that the liver recognizes these strange compounds as foreign, and takes steps to remove them from the body―but often poisons itself in the process (see Section 2.4, below). The analogy that I would use to describe unwanted drug actions at nontarget sites is of a traffic cop who spots a motorist about to run a red light at a busy intersection. The traffic cop yells “Stop!” The motorist hears the command and stops, thus averting a traffic accident. However, dozens of other people in the same city hear the command “Stop!” and interpret it within their own contexts. Metaphorically, this is what doctors risk when they inject most drugs into the general circulation. These two main problems―actions at non-target tissues and liver toxicity―and a few other problems are discussed in detail below. However, the central lesson is clear. The ability to concentrate medical agents near their intended targets would allow doctors both to prevent unwanted crosstalk and to protect the liver by using natural molecules that act quickly and then degrade harmlessly before they can travel far. 2.4 The Liver Is Particularly Vulnerable Ten drugs (Ticrynafen, Alpidem, Tolrestat, Tolcapone, Amineptine, Troglitazone, Trovafloxacin, Pemoline, Lumiracoxib, and Sitaxentan) have been withdrawn from the market because they damage the liver { }. Unanticipated liver toxicity is the single most important reason that approved drugs are withdrawn from the market, and more than 900 drugs are known to injure the liver { }. Drug-induced injury to the liver causes 5% of all hospital admissions and 50% of all acute liver failures. The reason for this vulnerability of the liver to drugs is that the liver is the body’s main organ for clearing foreign substances from the body { } { }. Many of the chemical transformations that occur in the liver increase the water solubility and decrease the fat solubility of the drugs acted upon. These transformations sometimes increase the reactivity and toxicity of the drugs. { }. An excellent article in Wikipedia explains more about this subject { }. An ability to concentrate drugs at their targets would likely reduce liver toxicity for two reasons. First, the amount of drug delivered would likely be see Section 2.11.1 below http://en.wikipedia.o rg/wiki/ Hepatotoxicity, M: More than 900, SR, nr4 http://en.wikipedia.org/wiki/Hepatotoxicity, M: The liver plays a central role, SR, nr1 http://en.wikipedia.o rg/wiki/ Hepatotoxicity, M: metabolic clearing house, SR, nr8 http://en.wikipedia .org/wiki/Hepatotoxicity, M: The central role, SR, nr9 http://en.wikipedia .org/wiki/Hepatotoxicity much less. Second, as discussed below, the nature of the drugs themselves would change, probably toward forms that would be less hepatotoxic. Detoxification of drugs by the liver not only may poison the liver, it may also lead to dangerous variation in drug dosing as mentioned above { }. The drug detoxification system varies because of genetic polymorphism, because of competition between drugs, and because many substances noncompetitively modify the actions of the detoxification enzymes { }. Localized administration of drugs that are degraded locally would avoid these problems. If this were possible, it would probably become standard practice—see below { }. This chapter, M: For example, a decrease http://en.wikipedia.o rg/wiki/ Hepatotoxicity, M: 1. Genetic diversity, nr18 This chapter, M: The Consequences of Restricted Location 2.5 Candidates for Concentration at the Target 2.5.1 Monoclonal Antibodies 2.5.1.1 Monoclonal antibodies as medicines. Monoclonal antibodies are increasingly used as medicines. It is possible to create a monoclonal antibody against almost any extracellular or cell surface target { }. A Wikipedia article on monoclonal antibody therapy { } lists 22 therapeutic monoclonal antibodies. Another Wikipedia article lists more than 100 therapeutic, diagnostic, and preventive monoclonal antibodies { }. Monoclonal antibodies are injected into patients in order to bind target antigens. These antigens are usually either proteins, complex carbohydrates, or a combination of the two. The antigens may exist as macromolecules that are free in the blood or lymph, or they may be attached to external cell surfaces. Individual antigen species are often distributed throughout the body. This is either because they are present on more than one tissue type, or because they are present on a tissue type that is present at many locations (such as skeletal muscle). http://en.wikipedia.o rg/wiki/ Monoclonal_antibody_therapy, SR, nr3 M: possible to create http://en.wikipedia.org/wiki/Monoclonal_antibody_therapy http:/ /en.wikipedia.org/wiki/ List_of_monoclonal_antibodies, nr33 2.5.1.2 How monoclonal antibodies act against their targets. Monoclonal antibodies bind their targets non-destructively. Binding of an antigen by an antibody may sequester the antigen, block the antigen’s activity, or in some cases even activate an antigen that is also a receptor―but usually does not damage the antigen or structures such as cell surfaces that support the antigen. Blocking of receptors by monoclonal antibodies can be medically useful, as when receptors that cancer cells need to grow are blocked { }. However, it is often desirable to kill the target cells. Since antibodies are not http://en.wikipedia.o rg/wiki/ Monoclonal_antibody_therapy, SR, nr4, M: prevent tumor growth themselves lethal, for monoclonal antibodies to efficiently kill targets such cancer cells or microbial pathogens, they must in some way be linked to a second agent that damages the target. Monoclonal antibodies are generally derived from immunoglobulin type IgG { }. All four IgG subclasses participate in a process called antibody-dependent cellular cytotoxicity { }. Hence monoclonal antibodies may kill their targets this way. If a monoclonal antibody is derived from another species, such as mouse, or if it contains other sequences that the patient’s immune system will recognize as foreign, binding of the monoclonal antibody to the intended target may provoke a secondary attack on the target by the host’s immune system { }. This is a second way that monoclonal antibodies can direct damaging agents to the targets they bind. It is also possible, at least in principle, for a monoclonal antibody to direct a cytotoxic drug to a target such as a cancer cell. One way is for the antibody to be linked to an enzyme that converts a harmless prodrug to a cytotoxic agent { }. Another is for monoclonal antibodies on the surfaces of drug-loaded liposomes to fasten those liposomes to their targets { }. Otherwise, for monoclonal antibodies to damage their targets, they must be linked to a radioisotope { } { }, or to some small-molecule or macromolecular damaging agent. This linkage can be covalent, but it can also take the form of bispecificity, where a hybrid molecule constructed from two different monoclonal antibodies binds both the target cells (such as a cancer cell) and a cytotoxic cell intended to kill the target { }. http://en.wikipedia .org/wiki/Monoclonal_antibody_therapy, SR, nr6, M: are large heterodimeric molecules http://en.wikipedia.org/wiki/Monoclonal_antibody_therapy, SR, nr10, M: There are four known ht tp://en.wikipedia.org/wiki/Monoclonal_antibody_therapy, SR, nr2 M: This may then stimulate http://en.wikipedia.o rg/wiki/Monoclonal_antibody_therapy, SR, nr28, M: Antibody-directed enzyme prodrug therapy http:/ /en.wikipedia.org/wiki/ Monoclonal_antibody_therapy, SR, nr29, M: Liposomes can carry drugs http://en.w ikipedia.org/wiki/Monoclonal_antibody_therapy, SR, nr5, M: a radioactive dose http://en.w ikipedia.org/wiki/Monoclonal_antibody_therapy, SR, nr27, M: high immunogenicity promotes http://en.w ikipedia.org/wiki/Bis pecific_antibody, nin 2.5.1.3 Cancer as a target of monoclonal antibodies. Cancer is an important target of therapeutic monoclonal antibodies. Cancer cells often display abnormal antigens. These may be antigens that ordinarily are present only before birth, or other antigens that are rare on healthy cells. Cancer cells may display abnormal combinations of antigens, and antigens that are inappropriate for their location in the body { }. Although monoclonal antibodies can be used to attack cancer cells, sophistication and discrimination may be needed for success. For example, a therapy that kills cells if and only if they a particular combination of antigens may be much safer than therapies that kill all cells carrying any one of those antigens. One can easily imagine that the former would selectively eliminate a cancer while the latter would devastate healthy tissues. The ability to spatially restrict a monoclonal antibody to chosen parts of the body would also be very valuable. Metastasis, the colonization by a cancer of tissues distant from the cancer’s origin, is cancer’s most dangerous http://en.wikipedia.o rg/wiki/Monoclonal_antibody_therapy, SR, nr, M: are only normally present feature. Since cancers often retain antigenic features of their tissue of origin, the ability to kill cells carrying those antigens when the cells are in an inappropriate part of the body could eliminate much metastasis. 2.5.1.4 Autoimmune disease as a target of monoclonal antibodies Autoimmune disease, which can take many forms, is another important target of monoclonal antibody therapy. Natalizumab, which is discussed below in Section 2.11.4, acts by binding integrin α4; this probably hinders immune system cells as they pass through blood vessel walls and invade solid tissues. Infliximab and adalimumab (discussed below in this section) bind and inhibit Tumor Necrosis Factor (TNF, formerly called TNF-α), and thus benefit patients with rheumatoid arthritis, Crohn’s disease, and ulcerative colitis { }. Basiliximab and daclizumab inhibit interleukin-2 on activated T cells and thereby reduce acute rejection of kidney transplants { }. Omalizumab inhibits human IgE (immunoglobulin type E) and is useful in moderate-to-severe allergic asthma { }. Immune activity is needed throughout the body. Therefore, systemic disabling of any immune system component would seem to present risks that localized disabling would not. http://en.w ikipedia.org/wiki/Monoclonal_antibody_therapy, SR, nr30, M: Liposomes can carry drugs http://en.wikipedia.org/wiki/ Monoclonal_antibody_therapy, SR, nr31, M: Basiliximab and daclizumab http://en.wikipedia.org/wiki/Monoclonal_antibody_therapy, SR, nr32, M: moderate-to-severe 2.5.1.5 Four specific examples. It is wise to check general assertions against specific examples. The feasibility and benefits of spatial restriction of four existing medical monoclonal antibodies are estimated here. Natalizumab was chosen because it is one of the 50 withdrawn drugs discussed below (see Section 2.11.4). Abciximab, adalimumab, and bevacizumab were chosen because they are near the top of Wikipedia’s list of 22 therapeutic monoclonal antibodies { } and seemed interesting. As discussed below, one of these monoclonal antibodies (bevacizumab) would surely be improved by spatial restriction within the body. Two others (natalizumab and adalimumab) would probably also be improved by spatial restriction, although the potential benefits are less. The fourth monoclonal antibody, abciximab, would also probably benefit from spatial restriction, but it is difficult to see how this could be done, since it functions in circulating blood. http:/ /en.wikipedia .org/wiki/ Monoclonal_antibody_therapy 2.5.1.6 Natalizumab. Natalizumab, is used to treat multiple sclerosis and Crohn’s disease { }. (Natalizumab is discussed below in section 2.11, an analysis of withdrawn drugs, because it was briefly withdrawn from the market.) http://en.w ikipedia.o rg/wiki/Natalizumab Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged. It often progresses to physical and cognitive disability. Crohn’s disease is an inflammatory disease of the intestines. It causes abdominal pain, diarrhea, vomiting, an weight loss. Natalizumab binds the α4 integrin chain. Natalizumab probably reduces the ability of inflammatory immune cells to attach to and pass through the blood-brain barrier and the intestines. Natalizumab is effective. In multiple sclerosis patients, natalizumab prevents relapse, vision loss, and cognitive decline, and improves the quality of life. It also increases remission rates and prevents relapse in Crohn’s disease. However, inflammation has benefits as well as costs. It is often a necessary response to infection and is required for removal of cellular debris. If natalizumab is administered systemically, it may suppress inflammation where it is needed, as well as where it is harmful. Thus, it natalizumab seems likely to be improved by spatial restriction within the body. 2.5.1.7 Abciximab. Abciximab { } binds the glycoproteinIIb/IIIa receptor. This receptor is present on blood platelets, and its activation by fibrinogen causes the platelets to aggregate and to form clots. Abciximab’s binding of the receptor prevents its activation; hence abciximab prevents blood clot formation. Abciximab is used to stop platelets from aggregating and forming clots during medical procedures such as angioplasty. The main complication of abciximab therapy is increased risk of bleeding, especially gastrointestinal hemorrhage. Although restriction of abciximab to the region of the clot would probably avoid this complication, it is hard to see how this could be done.in circulating blood. Hence , abciximab is not likely to benefit from spatial restriction. http://en.wikipedia .org/wiki/Abciximab 2.5.1.8 Adalimumab. Adalimumab binds tumor necrosis factor (TNF) and prevents it from activating TNF receptors. Adalimumab is used to treat several autoimmune diseases, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, moderate to severe chronic psoriasis and juvenile idiopathic arthritis. TNF is produced by several tissue types and affects several tissue types―facts which suggest that inhibition of TNF might have multiple unwanted consequences. TNF is made by macrophages, lymphoid cells, mast cells, endothelial cells, cardiac myocytes, fibroblasts, adipose cells and neurons { } { }. TNF stimulates the hypothalamus to produce corticotropin releasing hormone { }. It stimulates the brain to reduce appetite { } and it induces fever { }. TNF stimulates the liver’s acute phase response, increasing C-reactive protein and other mediators { }. It increases insulin resistance in liver and other tissues { }. TNF also inhibits CD4 T-cell expansion { }. Local increases in TNF concentration induce inflammation including heat, swelling, redness, pain and loss of function { }. This has a role in fighting infection. There may be circumstances where a general, systemic inhibition of TNF activity would be beneficial. High concentrations of TNF induce shock, and prolonged exposure induces cachexia; both effects are highly undesirable { }. However, it seems reasonable that in most cases, systemic inhibition of TNF would risk undesirable side effects. Generally recognized side effects of adalimumab include revival of latent tuberculosis, opportunistic fungal infections, and other opportunistic infections { }. Rare reported side effects include lymphoma, congestive heart failure, demyelinating disease, a lupus-like syndrome, and induction of auto-antibodies { }. Hence, adalimumab therapy is moderately likely to benefit from spatial restriction, and such spatial restriction is plausible (see subsequent chapters). http://en.wikipedia .org/wiki/Tumor_necrosis_factor-alpha, SR, NR38, M: TNF was thought http://en.wikipedia.o rg/wiki/ Tumor_necrosis_factor-alpha, nr38, SR, M: On the hypothalamus http://en.wikipedia.o rg/wiki/ Tumor_necrosis_factor-alpha, SR, M: corticotropin releasing hormone, nr39 http://en.wikipedia .org/wiki/Tumor_necrosis_factor-alpha, SR, nr40, M: Suppressing appetite http://en.wikipedia .org/wiki/Tumor_necrosis_factor-alpha, nr41, SR, M: Fever http:/ /en.wikipedia .org/wiki/Tumor_necrosis_factor-alpha, nr42, SR, M: On the liver http://en.wikipedia.org/wiki/Tumor_necrosis_factor-alpha, nr43, SR, M: induces insulin resistance http://en.w ikipedia.org/wiki/Tumor_necrosis_factor-alpha, , nr46, SR, M: expansion and function http://en.wikipedia.org/wiki/ Tumor_necrosis_factor-alpha, SR, nr44, M: A local increase http://en.wikipedia.o rg/wiki/ Tumor_necrosis_factor-alpha, nr45, SR, M: Whereas high http://en.w ikipedia.org/wiki/TNF_inhibition, SR, nr48 Scheinfeld_N J Dermatolog Treat. 2004 Sep;15(5): 280 -94. A comprehensive review and evaluatio n of the sid e effects of the tumor necrosis factor alpha blockers etanercept, infliximab and adalimumab, nr47, HR, NAO 2.5.1.9 Bevacizumab Bevacizumab binds and inhibits vascular endothelial growth factor (VEGF). VEGF stimulates both angiogenesis (the growth of new blood vessels from pre-existing vessels) and vasculogenesis (spontaneous formation of blood vessels from non-vascular tissue). VEGF creates new blood vessels during embryogenesis { }, and is part of the system that restores the oxygen supply in tissues where it is deficient { }. VEGF induces new blood vessels after injury { }. It creates new blood vessels in muscle after exercise { }. It also promotes collateral circulation, new blood vessels that bypass blocked vessels { }. There are times, however, when growth of new blood vessels is undesirable. First, it is usually very undesirable to allow new blood vessels to invade and nourish a solid tumor. Solid cancers cannot grow beyond a limited size without an adequate blood supply; however, cancers that express VEGF can grow and metastasize { }. Thus, bevacizumab is used to treat some cancers. http://en.wikipedia.o rg/wiki/ Vascular_endothelial_growth_factor. SR, nr53, M: normal function is http://en.w ikipedia.org/wiki/Vascular_endothelial_growth_fa ctor, nr52. SR, M: when blood circulation ht tp://en.wikipedia.org/wiki/Vascular_endothelial_growth_factor. SR, nr54, M: is a sig nal protein http://en.w ikipedia.org/wiki/Vascular_endothelial_growth_factor. nr55, SR, M: muscle following exercise http://en.w ikipedia.o rg/wiki/Vascular_endothelial_growth_fa ctor. SR, nr56, M: collateral circulation http://en.wikipedia.o rg/wiki/ Vascular_endothelial_growth_factor. SR, nr57, M: grow and metastasize VEGF expression can also have undesirable effects on the retina. VEGF promotes both diabetic retinopathy and the wet form of age-related macular degeneration { }. Bevacizumab is used to treat these conditions. VEGF is also involved in rheumatoid arthritis. It is released in joints in response to tumor necrosis factor. It increases endothelial permeability and swelling, and also stimulates capillary formation { }. Bevacizumab has been less successful against cancer than was hoped. It benefits only a minority of cancer patients, and only for a while { }. It does not reduce recurrence of non-metastatic colon cancer { }, and does not extend the survival of female breast cancer patients { }. The reasons for bevacizumab’s failure to inhibit some cancers is not known. However, one possibility is that since bevacizumab only sequesters VEGF, and does not destroy it, that the concentration of VEGF near tumors increases until it overwhelms the bevacizumab. A second possibility is that tumors evolve to produce other inducers of angiogenesis. Two potent angiogenesis inducers that have been mentioned in this regard are fibroblast growth factor 2 and hepatocyte growth factor { }. Systemic administration of bevacizumab is predicted to have adverse side effects that result from its inhibition of new blood vessel formation { }. It is predicted to interfere with wound healing, for example, and with collateral circulation (see above). It may exacerbate coronary and peripheral artery disease { }, and make conditions such as pulmonary emphysema, where there is already a deficit of VEGF in the pulmonary arteries { }, even worse. Actual reported side effects of bevacizumab include hypertension and increased risk of bleeding. Perforations can appear in the stomach, intestines, and nasal septum. In addition, posterior reversible encephalopathy syndrome, and renal thrombotic microangiopathy have been reported { } These effects are largely avoided when bevacizumab is used to treat vessel overgrowth in the eye, because it is introduced directly into the eye. It does not greatly affect VEGF activity in the rest of the body { }. Thus, restriction of bevacizumab to just its target tissues increases its value. It seems plausible that bevacizumab or some derivative of it will eventually be made more effective against cancers. Either its interaction with VEGF will be changed so that the VEGF is destroyed and/or monoclonal antibodies against additional angiogenic factors such as hepatocyte growth factor and fibroblast growth factor 2 will be added. While these changes might greatly reduce the ability of tumors to find nourishment within the http:/ /en.wikipedia .org/wiki/Vascular_endothelial_growth_factor. SR, nr60.M: is also important indiabetic retinopathy http://en.w ikipedia.o rg/wiki/Vascular_endothelial_growth_fa ctor. SR, nr62, M: formation ofcapillaries http://en.wikipedia.o rg/wiki/ Vascular_endothelial_growth_factor. SR, nr63, M: Bergers and Hanahan, M: Approximately 10-15% http://en.w ikipedia.org/wiki/Bevacizumab M: A study released in April 2009, nin http://en.wikipedia.o rg/wiki/ Bevacizumab M: in 3,000 female breast cancer patients, nin http://en.wikipedia.o rg/wiki/ Vascular_endothelial_growth_factor. SR, nr64, M: are potent angiogenic http:/ /en.wikipedia .org/wiki/Bevacizumab M: interfere with these normal processes, nin http://en.wikipedia.o rg/wiki/ Bevacizumab M: interfere with these normal processes, nin http://en.wikiped ia.org/wiki/Vascular_endothelial_growth_factor. SR, nr61, M: in the pulmonaryarteries http://en.wikipedia.o rg/wiki/ Bevacizumab M: The main side effects, nin http://en.wikipedia.o rg/wiki/Bevacizumab M: directly into the eye, nin body, they would also likely have devastating side effects unless confined to a small region around the target tumor. 2.5.2 Nitric Oxide Nitric oxide is therapeutic in many situations. It promotes neovascularization of hearts that have been damaged by ischemia { }. It limits apoptosis and reperfusion damage in hearts that have suffered ischemia, but then regained a normal blood supply { }, and does the same for liver { }. Treatment with dipyridamole increases the concentration of nitric oxide in tissues of diabetic mice. This relieves peripheral ischemia and promotes angiogenesis in those mice { }. However, nitric oxide also reduces synthesis of growth hormone and prolactin by the anterior pituitary gland. { }. Thus, long-term exposure to systemic nitric oxide, as part of a treatment for ischemia somewhere in the body, would likely interfere with the normal action of other hormones. As the above research findings indicate, use of nitric oxide to treat ischemia would probably provide maximum benefit if the nitric oxide could be restricted to the ischemic tissue―or at least kept away from the anterior pituitary. Abegunewardene_N Microcirculation. 2010 Jan;17(1 ):69-78. Local transient myocardial liposomal gene transfer of inducible nitric oxide synthase does not aggravate myocardialfunction and fibrosis and leads to moderate neovascularization in chronic myocardial ischemia in pig s. NAO, HR, M: abst Gao_F Circulation. 2002 Mar 26;105(1 2): 1497-502 Nitri c oxide mediates the antiapoptotic effect of insulin in myocardial ischemia-reperfusion: the roles of PI3-kinase, Akt, and endothelial nitric oxide synthase phosphorylation. YAO, HR, M: abst Yang_LQ Anesthesiology. 2011 Mar 4. [Epub ahead of print] Remifentanil Preconditioning Reduces Hepatic Ischemia-Reperfusion Injury in Rats via Inducible Nitric O xide Synthase Expression. http://www.ncbi.nlm.nih.gov/pubmed/21383616 NAO, HR, M: abst Pattillo_CB Free Radic Biol Med. 2011 Jan 15;50(2): 262-9. Dipyridamole reverses peripheral ischemia and induces angiogenesis in the Db/Db diabetic mouse hind-lim b model bydecreasing oxidative stress. NAO, HR, M: abst Vankelecom_H Mol Cell Endocrinol 1997 May 16;129(2): 157-167 Involvement of nitric oxide in the interf eron-gamma-induced inhibition ofgrowth hormone and prola ctin secretion in anterior pituitary cell cultures, NAO, HR, M: abst 2.5.3 Leptin Leptin protein of humans consists of 167 amino acid residues { }. Leptin is part of the body’s feedback mechanism for curbing appetite and preventing overeating. However, it is also works against obesity by regulating energy metabolism and helps the body adjust to obesity { }. Humans and mice lacking leptin are constantly hungry and generally obese { }{ } { }. Most of the body’s leptin is produced by the adipocytes of white adipose tissue { }. The amount of circulating leptin in the blood is is directly proportional to the total amount of fat in the body { }. Leptin counteracts appetite by acting on receptors in the hypothalamus { }. Within the hypothalamus, leptin counteracts the effects of neuropeptide Y and anandamide, two potent feeding stimulants, and promotes the synthesis of α-melanocyte stimulating hormone, an appetite http://en.wikipedia.org/wiki/Leptin, SR, M: a protein of 167 amino, nr6 http://en.wikipedia.org/wiki/ Leptin, SR, M: a 16 kDa protein hormone, nr4 http://en.wikipedia.o rg/wiki/ Leptin, SR, M: they fall into two classes, nr5 http://en.wikipedia.org/wiki/Leptin, SR, M: The absence of leptin, nr15 http://en.wikipedia.org/wiki/Leptin, SR, M: resulting in severe obesity, nr20 http://en.wikipedia.o rg/wiki/ Leptin, SR, M: It is manufa ctured primarily, nr7 http://en.wikipedia.org/wiki/Leptin, SR, M: level of circulating leptin, nr8 http://en.wikipedia.o rg/wiki/ Leptin, SR, M: in the hypothala mus of the brain, nr10 suppressant { } { } { } { }. Leptin inhibits the activity of neurons containing agouti-related peptide, an action that also reduces hunger { }. Obesity is a very serious public health problem, and leptin is an obvious candidate to treat it. And, in fact, leptin has been used in clinical trials to control obesity in people who lack leptin { }. However, recombinant leptin administered systemically was only moderately successful. Only the most obese subjects who were given the highest doses of exogenous leptin produced statistically significant weight loss { }. As a systemically administered drug, leptin has many problems. Its circulating half-life and solubility are both low. Furthermore, some participants quit the trials due to inflammation at the leptin injection site { }. An additional problem with using systemically administered leptin to control obesity is that, unless they are genetically deficient in leptin, obese people have high blood concentrations of leptin. Obese people become leptin-resistant { }, and leptin resistance also develops with age { }. Further complicating the use of systemically administered leptin to control obesity is the fact that leptin has additional physiological effects. Leptin acts on the immune system { }, for example, and on bone { }, and affects the blood pressure { }. And although the changes induced would usually be desirable in an obese person, there certainly might be exceptions. For example, leptin promotes angiogenesis (blood vessel formation), a change that might be contraindicated in cancer patients { }. Some functions of leptin may not yet be appreciated. Although, as mentioned above, most of the body’s leptin is made by adipocytes of white adipose tissue, leptin is also made by brown adipose tissue, placenta, ovaries, skeletal muscle, the stomach, mammary epithelial cells, bone marrow, liver, and the pituitary gland { }. Some of the synthesized leptin may act at short range in ways yet to be discovered, with effects that may disrupted by high concentrations of circulating leptin. http://en.wikipedia.org/wiki/ Leptin, SR, M: the effects of neuropeptide Y, nr11 http://en.wikipedia.org/wiki/Leptin, SR, M: the effects of anandamid e, nr12 http://en.wikipedia.org/wiki/Leptin, SR, M: synthesis of α -MSH, nr13 http://en.wikipedia.org/wiki/Leptin, SR, M: a feeling ofsatiety, nr19 http://en.wikiped ia.org/wiki/Leptin, SR, M: and agouti-related peptide, nr37 http://en.wikipedia.o rg/wiki/Leptin, SR, M: of recombinant human leptin, nr21 http://en.wikipedia.o rg/wiki/ Leptin, SR, M: significant weight lo ss, nr22 http://en.wikipedia.o rg/wiki/ Leptin, SR, M: It was co ncluded that, nr23 http://en.wikipedia .org/wiki/Leptin, SR, M: obese individuals generally exhibit, nr43 Beretta_E Pediatr Res. 2002 Aug;52(2):189-98 Long-Term Suppressionof Weight Gain, Adiposity, and Serum Insulin by Central Leptin Gene Therapy in Prepubertal Rats: Effects on Serum Ghrelin and Appetite-R egulating Genes. M: resistance to peripheral, nr19 http://en.wikipedia.org/wiki/Leptin, SR, M: activity in immune system, nr38 http://en.wikipedia .org/wiki/Leptin, SR, M: acts to reduce cancellous bone, nr42 http://en.wikipedia.o rg/wiki/ Leptin, SR, M: blood pressure in rats, nr40 http://en.wikipedia .org/wiki/Leptin, SR, M: Leptin promotes angio genesis, nr39 http://en.wikipedia.org/wiki/ Leptin, SR, M: brown adipose tissue, placenta, nr9 Some of leptin’s drawbacks as a systemically injected drug might be altered by genetically engineering the leptin protein. An Fc-leptin fusion protein, for example, retains leptin’s biological activity, but is more soluble and more stable { }. However, a more promising approach (it seems to me) is to curb a person’s appetite by expressing small amounts of supplementary leptin in or near the hypothalamus, where it can act directly. This approach was tried in rats, and seems promising. http://en.wikipedia.o rg/wiki/ Leptin, SR, M: from the immunoglobulingamma, nr24 A genetic construct expressing rat leptin was given intracerebroventricularly to male and female rats { }. Synthesis of leptin in the brains of rats substantially reduced their appetites { }, and the treated rats weighed one-third less than control rats { }. The treated rats had greatly reduced adiposity { }. There were other medically desirable changes as well. Serum leptin was reduced by a whopping 90% in treated animals { } and serum insulin was reduced by about 75% { }. The level of free fatty acids was also reduced { }. The reduction in weight and adiposity caused by expression of leptin in the brain was not due entirely to reduced food consumption. Energy expenditure also increased. At least part of this was probably due to nonshivering thermogenesis in brown adipose tissue { }{ }. This is a case where delivery of small amount of a therapeutic agent to exactly the right tissue is far superior to delivery of large amounts of that agent to the general circulation. Beretta_E Pediatr Res. 2002 Aug;52(2):189-98 Long-Term Suppression of Weight Gain, Adiposity, and Serum Insulin by Central Leptin Gene Therapy in Prepubertal Rats: Effects on Serum Ghrelin and Appetit e-Regulating Genes. M: abst, nr1 Beretta_E Pediatr Res. 2002 Aug;52(2):189-98 Long-Term Suppression of Weight Gain, Adiposity, and Serum Insulin by Central Leptin Gene Therapy in Prepubertal Rats: Effects on Serum Ghrelin and Appetite-Regulating Genes. M: administration of one icv, nr33 Beretta_E Pediatr Res. 2002 Aug;52(2):189-98 Long-Term Suppressionof Weight Gain, Adiposity, and Serum Insulin byCentral Leptin Gene Therapy in Prepubertal Rats: Effects on Serum Ghrelin and Appetite-Regulating Genes. M: with 33-35% reduction, nr30 Beretta_E Pediatr Res. 2002 Aug;52(2):189-98 Long-Term Suppression ofWeight Gain, Adiposity, and Serum Insulin by Central Leptin Gene Therapy in Prepubertal Rats: Effects on Serum Ghrelin and Appetite-Regulating Genes. M: abst, nr2 Beretta_E Pediatr Res. 2002 Aug; 52(2):189-98 Long-Term Suppression ofWeight Gain, Adiposity, and Serum Insulin by Central Leptin Gene Therapy in Prepubertal Rats: Effects on Serum Ghrelin and Appetite-Regulating Genes. M: reduced by 90%, nr31 Beretta_E Pediatr Res. 2002 Aug;52(2):189-98 Long-Term Suppression of Weight Gain, Adiposity, and Serum Insulinby Central Leptin Gene Therapy in Prepubertal Rats: Effects on Serum Ghrelin and Appetite-Regulating Genes. M: insulin by 72-76%, nr32 Beretta_E Pediatr Res. 2002 Aug;52(2):189-98 Long-Term Suppressionof Weight Gain, Adiposity, and Serum Insulin by Central Leptin Gene Therapy in Prepubertal Rats: Effects on Serum Ghrelin and Appetite-Regulating Genes. M: abst, nr3 Beretta_E Pediatr Res. 2002 Aug;52(2):189-98 Long-Term Suppression ofWeight Gain, Adiposity, and Serum Insulin by Central Leptin Gene Therapy in Prepubertal Rats: Effects on Serum Ghrelin and Appetite-Regulating Genes. M: abst, nr5 Beretta_E Pediatr Res. 2002 Aug;52(2):189-98 Long-Term Suppression of Weight Gain, Adiposity, and Serum Insulinby Central Leptin Gene Therapy in Prepub ertal Rats: Effects on Serum Ghrelin and Appetite-Regulating Genes. M: abst, nr6 2.5.4 Growth Hormone Human growth hormone is a protein of 191 amino acids { }. It is secreted by specialized cells within the anterior pituitary gland { }. Growth hormone is used to treat cases of growth hormone deficiency { }, and other conditions that cause short stature { }. Human growth hormone may also have therapeutic uses in restricted regions of the body. As one example, human growth hormone increases the sensitivity of U937 (human myeloid leukemia) cells to the anti-cancer drug daunorubicin. The human growth hormone prevents degradation of the inhibitor I-κB { }. This in turn impedes action of the nuclear factor NF-κB { }, and allows apoptosis to occur { }. Human growth hormone may also protect brain neurons from ischemiainduced injury. A substance that is probably growth hormone is strongly upregulated after brain injury and specifically associates with stressed neurons and glia. Moreover, growth hormone administered centrally 2 hours after a hypoxic-ischemic brain injury in juvenile rats protects neurons { }. http://en.wikipedia.o rg/wiki/Growth_hormone SR, M: a protein-based peptide, nr1 http://en.wikipedia .org/wiki/Growth_hormone SR, M: within the lateral wings, nr2 http://en.wikipedia.org/wiki/Growth_hormone SR, M: indicated onlyin limited, nr5 http://en.wikipedia.o rg/wiki/ Growth_hormone SR, M: Examples of other causes, nr6 Cherbonnier_C Cancer Gene Therapy (2002) 9: 497–504 Human growth hormone gene transfer into tumor cells may improve cancer chemotherapy. M: abst, nr6 Cherbonnier_C Cancer Gene Therapy (2002) 9: 497–504 Human growth hormone gene transfer into tumor cells may improve cancer chemotherapy. M: Altogether these approaches, nr15 Cherbonnier_C Cancer Gene Therapy (2002) 9: 497–504 Humangrowth hormone gene transfer into tumor cells may improve cancer chemotherapy. M: criti cal cell substrates, nr13 Scheepens_ A J Pediatr Endocrinol Metab 2000;13 Suppl 6:1483-91 A role for the somatotropic axis in neural development, injury and disease. NAO, SR, M: abst However, systemic administration of human growth hormone to patients is unwise if it can be avoided. Prolonged overexposure to human growth hormone causes a complex syndrome called acromegaly { }. Shorter side http://en.wikipedia.org/wiki/Growth_hormone SR, M: Prolonged GH excess, nr4 effects of treatment include injection site reactions, joint swelling, joint pain, and carpal tunnel syndrome { }. Other side effects, at least in children, include headache, idiopathic intracranial hypertension, and slipped capital femoral epiphysis { }. Human growth hormone activity, even within the normal range, promotes cancer and diabetes { }. Higher-than-normal activity may well be even more dangerous. Moreover, since the cancer and diabetes take years to appear, they might not be noticed in patient populations that were unhealthy anyway. Thus, spatial restriction of therapeutic human growth hormone to just the region near a tumor, or to just an injured brain, would probably increase its safety. http://en.wikipedia.org/wiki/Growth_hormone SR, M: Use of GH as a drug, nr7 Darendeliler_F Horm Res. 2007;68 Suppl5:41-7 Headache, idiopathic intracranial hypertension and slipped capital femoral epiphysis during growth hormone treatment: a s afety update from the KIGS database, HR, NAO, M: abst Guevara-Aguirre_J Sci Transl Med. 2011 Feb 16;3(70): 70ra13. Growth hormone receptor defici ency is associated witha majo r reductio n in pro-aging signaling, cancer, and diabetes in humans NAO, HR, M: abst 2.5.5 Insulin-Like Growth Factor-1 Insulin-like growth factor-1 (IGF-1) consists of 70 amino acids and closely resembles insulin { }. Most of the body’s IGF-1 is produced by the liver, and circulates in the blood as an endocrine hormone { }. However, it is also produced in other tissues, where it acts locally, in an autocrine/paracrine fashion { }. Growth hormone strongly stimulates IGF-1 synthesis in the liver { }. About 98% of IGF-1 is complexed with one of six IGF binding proteins { }. The most abundant of these, IGFBP-3, binds about 80% of IGF-1 in a 1:1 molar ratio { }. IGFBP-3 sequesters IGF-1 and prevents it from acting (see below). IGF-1 acts on cells by binding its receptor IGF1R, which is present on many cell types { }. IGF-1 stimulates proliferation and inhibits apoptosis { }. IGF-1 stimulates systemic body growth, and promotes growth of nearly every cell in the body, especially skeletal muscle, cartilage, bone, liver, kidney, nerves, skin, hematopoietic cells, and lungs { }. http:/ /en.wikipedia .org/wiki/IGF-1, SR, M: IGF-1 consists of 70 amino acids, nr1 http://en.wikipedia.o rg/wiki/IGF-1, SR, M: primarily by the liver, nr2 http://en.wikipedia.o rg/wiki/ IGF-1, SR, M: paracrine/autocrine fashion, nr3 http://en.wikipedia.o rg/wiki/ IGF-1, SR, M: retarded by undernutrition, nr4 http://en.wikipedia.o rg/wiki/ IGF-1, SR, M: Approximately 98%, nr5 http://en.wikipedia .org/wiki/IGF-1, SR, M: most abundant protein, nr6 http://en.wikipedia.org/wiki/IGF-1, SR, M: many cell types in manytissues, nr8 http://en.wikipedia.o rg/wiki/ IGF-1, SR, M: potent natural activators, nr9 http://en.wikipedia.o rg/wiki/ IGF-1, SR, M: especially skeletal muscle, nr10 IGF-1 has many potential therapeutic uses. If applied locally, it might prevent skeletal muscle wasting in the elderly { } and in people with cardiac insufficiency { }{ }. Localized expression of IGF-1 can also prevent dilated cardiomyopathy. IGF-1 stimulates proliferation of cardiac myocytes { } and inhibits the cardiomyocyte elongation that characterizes dilated hearts. { }. It restores normal calcium dynamics { } and attentuates the generation of reactive oxygen species { }. It normalizes heart weight, left N AO, Grounds_MD Biogerontology.2002;3(1-2):19-24. Reasons for the degeneration ofageing skeletal muscle: a central role for IGF-1 signalling.M: abst, HR, nr10 NAO, Rosenthal_N Int J Cardiol 2002 Sep;85(1):185 Gene therapy for cardiac cachexia? M: abst, SR NAO, Rosenthal_N Int J Cardiol 2002 Sep;85(1):185 Gene therapy for cardiac cachexia? M: abst, SR YAO, Welch_S Circ Res 2002 Apr 5;90(6):641-648 Cardiac-specific IGF-1 expression attenuates dilated cardiomyopathyin tropomodulin-overexpressing transgenic mice. M: Expression of Ki67 protein in left ventri cular myocyte nuclei, HR, nr34 YAO, Wel ch_S Circ Res 2002 Apr 5;90(6):641-648 Cardiac-specific IGF-1 expression attenuates dilated cardiomyopathy in tropomodulin-overexpressing transgenic mice. M: abst, HR, nr1-9 YAO, Welch_S Circ Res 2002 Apr 5;90(6):641-648 Cardiac-specific IGF-1 expression attenuates dilated cardiomyopathyin tropomodulin-overexpressing transgenic mice. M: Measurem ent of intracellular cal cium, HR, nr40 YAO, Welch_S Circ Res 2002 Ap r 5;90(6):641-648 Cardiac-specific IGF-1 expression attenuates dilated cardiomyopathy in tropomodulin-overexpressing transgenic mice. M: attenuates the generation, SR, nr24 ventricle weight, and right ventricle weight { }, as well as free wall and septal thickness { }, longitudinal axis, chamber diameter, and cavitary volume { }. It inhibits apoptosis { } and largely restores normal cardiac function { }{ }. However, IGF-1 can also stimulate the growth of cancer cells, protect them from apoptosis, and allow them to escape controls on their growth. IGF-1 stimulates the growth of non-small cell lung cancer cells { }. IGF-1 negatively regulates protein p53, a protein that limits cell proliferation { }. IGF-1 also increases telomerase activity, thus overriding an inherent limit to cell proliferation { }. IGF-1 blocks apoptosis { }{ }, a key defense against cancer, and increases tumor resistance to radiation treatment { }. Thus, IGF-1 has activities that are both beneficial and destructive, depending on the context. This argues that IGF-1 could confer more benefit and less harm if it were limited to physical contexts where it is clearly useful. YAO, Wel ch_S Circ Res 2002 Ap r 5;90(6):641-648 Cardiac-specific IGF-1 expression attenuates dilated cardiomyopathy in tropomodulin-overexpressing transgenic mice. M: In creased heart weight, HR, nr28 YAO, Wel ch_S Circ Res 2002 Apr 5;90(6):641-648 Cardiac-specific IGF-1 expression attenuates dilated cardiomyopathy in tropomodulin-overexpressing transgenic mice. M: f ree wall and septal thickness, HR, nr30 YAO, Welch_S Circ Res 2002 Apr 5;90(6):641-648 Cardiac-specific IGF-1 expression attenuates dilated cardiomyopathy in tropomodulin-overexpressing transgenic mice. M: and cavitary volume, HR, nr31 YAO, Welch_S Circ Res 2002 Apr 5;90(6 ):641-648 Cardiac-specific IGF-1 expression attenuates dilated cardiomyopathy intropomodulin-overexpressing transgenic mice. M: nearly 4-fold higher, HR, nr35 YAO, Welch_S Circ Res 2002 Apr 5;90(6 ):641-648 Cardiac-specific IGF-1 expression attenuates dilated cardiomyopathy intropomodulin-overexpressing transgenic mice. M: improvement of cardiac function, HR, nr33 YAO, Wel ch_S Circ Res 2002 Ap r 5;90(6):641-648 Cardiac-specific IGF-1 expression attenuates dilated cardiomyopathy in tropomodulin-overexpressing transgenic mice. M: depressed systolic function, HR, nr48 Lee_HY Cancer Res 2002 Jun 15;62(1 2): 3530-7 Insulin-like growth factor binding protein-3 inhibits the growthof non-smallcell lung cancer. M: abst, HR, nr4 YAO, Wel ch_S Circ Res 2002 Apr 5;90(6):641-648 Cardiac-specific IGF-1 expression attenuates dilated cardiomyopathy in tropomodulin-overexpressing transgenic mice. M: seems to depend on, HR, nr54 YAO, Welch_S Circ Res 2002 Ap r 5;90(6):641-648 Cardiac-specific IGF-1 expression attenuates dilated cardiomyopathy in tropomodulin-overexpressing transgenic mice. M: increases telomerase activity, HR, nr55 Lee_HY Cancer Res 2002 Jun 15;62(1 2): 3530-7 Insulin-like growth factor binding protein-3 inhibits the growthof non-smallcell lung cancer. M: abst, HR, nr14 Lee_HY Cancer Res 2002 Jun 15;62(12):3530-7 Insulin-like growth factor binding protein-3 inhibits the growthof non-small cell lung cancer. M: abst, HR, nr15 YAO, Lee_HY Cancer Res 2002 Jun 15;62(12):3530-7 Insulin-like growth factor binding protein-3 inhibits the growth of non-small cell lung cancer. M: has particular clinical, SR, nr50 2.5.6 Somatostatin Somatostatin is a polypeptide hormone of either 14 or 28 amino acids { }. Somatostatin is made as a 116-long amino acid precursor called preprosomatostatin that is cleaved by a protease to the prohormone prosomatostatin (92 amino acids long) and finally by endoproteolytic processing to the 14 or 28-aminoacid peptide { }. Somatostatin hormone activity is complex. In all vertebrates, there are six different somatostatin genes. Humans also have 5 distinct somatostatin receptors, and one of these has two forms, generated by alternative splicing of the cytoplasmic tail { }. Somatostatin is produced in a number of different places in the body, In the digestive system, it is produced in the stomach, the intestine and in the delta cells of the pancreas { }. Somatostatin is produced in several areas of the brain, including the arcuate nucleus, the hippocampus, and the brainstem nucleus of the solitary tract { }. Somatostatin’s most notable site of production, however, is in a part ot the brain termed the hypothalamus { }. The hypothalamic neurons from which somatostatin is released from are connected to the anterior pituitary gland. { }. Within the anterior pituitary gland, somatostatin inhibits the secretion of growth hormone { }. Krassas_GE Clin Ophthalmol. 2007 Sep;1(3):209-15 The efficacy of somatostatinanalogues in the treatment of diabetic retinopathy and thyroid eye disease. M: abst, nr1 Krassas_GE ClinOphthalmol.2007 Sep;1(3): 209-15 The efficacy of somatostatin analo gues in the treatment of diabetic retinopathy and thyroid eye dis ease. M: as 116-long, nr15 Krassas_GE Clin Ophthalmol. 2007 Sep;1(3):209-15 The effi cacy of somatostatin analo gues in the treatment of diabetic retinopathy and thyroid eye dis ease. M: There are five, nr19 http://en.wikipedia.o rg/wiki/ Somato statin M: secreted in several locations, SR, nr5 http://en.wikipedia.o rg/wiki/ Somato statin M: byseveral other populations, SR, nr10 http://en.wikipedia.org/wiki/ Somatostatin M: produced by neuroendocrine neurons, SR, nr6 http://en.wikipedia .org/wiki/Somatostatin M: These neurons project, SR, nr7 http://en.wikipedia .org/wiki/Somatostatin M: where it inhibit, SR, nr8 High levels of circulating growth hormone stimulate release of somatostatin from the hypothalamus. Hence, somatostatin is part of an autoregulatory loop in which growth hormone inhibits its own release { }. Somatostatin is an inhibitory hormone generally { }. In addition to inhibiting the release of growth hormone from the anterior pituitary gland, as discussed above, somatostatin also inhibits the release of thyroid stimulating hormone from the anterior pituitary { } { }. It inhibits the release of seven gastric hormones { }, decreases the rate of gastric emptying, and reduces smooth muscle contractions and blood flow within the intestine { }. Somatostatin also inhibits the release of insulin and glucagon from the pancreas { }. Somatostatin has a very short half-life within the general blood circulation, just two to three minutes { }. Hence, somatostatin is too labile to serve as a good injectable drug. However, several somatostatin analogs have developed that are at least as potent hormonally, and that persist in the body much longer. Octreotide is a synthetic oligopeptide that mimics somatostatin’s activity, though is a more potent inhibitor of growth hormone, glucagon, and insulin than is somatostatin { }. Octreotide is given parenterally { }, and has an in vivo half-life of about 90 minutes { }. Lanreotide is another long-acting analog of somatostatin { }. http://en.wikipedia.o rg/wiki/Somato statin M: negative feedback effects, SR, nr9 http://en.wikipedia.org/wiki/ Somatostatin M: Somatostatin is classified, SR, nr11 http://en.wikipedia.org/wiki/ Thyroid-stimulating_hormone, SR, M: Somatostatin is also produced http://en.wikipedia.o rg/wiki/ Somato statin M: Inhibit the release of thyroid, SR, nr13 http://en.w ikipedia.org/wiki/Somatostatin M: Somatostatin is homolo gous with, SR, nr15 http://en.wikipedia.o rg/wiki/ Somato statin M: Decrease rate of gastric, SR, nr16 http://en.w ikipedia.org/wiki/Somatostatin M: release of pancreatic hormones, SR, nr17 http://en.wikiped ia.org/wiki/Somatostatin M: a much longer half-life, SR, nr20 http://en.wikipedia.org/wiki/Somatostatin M: is an octapeptide, SR, nr19 http://en.wikipedia.org/wiki/Somatostatin M: intramuscularly, SR, nr21 http:/ /en.wikipedia .org/wiki/Somatostatin M: a much longer half-life, SR, nr20 http://en.wikipedia.o rg/wiki/Somato statin M: Lanreotide (INN ) is a medication, SR, nr23 Somatostatin analogs show promise in the treatment of diabetic retinopathy, as suppressors of vessel proliferation { }. Diabetic retinopathy is the most frequent chronic microvascular complication of diabetes. It is the leading cause of blindness among people of working age { }. Early signs of retinopathy appear in all people with type 1 diabetes after 20 years, and in about 80% of those with type 2 diabetes after 20 years { }. Diabetic retinopathy is characterized by neovascularization { } and possible autoimmunity { }{ }. When used to treat diabetic retinopathy, octreotide (see above) suppresses new bleeding and stops visual loss in patients who have failed conventional photocoagulation therapy { }{ }. However, octreotide has a maximum tolerated dose { }, presumably because of effects elsewhere in the body (see below). Analogs of somatostatin that are more potent than octreotide exist, for example SOM230 { }. These might be even more effective in treating diabetic retinopathy, if they do not have unacceptable side effects. Octreotide also shows modest promise in treating thyroid eye disease { }. Krassas_GE Clin Ophthalmol. 2007 Sep;1(3): 209-15 The efficacy of somatostatinanalogues in the treatment of diabetic retinopathy and thyroid eye disease. M: abst, nr3 Krassas_GE Clin Ophthalmol. 2007 Sep;1(3):209-15 The efficacy of somatostatinanalogues in the treatment of diabetic retinopathy and thyroid eye disease. M: working age, nr9 Krassas_GE Clin Ophthalmol. 2007 Sep;1(3):209-15 The efficacy of somatostatinanalogues in the treatment of diabetic retinopathy and thyroid eye disease. M: early signs of, nr10 Krassas_GE Clin Ophthalmol. 2007 Sep;1(3):209-15 The efficacy of somatostatinanalogues in the treatment of diabetic retinopathy and thyroid eye disease. M: the loss of pericytes, nr11 K rassas_GE Clin Ophthalmol. 2007 Sep;1(3): 209-15 The efficacy of somatostatinanalogues in thetreatment of diabetic retinopathy and thyroid eyedisease. M: finding of antipericyte, nr12 Krassas_GE Clin Ophthalmol. 2007 Sep;1(3):209-15 The effica cy of somato statin analogues inthe treatment of diabetic retinopathy and thyroid eye disease. M: class II DR, nr13 Krassas_GE Clin Ophthalmol. 2007 Sep;1(3):209-15 The effica cy of somatostatinanalogues in the treatment of diabetic retinopathy and thyroid eye disease. M: abst, nr4 Krassas_GE Clin Ophthalm ol. 2007 Sep;1(3):209-15 The efficacy of somatostatin analogues inthe treatment of diabetic retinopathy and thyroid eye disease. M: maximally to lerated dose, nr31 Krassas_GE Clin Ophthalmol. 2007 Sep;1(3):209-15 The efficacy of somatostatinanalogues in the treatment of diabetic retinopathy and thyroid eye disease. M: a rather high affinity, nr38 Krassas_GE Clin Ophthalmol. 2007 Sep;1(3):209-15 The efficacy of somatostatinanalogues in the treatment of diabetic retinopathy and thyroid eye disease. M: abst, nr5 Krassas_GE Clin Ophthalmol. 2007 Sep;1(3):209-15 The effica cy of somato statin analogues inthe treatment of diabetic retinopathy and thyroid eye disease. M: role of these, nr36 Somatostatin analogs might also protect women against breast cancer { }. Pasireotide, a somatostatin analog, protects female rats from mammary hyperplasia that can lead to breast cancer. Pasireotide does this by blocking harmful effects of circulating growth hormone and IGF-1. However, systemic treatment of patients with somatostatin analogs has side effects { }. These include biliary dysfunction, gastroenterologic disorders, and pancreatic insufficiency. The pancreatic insufficiency results from the somatostatin analogs’ suppression of pancreatic enzymes The above examples taken together suggest that somatostatin analogs might be more effective with fewer side effects if they were concentrated at their targets. However, if this could be done, it might not be necessary to use analogs; somatostatin itself might be the drug of choice. Kleinberg_DL Pituitary. 2011 Mar;14(1 ):44-52 Pasireotide, an IGF-I action inhibitor, prevents growth hormone and estradiol-induced mammary hyperplasia, SR, NAO Saif_MW Expert Opin Drug Saf. 2010 Nov;9(6):867-73 Chronic octreotide therapy can induce pancreatic insufficiency: a common but under-recognized adverse effect. SR, NAO 2.5.7 Lithium Lithium has several uses or potential uses as a drug { }. First, it is a mood stabilizer. It is used to treat bipolar disorder. It treats both mania and depression, and is said to be more effective in treating mania. It may reduce the risk of suicide in some bipolar patients. Lithium is also effective against some headaches { }. It stimulates production of white blood cells in the bone marrow { }, and is used to treat an inflammatory skin disorder called seborrhoeic dermatitis { }. Lithium is given as a salt, such as lithium carbonate, lithium citrate, lithium sulfate, or lithium orotate { }. Upon ingestion, it becomes widely distributed in the central nervous system and interacts with a number of neurotransmitters and receptors, decreasing norepinephrine release and increasing serotonin synthesis. It can take up to a month for lithium to have a mood-stabilizing effect, during which time lithium ions presumably bathe most or all of the body’s tissues. http://en.wikipedia .org/wiki/Lithium_therapy http://en.wikipedia .org/wiki/Lithium_therapy http://en.wikipedia.o rg/wiki/Lithium_therapy M: leukopenia http://en.wikipedia.org/wiki/Lithium_therapy M: seborrhoeic dermatitis http:/ /en.wikipedia.org/wiki/ Lithium_therapy Lithium treatment can have unwanted side effects. First, it inhibits antidiuretic hormone, causing water loss { }. Second, it causes histological and functional changes to the kidney that are serious enough to discourage long-term lithium use unless it is definitely indicated { }. A third side effect of chronic lithium treatment is that it impairs endothelium-dependent vasorelaxation in various tissues. { }, and in particular reduces the survival of ischemic skin in an experimental skin-flap system { }. Lithium is thought to act by reducing the concentration of nitric oxide in skin { }. http:/ /en.wikipedia.org/wiki/ Lithium_therapy M: The reason why water is lost http://en.wikipedia.o rg/wiki/ Lithium_therapy M: functional changes in Nezami_BG J Surg Res. 2010 May 21. Chronic lithium impairs skin tolerance to ischemia in random-pattern skin flapof rats. http://www.ncbi.nlm.nih.g ov/pubmed/20605607, NAO Nezami_BG J Surg Res. 2010 May 21. Chronic lithium impairs skin to lerance to ischemia in random-pattern skin flap ofrats. http://www.ncbi.nlm.nih.gov/pubmed/20605607, NAO Nezami_BG J Surg Res . 2010 May 21. Chronic lithium impairs skin to lerance to ischemia in random-pattern skin flapof rats. http://www.ncbi.nlm.nih.gov/pubmed/20605607, NAO Lithium appears to affect four organs or tissues (see above): the central nervous system, the kidney, the skin, and the bone marrow. It seems reasonable that restricting lithium to any one of the four might prevent unwanted effects at the others. 2.5.8 Other Candidates for Local Administration Pulmonary hypertension is a serious disease { } that can be treated with certain prostaglandins. However, the prostaglandins have adverse side effects. An inhaled form of a prostaglandin, used to treat pulmonary hypertension, is deposited directly in the lungs. This causes fewer side effects than do other methods of administering the prostaglandin, although coughing and throat irritation commonly occur { }. However, total restriction of the therapeutic prostaglandin to its target would be even better. http://en.wikipedia.o rg/wiki/ Pulmonary_hypertension http://en.wikipedia.o rg/wiki/ Pulmonary_hypertension M: coughing and throat irritation commonly occur As discussed above, cancers depend on their blood supply for nourishment and use the blood vasculature to metastasize. Potent vasoconstrictors can restrict the growth of cancers. Endothelins are powerful vasoconstrictors that can cause strokes in healthy rats { }. Although endothelin-1 may actually aid the spread of cancer under some circumstances { }, endothelin-1 administered locally can also inhibit the progression of prostate cancer { }, probably by constricting the arterioles that nourish the cancer. If an endothelin-1 derivative could be constructed that lacked the mitogenic, angiogenic, and anti-apoptotic properties of endothelin-1, but that retained the vasoconstrictive property, it might be very useful against cancer. However, to be safe, it would probably have to be restricted to the region of the cancer. http://en.w ikipedia.o rg/wiki/Endothelin M: When applied directly Bagnato_A (2008). "The endothelin axis incancer". Int. J. Biochem. Cell Biol.40 (8): 1443–51. NAO Weydert_CJ Cancer Biology & Therapy 8:8 , 720-729; 15 April 2009 Endothelin-1 inhibits prostate cancer growth in vivo throughvasoconstriction of tumor-feeding arterioles https://www.landesbioscience.com/journals/cbt/11WeydertCBT8-8.pdf YAO, M: abst 2.6 Access to Blood Vessels from Lymphatic Vessels In addition to the above examples, one possibility deserves special discussion. This is the possibility of accessing blood vessels from the lymphatic system. As discussed in Chapter 9, lymphatic vessels may permit spatially limited access to the body. This restricted access could be exploited to concentrate therapeutic agents in chosen regions of the body. This possibility may also permit access to blood vessels from the lymphatic system, because there is a strong tendency for lymphatic vessels to run parallel to both arteries and veins { }. Chapter 9, moin The ability to access blood vessels from the lymphatic system might be important for two reasons. The first is that natural homing of cells to specific regions of tissue occurs through blood vessels. Cells traveling to specific regions of tissue can exit the blood circulatory system via a process called extravasation or diapedesis. Diapedesis (discussed in the Homing chapter, Chapter 11) involves circulating cells binding to blood vessel walls, and then physically traversing those walls. However, as they travel through the blood, cells must recognize the segment of blood vessel that they are supposed to bind before they can exit. Providing the necessary signal(s) in the right segment of a blood vessel is one of the harder problems of engineered homing. Access to blood vessels from outside the vessels might allow this. The second reason that access to specific regions of blood vessels from outside the vessels might be valuable is that it is sometimes medically desirable to dilate blood vessels or blood vessel segments. Many natural and synthetic dilators of blood vessels are known (including nitric oxide, discussed above). Here, I discuss just one, calcium channel blockers; however, the principles elucidated apply to others as well. Calcium channel blockers are substances that reduce movement of Ca2+ ions through calcium channels { }. They dilate arteries and are especially effective against large vessel stiffness, one of the common causes of elevated systolic blood pressure in elderly patients { }. Calcium channel blockers also affect the heart and the brain. They are discussed in a good Wikipedia article { }. Another effect of calcium channel blockers is to slow and weaken the contractions of the heart { } { }. This is desirable in some patients, such as patients with atrial fibrillation whose hearts are otherwise healthy, and in patients with with cardiac ischemia, in which it is desirable to reduce oxygen demand { }. However, it is very undesirable in patients with serious cardiomyopathy { }. In addition, calcium channel blockers may damage the brain and impair memory { }. Thus, while calcium channel blockers may be beneficial in widening large arteries, their effects on the heart are often deleterious, and their effects on the brain are nearly always deleterious. Accessing the vessel walls from lymphatic vessels might allow restriction of the vasodilator to just a few big arteries. http://en.w ikipedia.org/wiki/Calcium_channel_blocker M: are a class, SR, nr1 http://en.wikipedia.o rg/wiki/ Calcium_channel_blocker M: against large vessel, SR, nr10 http:/ /en.wikipedia.org/wiki/ Calcium_channel_blocker http://en.w ikipedia.o rg/wiki/Calcium_channel_blocker M: also slow down the conduction, SR, nr7 http://en.wikipedia.o rg/wiki/Calcium_channel_blocker M: also slow down the conduction, SR, nr7 http://en.wikipedia.org/wiki/ Calcium_channel_blocker M: such as verapamil, SR, nr6 http://www.scienceblog.com/community/old er/1997/B/19 9702039.html, SSR, nr12 http://en.wikipedia.org/wiki/Calcium_channel_blocker M: known as nondihydropyridines, SR, nr5 2.7 Sharpening the Focus with Two Molecules Homing, the process of transporting cells, drugs, or other substances to chosen parts of the body, is discussed in Chapters 9, 10, and 11. Here, I discuss just one aspect of concentrating biological activity. Let us imagine that we have a strain of xenobiotherapeutic bacteria that make some protein that benefits ischemic cardiac muscle. When injected into a cardiac patient, these imaginary bacteria migrate to the patient’s heart, and attach themselves harmlessly to some heart-specific structure. Once in place, the bacteria continually make and export the heart-benefiting protein. Let us also imagine that while this protein benefits ischemic heart tissue, it endangers the rest of the body. Although the protein will slowly degrade and lose activity, it seems inevitable that quantities of this protein will escape the heart and enter other tissues. If might be possible to minimize the consequences of this imaginary protein’s escape into other tissues by breaking the protein into two complementary parts which must physically interact for the protein to have biological activity. If the protein parts diffused separately, the strength of the protein’s biological activity would fall as the product of their concentrations. The fall in biological activity with distance from the site of release would be much sharper for a two-component protein than for a single-component protein. The same principle is used successfully in two-photon excitation microscopy to sharpen the area where fluorescence occurs { }. Two photons must be absorbed simultaneously to excite fluorescence; and the probability of this decreases quadratically as the excitation intensity decreases. This scheme might also be feasible with histidine-rich lytic peptides and 2+ Zn ions (see Chapter 4). http://en.w ikipedia.org/wiki/Two-photon_excitation_microscopy 2.8 Research Benefits of Concentration at the Target The ability to concentrate a biological agent at a target site might also reveal information about the drug’s mechanism of action. It could do this by revealing or ruling out involvement of non-target tissues in the drug’s action. It is easy to imagine, for example, how a drug that appeared to act on the heart might actually affect either the nervous system or the adrenal gland, which would then influence the heart. Similarly, a drug that appeared to affect cartilage at joints might actually affect the immune system in the bone marrow, which would in turn affect the joints.. There may be undiscovered involvement of non-target organs in the functions of currently marketed drugs. Studies on whole animals and clinical trials on humans might not reveal these, but restriction of the drug to the target organ probably would. Knowledge of involvement of non-target organs could be valuable in explaining and predicting variability in the drug’s effects on patients. To extend one of the examples given above, a drug that appeared to affect joints directly, but which actually affected the immune system, might have atypical effects in patients with compromised immune systems. 2.9 The Consequences of Restricted Location for Drug Characteristics Below is an analysis of 50 drugs that have been withdrawn from the market due to adverse side effects. I conclude that about 70% of those withdrawn drugs would be improved if they could be restricted to their targets. Ironically, however, if doctors had the ability to restrict drugs to their target locations, it is very likely that not only would the 50 withdrawn drugs remain absent from the market, but that hundreds of other drugs would eventually join them as unsalable. The reason is that new and far better alternatives would emerge: drugs consisting of natural or almost-natural molecules. (The antibiotics among the 50 withdrawn drugs may be exceptions to this generalization; antibiotics seldom mimic natural molecules, and therefore might not be replaceable by natural molecules.) 2.10 Analysis of 50 Withdrawn Drugs - General Remarks This section gives an analysis of 50 drugs that have been withdrawn from the market in at least one country. The analysis asks how many of the 50 withdrawn drugs would be improved by restriction to their intended targets. The answer is that about 35 (70%) of them would. Almost all drugs would be improved by keeping them away from developing fetuses and nursing infants. Hence, this point is made here, but not included in the analysis below. Some withdrawn drugs have been replaced by chemically similar variants that are safer. Phenformin and buformin, for example, were replaced by metformin. It is plausible that even if all three drugs could be restricted to their targets, that metformin would continue to be used instead of the others. Hence, even in cases where the action of a drug might be improved by restriction to the target, the drug might not re-enter the market. My analysis of these 50 withdrawn drugs is cursory. I am not an expert on them. It is possible that some of these drugs depend for their effectiveness on action at non-target tissues. This issue was mentioned above, but bears repeating. One can imagine that a muscle relaxant’s true site of action is not the muscle, but the central nervous system, and that the same might be true of a drug that relieved joint pain. One can imagine that a drug which reduces muscle wastage might act at the gonads where testosterone is produced, at the pituitary gland where growth hormone is produced, or at the intestine where vitamin D is absorbed. There may even be cases where the drug manufacturers themselves are unaware of the involvement of non-target tissues. This discussion of withdrawn drugs is based on a list of withdrawn drugs maintained by Wikipedia { }. However, the Wikipedia list is updated frequently, and may no longer match this list exactly. One drug on the Wikipedia list, Flosequinan, is omitted from this discussion because too little information about it is available on the Internet. http://en.wikiped ia.org/wiki/List_of_withdrawn_drugs 2.11 Drugs That Would Benefit from Spatial Restriction 2.11.1 Liver Toxicity * Ticrynafen (tienylic acid) was withdrawn in 1982 Ticrynafen is a diuretic and was marketed as a way to reduce hypertension. However, ticrynafen irreversibly inactivates the liver enzyme CYP2C9, which in turn causes hepatitis. CYP2C9 is an important detoxifier of foreign substances. Ticrynafen’s diuretic action presumably occurred at the kidney, and presumably did not involve the liver. Thus, ticrynafen would benefit from restriction to the kidney. Wikipedia article on ticrynafen: { } Wikipedia article on CYP2C9: { }. http://en.wikipedia.o rg/wiki/ Ticrynafen http://en.wikipedia.o rg/wiki/ CYP2C9 * Alpidem (Ananxyl) was withdrawn in 1996. Alpidem was used to treat anxiety, but was withdrawn because it caused some cases of severe liver injury. Alpidem’s anti-anxiety effect presumably involved the nervous system, and conceivably other organs such as the adrenal glands. Restricting it to just the target organs would presumably spare the liver. Wikipedia article on Alpidem: { } http://en.wikipedia.o rg/wiki/ Alpidem * Tolrestat (Alredase) { } was withdrawn in 1997. Tolrestat is an aldose reductase inhibitor. It was approved to control complications of diabetes, especially damage to the eye and to nerves. It prevents conversion of glucose to sorbitol. Sorbitol does not diffuse easily through cell membranes, but instead accumulates and causes osmotic damage. Tolrestat was withdrawn because of severe liver toxicity. Restriction of tolrestat to one of its intended targets, the eye, might preserve one of its benefits while avoiding its chief drawback, liver toxicity. Wikipedia article on tolrestat: { } Wikipedia article on aldose reductase: { } Wikipedia article on aldose reductase inhibitors: { } http://en.wikipedia.o rg/wiki/ Tolrestat http://en.wikipedia.o rg/wiki/ Tolrestat http://en.w ikipedia.org/wiki/Aldose_reductase http://en.w ikipedia.org/wiki/Aldose_reductase_inhibitor * Tolcapone (Tasmar) was withdrawn in 1998. Tolcapone was used to treat Parkinson’s disease, as an adjunct to levodopa/carbidopa medication. The drug inhibits catechol-O-methyl transferase, preventing the unwanted conversion of levodopa to 3-methoxydopa. Since tolcapone crosses the blood-brain barrier, it inhibits catechol-Omethyl transferase in both the central and peripheral nervous systems. Tolcapone was withdrawn because it poisons the liver. Tolcapone was replaced by a safer related drug, entacapone. Because entacapone is safer, it might well continue to supplant and exclude tolcapone even if restriction to the target organ system (the nervous system) were possible. The most frequent adverse side effect of entacapone is dyskinesia, involuntary movements caused by levodopa. This is presumably a consequence of entacapone’s action at its intended target and could not be ameliorated by spatial restriction of entacapone. However, entacapone also causes diarrhea, nausea, abdominal pain, red-brown urine (harmless), and dry mouth; some of these might be avoided by restriction of entacapone to its target. Thus, both tolcapone and, to some extent, its replacement drug, might benefit from spatial restriction within the body. Wikipedia article on tolcapone: { } Wikipedia article on entacapone: { } http:/ /en.wikipedia .org/wiki/Tolcapone http://en.w ikipedia.org/wiki/Entacapone * Amineptine (Survector) was withdrawn in 2000. Amineptine is a powerful, fast-acting antidepressant, which acts by inhibiting the uptake of dopamine and, to a lesser extent, of norepinephrine. It was withdrawn for three reasons: liver toxicity, adverse effects on the skin, and the potential for abuse. Aminetine’s liver toxicity can be serious. In addition, it causes severe, incurable acne. Finally, it has unwanted behavioral and psychiatric effects. Amineptine has a short-lived stimulant effect, which as led to abuse. In addition, it causes suicidal ideation, insomnia, irritability, and nervousness. Presumably, amineptine’s adverse effects on the liver and the skin could be prevented by restriction of amineptine to its targets in the nervous system. On the other hand, amineptine’s behavioral and psychiatric adverse effects presumably could not be prevented by this. Thus, amineptine would benefit significantly from spatial restriction to its target, but still might be unacceptably dangerous. Wikipedia article on amineptine: { } http://en.wikipedia.o rg/wiki/ Amineptine * Troglitazone (Rezulin) was withdrawn in 2000 Troglitazone is an anti-diabetic, anti-inflammatory drug that was prescribed to treat type 2 diabetes. It increases the sensitivity of the liver, the skeletal muscles and fat tissues to insulin { }. Its molecular mechanism of action is to activate peroxisome proliferator-activated receptors (PPARs). Troglitazone is a ligand to both PPARα and―more strongly―PPARγ. Troglitazone also contains an α-tocopheroyl moiety, potentially giving it vitamin E-like activity in addition to its PPAR activation. Troglitazone was withdrawn because it can poison the liver. Troglitazone was replaced by the related drugs pioglitazone and rosiglitazone. Pioglitazone has multiple benefits. It decreases insulin resistance in the liver and peripheral tissues. Increases the expense of insulin-dependent glucose. It decreases withdrawal of glucose from the liver. It decreases the amounts of glucose, insulin, and glycated hemoglobin in the blood. It also decreases blood triglycerides and increases the blood concentration of highdensity lipoprotein, which together seem to decrease atherosclerotic plaque. Pioglitazone has also been used to treat non-alcoholic fatty liver. However, this treatment is considered experimental. http:/ /www.dia betesmonitor.com/rezulin.htm M: action of the liver Pioglitazone has several adverse side effects. Women who take pioglitazone have increased bone fractures of the upper arms, hands, and feet. Pioglitazone can cause fluid retention, peripheral edema, and congestive heart failure. It increases subcutaneous adipose tissue, and causes mild weight gain. It may also cause bladder cancer and macular edema. Other adverse effects of pioglitazone include Upper respiratory tract infection, sinusitis, headache, myalgia and tooth problems. Pioglitazone and other members of its class (thiazolidinediones) strongly bind the outer mitochondrial membrane protein mitoNEET. mitoNEET may transport iron into mitochondria. Rosiglitazone (Avandia) is an anti-diabetes drug. Rosiglitazone binds PPAR receptors in fat cells and makes the cells more responsive to insulin. Rosiglitazone may increase the risk of heart failure, although this is controversial. It may also cause stroke, and probably causes macular edema―which may lead to partial blindness. Taken together, troglitazone, pioglitazone, and rosiglitazone have adverse effects on liver, heart, brain, bones, eyes, and the bladder and have minor adverse effects on a few other tissues. It seems reasonable that restricting them to adipose tissue could avoid much of this. Alternatively, individual members of the group could be improved by restricting them to tissues where they provide a benefit, but do no harm. Wikipedia article on troglitazone: { } Wikipedia article on PPARs: { } Wikipedia article on pioglitazone: { } Wikipedia article on rosiglitazone: { } http://en.wikipedia.org/wiki/Troglitazo ne http://en.wikipedia.o rg/wiki/ Peroxisome_proliferator-activated_recepto r http://en.w ikipedia.org/wiki/Pioglitazo ne http://en.w ikipedia.org/wiki/Rosiglitazone * Trovafloxacin (Trovan) was withdrawn in 2001, Trovafloxacin is a broad-spectrum antibiotic. It inhibits the uncoiling of supercoiled DNA in susceptible bacteria by blocking the activity of DNA gyrase and topoisomerase IV. It was withdrawn because it can cause serious, sometimes fatal, liver damage. Except when a bacterial infection is in the liver, restricting this antibiotic to its target area would likely make it much safer while preserving its effectiveness. Wikipedia article on trovafloxacin: { } http://en.wikipedia.o rg/wiki/Trovafloxacin * Pemoline (Cylert) was withdrawn from the US market in 2005. Pemoline was used to treat attention-deficit hyperactivity disorder and narcolepsy. Pemoline acts by inhibiting the re-uptake of dopamine and increasing the release of dopamine and norepinephrine in the central nervous system. Pemoline was withdrawn from the US market because it can cause liver failure. Since the target of pemoline is the central nervous system and the site of injury is the liver, pemoline would likely benefit from restriction to the target site. Wikipedia article on pemoline { } http://en.w ikipedia.org/wiki/Pemoline * Lumiracoxib (Prexige) was progressively withdrawn around the world in 2007—2008. Lumiracoxib is an inhibitor of cyclooxygenase-2 (COX-2) that was used against arthritis. It was withdrawn from most markets because of liver toxicity. The intended target for lumiracoxib was presumably outside the liver, while the site of injury was the liver. Restricting lumiracoxib to its target tissue would probably improve it. Wikipedia article on lumiracoxib { } http://en.wikipedia .org/wiki/Lumiracoxib * Sitaxentan (Thelin) was withdrawn by Pfizer in 2010. Sitaxentan was used to treat pulmonary arterial hypertension. Sitaxentan is a small molecule that binds to the endothelin A receptor and prevents it from being activated by endothelin-1. This, in turn prevents sodium retention and hypertension. Sitaxentan does not block activation of the endothelin B receptor. Activation of the endothelin B receptor releases nitric oxide and promotes urine production, lowering blood pressure. Sitaxentan damages the liver. The intended target of sitaxentan is presumably the endothelial cells of major arteries, while the site of injury is the liver. If sitaxentan were restricted to acting on arteries outside the liver, it might retain most of its beneficial activity while losing its hepatotoxicity. Wikipedia article on Sitaxentan - { } Wikipedia article on pulmonary hypertension - { } Wikipedia article on endothelins - { } http:/ /en.wikipedia .org/wiki/Sitaxentan http://en.wikipedia.o rg/wiki/ Pulmonary_hypertension http://en.wikipedia.o rg/wiki/ Endothelin 2.11.2 Growth Factors in the Blood * Fen-phen was withdrawn in 1997. Fen-Phen was a combination of fenfluramine and phentermine or later dexfenfluramine and phentermine. Fenfluramine and dexfenfluramine were withdrawn, but phentermine remains on the market. Fen-phen is an appetite suppressor. The fenfluramine component acts by increasing the amount of the neurotransmitter serotonin, a chemical that regulates mood, appetite and other functions. Fenfluramine causes the release of serotonin by disrupting vesicular storage of the neurotransmitter, and reversing serotonin transporter function. The end result is a feeling of fullness and loss of appetite. Fen-phen was withdrawn because it caused fatal pulmonary hypertension, damage to the aortic and mitral heart valves, and cardiac fibrosis. Fenfluramine and its metabolite norfenfluramine stimulate serotonin receptors, in particular 5-HT2B receptors which are plentiful in human cardiac valves. This may stimulate inappropriate valve cell division. The intended target of fenfluramine appears to be the appetite centers of the brain, while the site of harm is the vascular system, especially the heart. Restriction of fenfluramine to its intended target would probably improve it. Wikipedia article on Fen-Phen: { } Wikipedia article on fenfluramine: { } Wikipedia article on pulmonary hypertension: { } http://en.wikipedia.o rg/wiki/ Fen-phen http://en.w ikipedia.org/wiki/Fenfluramine http://en.w ikipedia.org/wiki/Pulmonary_hypertension * Pergolide (Permax) was voluntarily withdrawn by its manufacturer 2007 from the US market. It remains available elsewhere. Pergolide is used to treat Parkinson’s disease, hyperprolactinemia, and restless leg syndrome. Pergolide causes malfunction of the heart valves. Pergolide is a agonist of the dopamine D2, D1, and serotonin 5-HT1A, 5-HT1B, 5-HT2A, 5HT2B, and 5-HT2C receptors. It may have weak activity at other dopamine receptor subtypes as well. Pergolide’s action at the 5-HT2B serotonin receptors of cardiac myocytes is thought to cause the main problem. This action probably causes proliferative valve diseases by the same mechanism as does fenfluramine (see above); Pergolide’s intended target is the nervous system, while the main site of damage is the heart. Restricting pergolide to its intended target would probably improve it. Wikipedia article on pergolide: { } http://en.wikipedia.o rg/wiki/Pergolide 2.11.3 Changes in Heart Rhythm * Terodiline (Micturin) was withdrawn in 1991. Terodiline is a spasmolytic used to treat gastrointestinal and genitourinary colic. It was withdrawn because it promoted cardiac arrhythmia. Terodiline has been replaced by the more benign drug tolterodine. Hence terodiline might not re-enter the market even if it could br restricted to its intended target. Nevertheless, keeping terodiline away from the heart would probably improve it. Wikipedia article on terodiline: { } Online journal article describing tolterodine: { }. http://en.w ikipedia.org/wiki/Terodiline http://jo urnals.lww.co m/cardiovascularpharm/Fulltext/2006/11000/In_Vitro_Preclinical_Cardiac_ Assessment_of.2.aspx * Astemizole (Hismanal) { } was withdrawn in 1999. Astemizole is a second-generation antihistamine drug with a long duration of action. It suppresses itch. In addition, although it was not used for this purpose, experiments with mice suggest that Astemizole might lessen muscle atrophy in immobile patients. Moreover, Astemizole has potent activity against malaria, including strains of malaria that resist chloroquine. Astemizole may be metabolized by P450 cytochrome enzyme CYP3A4, although Wikipedia { } and another published article { } disagree about this. Astemizole is said to have rare, but potentially fatal, interactions with inhibitors of CYP3A4, such as erythromycin and grapefruit juice { }. Astemizole may also cause life-threatening cardiac arrhythmias { }. Astemizole favorably affects several target tissues: the skin, skeletal muscle, and at least some body organs affected by malaria (which may include the liver). Its harmful actions appear to occur in the liver and either in the heart or in that part of the nervous system that controls the heart. Since the intended targets tissues are largely separable from the tissues where harm occurs, Astemizole would likely benefit from spatial restriction. http://en.wikipedia .org/wiki/Astemizole http://en.w ikipedia.org/wiki/Astemizole Matsumoto_S British Journal ofClinical Pharmacology Volume 51, Issue 2, pages 133–142, February 2001 Involvement of multiple human cytochromes P450 in the liver microsomal metabolism of astemizole and a com parisonwith terfenadine. YAO http://en.wikipedia.org/wiki/Astemizole http://en.wikipedia.o rg/wiki/ Astemizole * Grepafloxacin (Raxar) was withdrawn in 1999 Grepafloxacin is a broad-spectrum antibacterial agent, that was taken orally. Grepafloxacin was withdrawn world wide from markets because of its side effect of lengthening the QT interval on electrocardiograms, leading to cardiac events and sudden death. Restricting grepafloxacin to infected tissues, unless those tissues included the heart, would likely improve it. Wikipedia article on grepafloxacin: { } Wikipedia article on long QT syndrome: { } http://en.wikipedia.o rg/wiki/ Grepafloxacin http://en.wikipedia.org/wiki/Long_QT_Syndrome * Cisapride (Propulsid) was withdrawn in many countries beginning in 2000. Cisapride is a gastroprokinetic agent. It enhances gastric mobility by increasing the frequency of contractions in the small intestines, or by making them stronger, but without disrupting their rhythm. It increases the mobility of the upper gastrointestinal tract. Cisapride was used to treat irritable bowel syndrome, gastritis, acid reflux disease, gastroparesis (partial paralysis of the stomach, often a complication of diabetes), and functional dyspepsia. The specfic symptoms treated include abdominal discomfort, bloating, constipation, heart burn, nausea, and vomiting. Cisapride was withdrawn because it causes long QT syndrome, which predisposes people to arrhythmias. Restricting cisapride to the gastrointestinal tract and keeping it away from the heart would very likely improve it. Wikipedia article on cisapride: { } Wikipedia article on gastroprokinetic agents: { } Wikipedia article on long QT syndrome: { } http:/ /en.wikipedia .org/wiki/Cisapride http://en.wikipedia.org/wiki/Gastroprokinetic_agent http://en.wikipedia.org/wiki/Long_QT_Syndrome * Rofecoxib (Vioxx) was withdrawn in 2004. Rofecoxib is a cyclooxygenase-2 (COX-2) inhibitor that was used to treat osteoarthritis, dysmenorrhea and acute pain. It had the same benefits as traditional non-steroidal anti-inflammatory drugs (such as aspirin), but without the risk of stomach ulcers. Rofecoxib was withdrawn because it often caused heart attacks, strokes, and kidney damage. Researchers have speculated that rofecoxib’s cardiotoxicity may be caused by maleic anhydride metabolites formed when rofecoxib becomes ionized under physiological conditions The above process might occur in arthritic joints, for example, and the metabolites might make their way to the heart or kidneys. Thus, for the drug to be safe when restricted to joints, either the amount of metabolites formed would have to be reduced, or the metabolites would have to be degraded within the joints. It seems plausible that if rofecoxib could be concentrated in joints, that much less of it could be used, with a correspondingly lower burden of dangerous metabolites. Moreover, the same biological agents that provided the means to concentrate rofecoxib in joints might be used to detoxify its metabolites. Celecoxib (Celebrex) is related to rofecoxib, but is still on the market. Celecoxib is used to treat osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation and menstrual symptoms, and to reduce numbers of colon and rectum polyps in patients with familial adenomatous polyposis. Celecoxib has adverse effects, including ulcers, sulfa allergy, and perhaps heart attack and stroke. The intended targets are at least somewhat separable from the sites where harm occurs; hence, celecoxib could probably be improved by spatial restriction within the body. Wikipedia article on rofecoxib: { } Wikipedia article on celecoxib: { } http:/ /en.wikipedia.org/wiki/ Rofecoxib http://en.wikipedia.org/wiki/ Celecoxib * Co-proxamol (Distalgesic) was withdrawn in the United Kingdom in 2004. Co-proxamol is also called Dextropropoxyphene. It is an analgesic in the opioid category. Co-proxamol is a cough suppressant and local anesthetic―and can relieve restless leg syndrome. It was often given to people who cannot benefit from codeine. Co-proxamol was withdrawn from the market for two reasons. First, some patients suffered fatal overdoses. Second, it tends to promote cardiac arrhythmias. Co-proxamol’s intended target is the nervous system. It is not clear whether restricting co-proxamol to this target, or some portion of it, could reduce fatal overdoses. However, it seems likely that this would prevent dangerous cardiac arrhythmias. Hence, co-proxamol would be improved by restriction to the intended target. Wikipedia article on co-proxamol: { } http:/ /en.wikipedia .org/wiki/Dextropropoxyphene * Thioridazine (Melleril) was withdrawn in the United Kingdom in 2005. Thioridazine is used to treat schizophrenia and psychosis. It also kills multidrug-resistant Mycobacterium tuberculosis and multidrug-resistant Staphylococcus aureus at clinical concentrations. Thioridazine has several adverse effects. It interferes with heart function, prolonging the QT interval on electrocardiograms, and causing ventricular tachycardia and torsadas de pointes. It also damages the retina. In addition, thioridazine causes neuroleptic malignant syndrome, a lifethreatening neurological disorder. Finally, it may inflame salivary glands. The intended target sites of thioridazine are the nervous system and bacterial infections. The sites of harm are the nervous system, the heart, the retina, and salivary glands. Since, the intended target sites are partly separable from the sites of harm, thioridazine would be improved by spatial restriction. In particular, the ability to treat multidrug-resistant bacterial infections might be very valuable. Wikipedia article on thioridazine: { } http://en.wikipedia.org/wiki/Thio ridazine * Tegaserod (Zelnorm) was withdrawn in 2007. Tegaserod was used to treat irritable bowel syndrome and constipation. It stimulates motility of the gastrointestinal tract. Tegaserod causes heart attacks and strokes. The site of desired action and the sites of undesired action of tegaserod are distinct and could reasonably be separated. Thus, tegaserod could probably be be improved by restriction to its intended target. Wikipedia article on tegaserod: { } http://en.w ikipedia.o rg/wiki/Tegaserod 2.11.4 Other Reasons * Thalidomide is infamous. It was introduced in the late 1950s, and was sold from 1957-1961. Thalidomide is an anti-emetic drug that prevents morning sickness in pregnant women. However, it causes severe deformities in developing fetuses, including phocomelia, the abnormal shortness and underdevelopment of extremities. It is unlikely that thalidomide would ever again be prescribed for pregnant women under any circumstances.. Thalidomide has other uses, however. It is an immune system modulator that is used to treat multiple myeloma. Thalidomide also has potent anti-inflammatory activity which makes it useful in treating erythema nodosum leprosum, a painful skin condition that is a complication of leprosy. Thalidomide is prescribed for its anti-inflammatory effect when used to treat actinic prurigo, an autoimmune skin disease. Actinic prurigo is a sunlight-induced nodular skin eruption, very likely caused or aggravated by exposure to ultraviolet light. Thalidomide is also used to treat chronic bullous dermatosis, a blistering skin disease of childhood. The results are said to be encouraging { }. http://en.wikipedia.o rg/wiki/ Thalidomide Use of thalidomide as a medical agent is limited by its potential to cause peripheral neuritis, the inflammation of peripheral nerves. It seems plausible that if thalidomide could be restricted to the bone marrow, where much of the immune system develops, or to patches of inflamed skin, that its benefits might be retained while its adverse effects were avoided. Wikipedia article on thalidomide: { } Wikipedia article on actinic prurigo: { } Wikipedia article on chronic bullous dermatosis: { } http://en.wikiped ia.org/wiki/Thalid omid e http://en.wikipedia.o rg/wiki/Actinic_prurigo http://en.w ikipedia.org/wiki/Chronic_bullo us_disease_of_childhood * Phenformin was withdrawn in 1978. Phenformin was used to treat diabetes. It reduces gluconeogenesis in the liver. Phenformin was withdrawn because of its tendency to cause lactic acidosis. Lactic acidosis is a buildup of lactate and a lowering of pH in tissues, and is caused by impaired respiration Phenformin was replaced by metformin, which has the same benefits, but is much safer. Hence, phenformin is unlikely to be reintroduced under any circumstances. However, it is still likely that if phenformin could be restricted to its target in the liver, that it would retain its benefits, but be less likely to cause lactic acidosis. Hence, restriction of phenformin to its intended target would improve it. Wikipedia article on phenformin: { } Wikipedia article on lactic acidosis: { }. http://en.wikipedia.o rg/wiki/ Phenformin http://en.wikipedia.org/wiki/ Lactic_acidosis * Zimelidine was withdrawn worldwide in 1983 Zimelidine is an antidepressant. It is a serotonin re-uptake inhibitor. It strongly inhibits re-uptake of serotonin from the synaptic cleft. Zimelidine has several adverse side effects. One is an increase in suicide attempts among depressive patients. A second is multi-organ hypersensitivity, involving skin eruptions, flu-like symptoms, arthralgias, and sometimes eosinophilia. A third, very serious side effect of zimelidine is Guillain-Barré syndrome. Guillain-Barré syndrome is an acute inflammatory demyelinating polyneuropathy which affects the peripheral nervous system. The most common symptom is ascending paralysis, weakness beginning in the feet and hands and migrating towards the trunk. Although most patients recover completely, the syndrome can cause life-threatening complications particularly if the breathing muscles are affected or if there is malfunction of the autonomic nervous system. All forms of Guillain-Barré syndrome are due to an immune response to foreign antigens that is mistargeted at host nerve tissues instead. It is doubtful that spatial restriction of zimelidine would prevent it from inducing suicide attempts. However, restriction of this drug drug to the parts of the nervous system that control mood might be prevent inappropriate activation of the immune system. This, in turn, might prevent multi-organ hypersensitivity and Guillain-Barré syndrome. Wikipedia article on zimelidine: { } Wikipedia article on Guillain-Barré syndrome: { } http://en.wikipedia.o rg/wiki/ Zimelidine http://en.wikipedia.org/wiki/Guillain-Barr%C3%A9_syndrome * Phenacetin was withdrawn in 1983. Phenacetin was introduced in 1887. It is a fever reducer and a nonopioid analgesic. Phenacetin’s analgesic effects are due to its actions on the sensory tracts of the spinal cord. Phenacetin causes tumors of the renal pelvis and the ureters, and kidney damage. It also seems to cause cardiovascular disease, and it causes acute hemolysis in some patients. One intended target of phenacetin is the nervous system. The kidney cancer and kidney damage could presumably be avoided by restricting phenacetin to the nervous system. Wikipedia article on phenacetin: { } http://en.wikipedia.o rg/wiki/ Phenacetin * Nomifensine (Merital) was withdrawn in 1986 Nomifensine is an antidepressant. It is both motivational and anxiolytic. Nomifensine increases the amount of synaptic norepinephrine dopamine available to receptors by blocking the dopamine and norepinephrine reuptake transporters. Nomifensine is not sedating, does not interact with alcohol, and does not inflict withdrawal symptoms. Nomifensine has moderate potential for abuse. It can also poison the kidneys and the liver. However, the main problem with nomifensine is that it can cause hemolytic anemia. Restriction of nomifensine to the brain, or to those parts of the brain that control motivation and anxiety, might avoid many of nomifensine’s problems. Wikipedia article on nomifensine: { } http://en.w ikipedia.org/wiki/Nomifensine * Temafloxacin (Omniflox) was withdrawn in 1992. Temafloxacin belongs to the fluoroquinone class of antibiotics. Temafloxacin is an antibiotic. It was approved in the U.S. to treat lower respiratory tract infections, genital and urinary infections such as prostatitis, and skin infections. Adverse effects of this drug included allergic reactions and hemolytic anemia. Adverse effects of fluoroquinones generally include central nervous system toxicity, phototoxicity, cardiotoxicity, arthropathy, and tendon toxicity. Restriction of temafloxacin to the site of an infection might or might not avoid its complications of allergy and hemolytic anemia. Restriction of fluoroquinones generally to the site of an infection would probably avoid many of the listed complications. Wikipedia article on temafloxacin. { } Wikipedia article on fluoroquinones: { }. http://en.wikipedia.o rg/wiki/ Temafloxacin http://en.wikipedia.o rg/wiki/Fluoroquinolo ne_toxicity * Chlormezanone (Trancopal) was withdrawn in 1996. Chlormezanone is an anxiolytic and muscle relaxant drug. It was withdrawn because it occasionally caused toxic epidermal necrolysis { }. Toxic epidermal necrolysis is the detachment of the epidermis from the dermis all over the body. It affects many parts of the body, but especially the mucous membranes, such as the mouth, eyes, and vagina. Mortality from this condition is 30-40%. It is not known whether toxic epidermal necrolysis involves the immune system in skin cell death. Restricting chlormezanone to its intended targets (brain and muscles) while keeping it away from the sites where it causes harm (skin, immune system, or both), might plausibly preserve its function while reducing its potential danger. Wikipedia article on chlormezanone: { } http://en.wikipedia .org/wiki/Toxic_epidermal_necrolysis http://en.w ikipedia.o rg/wiki/Chlormezanone * Mibefradil (Posicor) was withdrawn in 1998. Mibefradil was used to treat hypertension and chronic angina pectoralis. It relaxes and widens blood vessels by blocking calcium channels. Mibefradil was withdrawn because it had dangerous interactions with other drugs. Both calcium channels and calcium channel blockers are complex. However, calcium channel blockers can interfere with cancer chemotherapy { }, with macrophage survival { }, and with innate immunity generally { }. Yanamandra_N J Pharmacol Exp Ther. 2011 Mar 4. Tipifarnib-induced apoptosis inacute myeloid leukemia and multiple myeloma cells is dependenton Ca2+ influx through plasma membrane Ca2+ channels. http://www.ncbi.nlm.nih.gov/pubmed/21378206 M: abst, YAO, nin Tano_JY Bio chem Biophys Res Commun. 2011 Mar 23. Requirem ent for non-regulated, constitutive calcium influx in macrophage survivalsignaling.http://www.ncbi.nlm.nih.gov/pubmed/21414290 NAO, M:abst, nin Liu_W Curr Opin Infect Dis. 2011 Ap r 5. Calcium channel blockers and modulationof innate immunity.http://www.ncbi.nlm.nih.gov/pubmed/21467929 NAO, M: abst, nin As suggested above { }, it might be possible to selectively access arteries and veins from lymphatic vessels that tend to run parallel to them. This could preserve the vasodilating property of mibefradil while reducing its harmful effects. Wikipedia article on mibefradil: { } Medicine.net article on mibefradil: { } Wikipedia article on calcium channels: { } Wikipedia article on calcium channel blockers: { } Thischapter, M: 2.6 Access to http://en.wikipedia .org/wiki/Mibefradil http://www.medicinenet.com/mibefradil-oral/article.htm http://en.w ikipedia.o rg/wiki/Calcium_channel, nin http://en.wikipedia.o rg/wiki/ Calcium_channel_blocker, nin * Etretinate was withdrawn in the 1990s. Etretinate was used to treat psoriasis. It was removed from the market because of its narrow therapeutic index, and because it caused birth defects. It also interferes with bone growth, and thus could not be used in children. Etretinate’s fundamental drawback was that it is highly lipophilic, and is thus stored in fat. Its elimination half-life is 100 days, and it can be detected in plasma for up to 3 years after the end of treatment. Etretinate was replaced by its safer metabolite Acitretin. Acitretin has an in vivo half-life of only two days, a desirable characteristic. However, Acitretin is reverse-metabolized in the body to etretinate; hence the problem of drug persistence is only lessened, not solved. Etretinate’s long persistence in the body is a general problem that might be solved if etretinate were restricted to its intended target―probably either the skin or the immune system, but certainly not fat tissue. Such restriction would presumably also prevent etretinate from interfering with bone growth. Wikipedia article on etretinate: { } Wikipedia article on Acitretin: { } http://en.wikipedia .org/wiki/Etretinate http://en.w ikipedia.org/wiki/Acitretin * Cerivastatin (Baycol, Lipobay) was withdrawn in 2001. Cerivastatin is a synthetic statin. Statins act on the liver, to inhibit HMG-CoA reductase, which is necessary for cholesterol production in the liver. Cerivastatin was withdrawn because it caused fatal rhabdomyolysis, the rapid breakdown of skeletal muscle. Rhabdomyolysis releases myoglobin into the blood, which may damage or destroy a kidney. Restriction of cerivastatin to the liver would very likely prevent rhabdomyolysis and improve its safety. Wikipedia article on cerivastatin: { } Wikipedia article on statins: { } Wikipedia article on rhabdomyolysis: { } http://en.w ikipedia.org/wiki/Cerivastatin http:/ /en.wikipedia.org/wiki/ Statin http://en.wikipedia.o rg/wiki/Rhabdomyolysis * Rapacuronium (Raplon) was withdrawn in many countries 2001. Rapacuronium is an anesthetic. It was used to facilitate endotracheal intubation. It was withdrawn because it can cause fatal bronchospasm. Restriction of rapacuronium to the trachea, while keeping it from the bronchioles, might very well make it more useful. Wikipedia article on rapacuronium: { } Wikipedia article on bronchospasm: { } http://en.wikipedia.org/wiki/Rapacuronium http://en.wikipedia.org/wiki/Bronchospasm * Natalizumab (Tysabri) was withdrawn from the U.S. market in 2005, but returned to the market in 2006. Natalizumab is used to treat multiple sclerosis and Crohn’s disease. Natalizumab is a humanized monoclonal antibody against α4 integrin. It probably reduces the ability of inflammatory immune cells to attach to and pass through the cell layers lining the intestine and the blood-brain barrier. Natalizumab is effective. In multiple sclerosis patients, natalizumab prevents relapse, vision loss, and cognitive decline, and improves the quality of life. It also increases remission rates and prevents relapse in Crohn’s disease. Natalizumab may cause progressive multifocal leukoencephalopathy, a rare neurological condition, when co-administered with interferon β-1a. If natalizumab were restricted to just the intestinal lining or just the walls of blood vessels where inflammatory immune cells enter the brain, its adverse effect on the nervous system might be avoided. Wikipedia article on natalizumab: { } http://en.wikipedia.org/wiki/ Natalizumab * Aprotinin (Trasylol) was withdrawn in 2007. Aprotinin inhibits trypsin and related proteases. It slows down blood clot breakdown (fibrinolysis), and reduces bleeding during complex surgery such as heart and liver surgery. It was administered by injection. Aprotinin was intended to decrease the need for blood transfusion during surgery and to reduce organ damage resulting from low blood pressure caused by blood loss. Aprotinin has several adverse side effects. These include anaphylaxis, acute renal failure, heart failure. and stroke. Limitation of Aprotinin to just the region where clotting is desired could greatly increase its safety. Admittedly, it is hard to see how this could be done. It would likely require speculative methods such as continuous release of a very labile variant of Aprotinin at the target site, or some means of physically immobilizing the enzyme in flowing blood. Wikipedia article on Aprotinin: { } http://en.w ikipedia.org/wiki/Aprotinin * Efalizumab (Raptiva) was withdrawn in 2009. Efalizumab was used to treat psoriasis. It is a humanized monoclonal antibody that binds to the CD11a subunit of lymphocyte function-associated antigen 1 and inhibits white blood cell migration out of blood vessels into tissues (diapedesis). Efalizumab was administered once weekly by subcutaneous injection. Efalizumab suppresses immunity and has the adverse effects that would be expected from such. These include bacterial sepsis, viral meningitis, invasive fungal disease and progressive multifocal leukoencephalopathy (PML), a brain infection caused by reactivation of latent JC virus infection. If efalizumab were restricted to just the skin, it might be much safer. Wikipedia article on efalizumab: { } http://en.wikipedia.o rg/wiki/ Efalizumab * Sibutramine (Reductil) was withdrawn in Europe, Australasia, and the U.S. in 2010. Sibutramine is used to treat obesity Sibutramine is a neurotransmitter re-uptake inhibitor. It reduces the reuptake of serotonin by 53%, of norepinephrine by 54%, and of dopamine by 16%. It thereby increases the levels of these substances in synaptic clefts and helps enhance satiety. The effect on serotonin, in particular, seems to reduce appetite. Sibutramine was withdrawn because it increased heart attack and stroke. Restriction of this drug to the brain’s satiety areas would be expected to preserve its beneficial effect on appetite while reducing its tendency to cause heart attacks and strokes. Wikipedia article on sibutramine: { } http://en.wikipedia.org/wiki/Sibutramine 2.12 Drugs That Would Not Benefit from Spatial Restriction 2.12.1 Addiction and Abuse * Lysergic acid diethylamide (LSD) was marketed in the 1950s and 1960s LSD was marketed as a psychiatric cure-all. It was withdrawn because it was used too often as a recreational drug. It is not known to have side effects. Restricting it to its intended target would probably not improve it in any way. Wikipedia article on lysergic acid diethylamide: { } http://en.wikipedia.o rg/wiki/ Lysergic_acid_diethylamide * Methaqualone (Quaaludes) was withdrawn in 1984 Methaqualone is a sedative, and a plausible alternative to barbituates. It was withdrawn because it was used recreationally too frequently. Restricting it to its intended target would probably not improve it in any way. Wikipedia article on methaqualone: { } http://en.wikipedia.o rg/wiki/ Methaqualone * Temazepam (Restoril, Euhypnos, Normison, Remestan, Tenox, Norkotral) was withdrawn 1999. Temazepam is a powerful hypnotic drug generally prescribed for the short-term treatment of severe insomnia. It also has powerful amnesic, anticonvulsant, anxiolytic, sedative, and skeletal muscle relaxant properties. Temazepam was withdrawn in Norway and Sweden because of diversion, abuse and a high rate of overdose deaths compared to related drugs. Restricting temazepam to its intended target would probably not improve it in any way. Wikipedia article on temazepam: { } http://en.wikipedia.org/wiki/Temazepam * Hydromorphone extended-release (Palladone, Dilaudid) was withdrawn in 2005. Hydromorphone extended-release is a potent, centrally-acting analgesic. It was withdrawn because of a high risk of accidental overdose when administered with alcohol. Restricting this drug to its intended target, the nervous system, would probably not improve it in any way. Wikipedia article on hydromorphone: { } http://en.wikipedia.o rg/wiki/ Hydromorphone 2.12.2 Damage Is at Intended Target * Diethylstilbestrol was withdrawn in the 1970s. From about 1940 to 1970, diethylstilbestrol was given to pregnant women under the mistaken belief that it would reduce pregnancy complications and losses. It was also used to treat breast and prostate cancers. Diethylstilbestrol was withdrawn because of the risk of teratogenicity. It causes a rare vaginal tumor in young women who were exposed to the drug in utero. Restricting diethylstilbestrol to its intended target, the uterus, would seem to confer no benefit for two reasons. First, the drug may have no benefit. Second, the intended target and the site of harm are the same, the uterus. Wikipedia article on diethylstilbestrol: { } http://en.wikipedia.o rg/wiki/ Diethylstilbestrol * Triazolam was withdrawn in the United Kingdom in 1991. Triazolam is used to treat severe insomnia. It is a benzodiazepine derivative with a short half-life. It has amnesic, anxiolytic, sedative, anticonvulsant and muscle relaxant properties., and it may cause birth defects. Triazolam was withdrawn because of the risk of adverse psychiatric reactions. Although this drug might conceivably be improved by restriction to just the sleep centers of the brain, this idea is highly speculative. The site of intended action is the same as the site of unwanted action, i.e. the brain. Wikipedia article on triazolam: { } http://en.wikipedia.org/wiki/Triazolam * Alosetron (Lotronex) was withdrawn in 2000 but reintroduced in 2002 on a restricted basis. Alosetron was used to treat diarrhea and sometimes caused constipation with fatal complications. Alosetron’s intended target and site of unintended harm appear to be the same. Wikipedia article on Alosetron: { } http:/ /en.wikipedia .org/wiki/Alosetron * Phenylpropanolamine (Propagest, Dexatrim) was withdrawn in the US in 2000 Phenylpropanolamine is an appetite suppressant. It was withdrawn because it caused strokes in women under 50 years of age when taken in high doses for weight loss. Phenylpropanolamine’s intended target and site of harm are generally the same, i.e. the brain. It might be that restriction of phenylpropanolamine to just the food appetite centers of the brain might improve it, but this is speculative. Wikipedia article on phenylpropanolamine: { } http://en.wikipedia .org/wiki/Phenylpropanolamine * Mixed amphetamine salts (Adderall XR) was withdrawn in Canada in 2005. The ban was later lifted. Adderall is used to treat attention deficit hyperactivity disorder and narcolepsy. Adderall increases alertness, increases libido, increases concentration and cognitive performance, improves mood, decreases fatigue. Adderall both increases release of and prevents re-uptake of epinephrin and norepinephrine in the brain. Adderall directly affects the mesolimbic reward pathway in the brain. Adderall increases blood pressure by raising cardiac output. It may also adversely affect vision. Adderall’s psychostimulant effect and the rise in blood pressure probably derive from effects on the brain. Perhaps the two effects could be separated within that organ, but this idea is very speculative. Wikipedia article on Adderall: { } Wikipedia article section on sites of amphetamine action: { } http:/ /en.wikipedia.org/wiki/ Adderall http://en.w ikipedia.org/wiki/Amphetamine#Primary_sites_of_action * Rimonabant (Acomplia) was withdrawn in 2008 Rimonabant is an anorectic and anti-obesity drug. Its purpose is to reduce appetite. It is an inverse agonist for the cannabinoid receptor CB1. Rimonabant was withdrawn because it induced severe depression and suicidal thoughts. Rimonabant’s intended target and site of undesired action appear to be the same. Wikipedia article on rimonabant: { } http://en.wikipedia.o rg/wiki/ Rimonabant * Gemtuzumab ozogamicin (Mylotarg) was withdrawn in the U.S. in 2010. Gemtuzumab includes a monoclonal antibody that binds CD33, a cell surface protein expressed in most leukemic blast cells. The monoclonal antibody is linked to a cytotoxic agent. Gemtuzumab was withdrawn because it causes veno-occlusive disease and is not effective against acute myeloid leukemia. Gemtuzumab also has numerous side effects that derive from its killing of normal hematopoietic cells in bone marrow. Keeping gemtuzumab away from bone marrow might make it safer, but could hardly change the fact that it is not effective. Wikipedia article on Gemtuzumab_ozogamicin: { } http://en.w ikipedia.org/wiki/Gemtuzumab_ozogamicin * Bepridil. (Vascor) is no longer sold in the U.S. Bepridil is a calcium channel blocker. It treats atrial fibrillation, but may cause ventricular arrhythmia―which is not a good tradeoff. The heart is both the intended target and the site of unwanted harm. Wikipedia article on Bepridil: { } http://en.wikipedia.o rg/wiki/ Bepridil 2.12.3 Other Reasons * Terfenadine (Seldane, Triludan) was withdrawn in 1998. Terfenadine is an antihistamine, used to treat allergic conditions. Terfenadine was withdrawn because of the risk of cardiac arrhythmias, caused by QT prolongation. Terfenadine is a prodrug. It is converted to its active form, fexofenadine, by the intestinal cytochrome P450 isoform CYP3A4. Due to this presystemic gut wall metabolism terfenadine normally is not measurable in the plasma. However, if terfenadine enters the blood, it is cardiotoxic. Erythromycin and grapefruit have CYP3A4 inhibitors that reduce the body’s ability to metabolize and remove terfenadine. These or other inhibitors can make the drug cardiotoxic after years of continued use with no previous problems. Terfenadine was replaced by its active form, fexofenadine. Introduction of terfenadine into the human body near the intended target would do no good, since terfenadine is not the active form. Wikipedia article on terfenadine: { } http://en.wikipedia.o rg/wiki/ Terfenadine * Ximelagatran (Exanta) was withdrawn in 2006. Ximelagatran is an anticoagulant that was meant to replace warfarin. It acts by inhibiting thrombin. In contrast to warfarin, ximelagatran does not require frequent monitoring. Ximelagatran poisons the liver. It is hard to see how a drug that is dissolved throughout the blood could be kept out of the liver. Wikipedia article on ximelagatran: { } http://en.wikipedia .org/wiki/Ximelagatran * Inhaled insulin (Exubera) was withdrawn in 2007 Inhaled insulin was withdrawn in the U.K. due to poor sales caused by national restrictions on prescribing, doubts over long-term safety, and too high a cost. The drug was effective, but not cost-effective. Moreover, the dosage calibration was confusing and dangerous. Restricting this drug to its intended target would not improve it in any way. Wikipedia article on Exubera: { } http://en.w ikipedia.org/wiki/Exubera Fifty withdrawn drugs are listed above. Thirty-five of these (Ticrynafen, Alpidem, Tolrestat, Tolcapone, Amineptine, Troglitazone, Trovafloxacin, Pemoline, Lumiracoxib, Sitaxentan, Fen-phen, Pergolide, Terodiline, Astemizole, Grepafloxacin, Cisapride, Rofecoxib, Co-proxamol, Thioridazine, Tegaserod, Thalidomide, Phenformin, Zimelidine, Phenacetin, Nomifensine, Temafloxacin, Chlormezanone, Mibefradil, Etretinate, Cerivastatin, Rapacuronium, Natalizumab, Aprotinin, Efalizumab, and Sibutramine) would probably be improved by spatial restriction within the body—although they might not be returned to service. Fifteen others (Lysergic acid diethylamide, Methaqualone, Temazepam, Hydromorphone extended-release, Diethylstilbestrol, Triazolam, Alosetron, Phenylpropanolamine, Mixed amphetamine salts, Rimonabant, Gemtuzumab, Bepridil, Terfenadine, Ximelagatran, and Inhaled insulin) would probably not be improved by spatial restriction within the body. Hence, some 70% of the withdrawn drugs would be substantially improved by restriction to chosen sites within the body. This argues that the ability to spatially restrict drugs within the body could be quite valuable. Appendix 1 – Key Words Below are key words and phrases in 2-point font. They can be used to search the above chapter. Increase the font size to view the key words. Text enclosed by parentheses is descriptive, and is not part of a search term. The numbers in parentheses indicate the number of times that each key word or phrase appears in the chapter text. Be sure to search with only the key words or phrases, and not with any spaces that precede or follow them. Numbers and Other Non-Letters 3-methoxy-dopa (1) /:/ 5-HT1A (serotonin receptor) (1) /:/ 5-HT1B (serotonin receptor) (1) /:/ 5-HT2A (serotonin receptor) (1) /:/ 5-HT2B (serotonin receptor) (3) /:/ 5-HT2C (serotonin receptor) (1) /:/ α-melanocyte (1) /:/ α-melanocyte stimulating hormone (1) /:/ α-tocopheroyl (1) /:/ α-tocopheroyl moiety (1) /:/ α4 (integrin) (3) /:/ A abciximab (monoclonal antibody) (12) /:/ abdominal discomfort (1) /:/ abdominal pain (2) /:/ acid reflux disease (1) /:/ Acitretin (5) /:/ acne (incurable) (1) /:/ acne (side effect) (1) /:/ Acomplia (rimonabant) (1) /:/ acromegaly (1) /:/ actinic prurigo (4) /:/ adalimumab (10) /:/ Adderall (mixed amphetamine salts) (9) /:/ addiction and abuse (2) /:/ adipocyte (2) /:/ adiposity (12) /:/ adrenal gland (1) /:/ age-related (1) /:/ agouti-related peptide (2) /:/ aldose reductase (5) /:/ alertness (1) /:/ allergic (3) /:/ allergy (2) /:/ Alosetron (6) /:/ Alpidem (7) /:/ Alredase (1) /:/ alternative splicing (1) /:/ amineptine (anti-depressant) (11) /:/ amnesic (2) /:/ amphetamine (4) /:/ analgesic (4) /:/ anandamide (2) /:/ Ananxyl (1) /:/ anaphylaxis (1) /:/ anesthetic (2) /:/ angina pectoralis (1) /:/ angiogenesis (7) /:/ angiogenic (3) /:/ angioplasty (1) /:/ ankylosing spondylitis (1) /:/ anorectic (1) /:/ anti-anxiety (1) /:/ anti-apoptotic (1) /:/ anti-cancer drug (1) /:/ anti-cancer toxin (1) /:/ antidiabetes (1) /:/ anti-diabetic (1) /:/ anti-emetic (1) /:/ anti-inflammatory (4) /:/ anti-obesity (1) /:/ anti-obesity drug (1) /:/ antibacterial (1) /:/ antibiotic (3) /:/ antibody-dependent cellular cytotoxicity (1) /:/ anticoagulant (1) /:/ anticonvulsant (2) /:/ antidepressant (3) /:/ antidiuretic hormone (1) /:/ antihistamine (2) /:/ anxiety (2) /:/ anxiolytic (4) /:/ aortic (heart valve) (1) /:/ apoptosis (7) /:/ appetite suppressant (2) /:/ aprotinin (10) /:/ arcuate nucleus (1) /:/ arrhythmia (2) /:/ arteries (9) /:/ arterioles (2) /:/ arthralgias (1) /:/ arthritic joints (2) /:/ arthropathy (1) /:/ ascending paralysis (1) /:/ aspirin (1) /:/ Astemizole (15) /:/ asthma (1) /:/ atherosclerotic plaque (1) /:/ atrial fibrillation (2) /:/ attention-deficit hyperactivity disorder (1) /:/ auto-antibodies (1) /:/ autocrine/paracrine (1) /:/ autoimmune (5) /:/ autoimmunity (1) /:/ autonomic nervous system (1) /:/ autoregulatory loop (1) /:/ Avandia (1) /:/ axon (1) /:/ B-C bacteria (6) /:/ bacterial sepsis (1) /:/ barbituate (1) /:/ basiliximab (2) /:/ Baycol (1) /:/ behavioral (effects) (2) /:/ benzodiazepine (1) /:/ Bepridil (5) /:/ bevacizumab (22) /:/ biliary dysfunction (1) /:/ bipolar disorder (1) /:/ birth defect (2) /:/ bispecificity (of engineered antibodies) (1) /:/ bladder (2) /:/ bladder cancer (1) /:/ bleeding (4) /:/ blindness (2) /:/ blistering skin disease (1) /:/ bloating (1) /:/ blocked vessel (blood vessel) (1) /:/ blood clot (2) /:/ blood platelet (1) /:/ blood pressure (7) /:/ blood transfusion (1) /:/ blood triglycerides (level of) (1) /:/ blood vasculature (1) /:/ blood vessel (7) /:/ blood-brain barrier (3) /:/ bone fracture (1) /:/ bone growth (2) /:/ bone marrow (8) /:/ brain injury (2) /:/ brainstem (1) /:/ breast cancer (4) /:/ breathing muscles (1) /:/ broad-spectrum (antibiotic) (2) /:/ bronchioles (1) /:/ bronchospasm (3) /:/ brown adipose (3) /:/ brown adipose tissue (3) /:/ buformin (1) /:/ bullous dermatosis (2) /:/ buprenorphine (1) /:/ C-reactive protein (1) /:/ Ca2+ (3) /:/ cachexia (3) /:/ calcium channel blocker (9) /:/ calcium dynamics (normal) (1) /:/ cancer chemotherapy (4) /:/ cannabinoid receptor CB1 (1) /:/ capillary formation (1) /:/ cardiac fibrosis (1) /:/ cardiac insufficiency (1) /:/ cardiac ischemia (1) /:/ cardiac myocyte (3) /:/ cardiac output (1) /:/ cardiac valves (1) /:/ cardiomyocyte elongation (1) /:/ cardiomyocyte elongation (pathological) (1) /:/ cardiomyopathy (14) /:/ cardiotoxic (2) /:/ cardiovascular disease (1) /:/ carpal tunnel syndrome (1) /:/ cartilage (2) /:/ catechol-O-methyl 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secretion (of human growth hormone) (2) /:/ sedative (3) /:/ segment (of blood vessel) (2) /:/ Seldane (1) /:/ sensory tracts of the spinal cord (1) /:/ septal thickness (of the heart) (2) /:/ serotonin (11) /:/ serotonin transporter (1) /:/ serum insulin (11) /:/ serum leptin (1) /:/ short stature (1) /:/ short-lived (2) /:/ short-range (1) /:/ short-term treatment (1) /:/ sibutramine (7) /:/ signal (4) /:/ signaling (3) /:/ single-component (diffusion) (1) /:/ sinusitis (1) /:/ sitaxentan (11) /:/ skeletal muscle (10) /:/ skeletal muscle wastage (1) /:/ skin eruption (1) /:/ skin-flap (experimental system) (1) /:/ slipped capital femoral epiphysis (2) /:/ sodium retention (1) /:/ solid tumor (1) /:/ solubility (in water or fat) (3) /:/ SOM230 (1) /:/ somatostatin (65) /:/ somatostatin analog (1) /:/ somatostatin receptor (1) /:/ somatotropic (1) /:/ sorbitol (2) /:/ spasmolytic (1) /:/ spatial restriction (of drugs) (20) /:/ spinal cord (2) /:/ Staphylococcus aureus (1) /:/ statin (2) /:/ stimulant (1) /:/ stomach (5) /:/ stomach ulcers (1) /:/ stroke (4) /:/ subcutaneous adipose tissue (1) /:/ subcutaneous injection (1) /:/ sublingual administration (of a drug) (1) /:/ subtypes (of dopamine receptors) (1) /:/ suicidal (2) /:/ suicide (3) /:/ sulfa allergy (1) /:/ sunlight-induced (1) /:/ supercoiled DNA (1) /:/ suppress (1) /:/ suppression of pancreatic enzymes (1) /:/ Survector (1) /:/ synaptic cleft (1) /:/ syndrome (21) /:/ synthesis (biosynthesis) (6) /:/ synthetic (3) /:/ systemic administration (2) /:/ systemic body growth (1) /:/ systemic disabling (1) /:/ systemic inhibition (2) /:/ systemic nitric oxide (1) /:/ systemic treatment (1) /:/ systemically (administration) (6) /:/ systemically injected (1) /:/ systolic blood pressure (1) /:/ T-U-V-W-X-Y-Z T-cell expansion (1) /:/ targeting (of medicines) (2) /:/ Tasmar (1) /:/ tegaserod (8) /:/ telomerase (2) /:/ temafloxacin (7) /:/ temazepam (7) /:/ tendon toxicity (1) /:/ Tenox (1) /:/ teratogenicity (1) /:/ terfenadine (14) /:/ terodiline (8) /:/ testosterone (1) /:/ thalidomide (13) /:/ Thelin (1) /:/ therapeutic index (1) /:/ thermogenesis (non-shivering) (1) /:/ thiazolidinediones (1) /:/ thioridazine (9) /:/ throat irritation (2) /:/ thrombin (1) /:/ thyroid eye disease (15) /:/ thyroid stimulating hormone (1) /:/ ticrynafen (9) /:/ tienylic acid (1) /:/ TNF (15) /:/ TNF-α (1) /:/ TNF receptors (1) /:/ tolcapone (11) /:/ tolrestat (9) /:/ tolterodine (2) /:/ tooth problems (1) /:/ topoisomerase IV (1) /:/ torsadas de pointes (1) /:/ toxic epidermal necrolysis (4) /:/ toxicity (15) /:/ toxins (2) /:/ trachea (1) /:/ tradeoff (1) /:/ Trancopal (1) /:/ Trasylol (1) /:/ triazolam (6) /:/ Triludan (1) /:/ troglitazone (11) /:/ trovafloxacin (6) /:/ Trovan (1) /:/ trypsin (inhibitor) (1) /:/ tuberculosis (2) /:/ tumor necrosis factor (4) /:/ tumor resistance to radiation treatment (1) /:/ two-component protein (diffusion) (1) /:/ two-photon excitation microscopy (2) /:/ Tysabri (1) /:/ U937 (human myeloid leukemia cell line) (1) /:/ ulcerative colitis (1) /:/ ultraviolet light (1) /:/ un-biological (drug chemistry) (1) /:/ uncoiling of supercoiled DNA (1) /:/ underdevelopment of extremities (1) /:/ upper respiratory tract infection (1) /:/ upregulated (human growth hormone) (1) /:/ ureters (1) /:/ urinary infections (1) /:/ uterus (2) /:/ vaccines (4) /:/ vagina (1) /:/ vaginal tumor (1) /:/ Vascor (1) /:/ vascular endothelial growth factor (VEGF) (12) /:/ vasculogenesis (1) /:/ vasoconstrictive (1) /:/ vasoconstrictors (2) /:/ vasodilating (1) /:/ vasodilator (1) /:/ vasorelaxation (endothelium-dependent) (1) /:/ VEGF (vascular endothelial growth factor) (14) /:/ veno-occlusive disease (1) /:/ ventricle (2) /:/ ventricular arrhythmia (1) /:/ ventricular tachycardia (1) /:/ vesicular storage (of serotonin) (1) /:/ vessel proliferation (1) /:/ Vioxx (1) /:/ viral meningitis (1) /:/ vision (3) /:/ visual loss (1) /:/ vitamin D (1) /:/ vitamin E (1) /:/ warfarin (2) /:/ weakness (muscular) (1) /:/ white adipose (2) /:/ white blood cell (1) /:/ women (7) /:/ wound healing (1) /:/ xenobiotherapeutic (1) /:/ ximelagatran (7) /:/ Zelnorm (1) /:/ zimelidine (8) /:/ Revised August 19, 2014, 2:10 PM