Download The Use of Engineered Microbes as Medical Agents

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2.10 Analysis of 50 Withdrawn Drugs - General Remarks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 transferase (2) /:/ cavitary volume (2) /:/ CD11a subunit (1) /:/ CD33 (1) /:/ CD4 T-cell (1) /:/ Celebrex (1) /:/ celecoxib (6) /:/ cell membrane (1) /:/ cell proliferation (2) /:/ cell surface protein (1) /:/ central nervous system (6) /:/ cerivastatin (7) /:/ chemical messengers (2) /:/ chlormezanone (6) /:/ chloroquine (1) /:/ cholesterol production (1) /:/ chronic angina pectoralis (1) /:/ chronic bullous dermatosis (2) /:/ chronic psoriasis (1) /:/
cimetidine (1) /:/ cisapride (8) /:/ clot (blood clot) (3) /:/ clotting (1) /:/ co-proxamol (9) /:/ codeine (1) /:/ cognitive (ability or disability) (4) /:/ cognitive performance (1) /:/ colic (gastrointestinal or genitourinary) (1) /:/ collateral circulation (3) /:/ colon cancer (1) /:/ competition between drugs (within the liver) (1) /:/ complex carbohydrates (as antigens) (1) /:/ congestive heart failure (2) /:/ constipation (3) /:/ constricting (of arterioles) (1) /:/ contractions (cardiac) (3) /:/ coronary (coronary artery
disease) (1) /:/ corticotropin releasing hormone (2) /:/ cough suppressant (1) /:/ coughing (2) /:/ cox-2 (cyclooxygenase-2) (2) /:/ Crohn (Crohn’s disease) (7) /:/ cross-talk (chemical cross-talk between tissues) (2) /:/ cyclooxygenase-2 (2) /:/ Cylert (1) /:/ CYP2C9 (liver enzyme) (4) /:/ CYP3A4 (liver enzyme) (4) /:/ cytochrome (p450, liver enzymes) (2) /:/ cytoplasmic tail (somatostatin receptor) (1) /:/
D-E
daclizumab (2) /:/ daunorubicin (1) /:/ deformities (birth defects) (1) /:/ delta cells of the pancreas (1) /:/ demerol (1) /:/ demyelinating (2) /:/ depression (psychological) (2) /:/ depressive (psychological) (1) /:/ detoxification (of drugs by liver) (3) /:/ detoxification enzymes (1) /:/ developing fetuses (2) /:/ Dexatrim (1) /:/ dexfenfluramine (2) /:/ dextropropoxyphene (2) /:/ diabetes (10) /:/ diabetic retinopathy (22) /:/ diapedesis (3) /:/ diarrhea (3) /:/ diazepam (1) /:/ diethylstilbestrol (7) /:/
differentiated nuclei (1) /:/ diffused medicines (2) /:/ diffusible interacting components (1) /:/ digestive system (1) /:/ dilated cardiomyopathy (13) /:/ dilators of blood vessels (synthetic) (1) /:/ dilaudid (1) /:/ dipyridamole (2) /:/ distalgesic (1) /:/ diuretic (2) /:/ diversion (of psychoactive drugs) (1) /:/ DNA gyrase (topoisomerase) (1) /:/ dopamine (8) /:/ dopamine receptor (D1, D2) (2) /:/ drug-induced injury to the liver (1) /:/ drug-loaded liposome (1) /:/ dry mouth (1) /:/ dyskinesia (involuntary
movements) (1) /:/ dysmenorrhea (1) /:/ dyspepsia (1) /:/ efalizumab (8) /:/ effective dose (of a drug) (2) /:/ elderly (2) /:/ electrocardiograms (2) /:/ embryogenesis (1) /:/ encephalopathy (1) /:/ endoproteolytic processing (1) /:/ endothelial (16) /:/ endothelial permeability (1) /:/ endothelin (6) /:/ endothelin a receptor (1) /:/ endothelin B receptor (2) /:/ endothelin-1 (7) /:/ endothelium-dependent vasorelaxation (1) /:/ endotracheal intubation (1) /:/ entacapone (9) /:/ eosinophilia (1) /:/
epidermis (detachment from dermis) (1) /:/ epinephrin (1) /:/ erythema nodosum leprosum (1) /:/ erythromycin (2) /:/ etretinate (11) /:/ Euhypnos (1) /:/ eukaryotic parasites (1) /:/ Exanta (1) /:/ exogenous leptin (1) /:/ extended-release (3) /:/ external cell surfaces (1) /:/ extracellular (1) /:/ extravasation (1) /:/ Exubera (3) /:/ eye (blood vessel overgrown in the eye) (20) /:/
F-G-H
familial adenomatous polyposis (1) /:/ fast-acting antidepressant (1) /:/ fatal pulmonary hypertension (1) /:/ fatigue (1) /:/ fatty acid (1) /:/ Fc-leptin fusion protein (1) /:/ feet (bone fractures, ascending paralysis) (2) /:/ female rat (2) /:/ Fen-phen (7) /:/ fenfluramine (10) /:/ fever (3) /:/ fexofenadine (2) /:/ fibrinogen (1) /:/ fibrinolysis (blood clot breakdown) (1) /:/ fibroblast (2) /:/ fibroblast growth factor 2 (2) /:/ first-pass effect (1) /:/ Flosequinan (1) /:/ flu-like symptoms (1) /:/ fluorescence
(2) /:/ fluoroquinone (1) /:/ foreign antigen (1) /:/ foreign substance (5) /:/ gastric emptying (1) /:/ gastric hormone (1) /:/ gastric mobility (1) /:/ gastritis (1) /:/ gastroenterologic disorder (1) /:/ gastrointestinal hemorrhage (1) /:/ gastrointestinal lumen (1) /:/ gastrointestinal tract (3) /:/ gastrointestinal wall (1) /:/ gastroparesis (1) /:/ gastroprokinetic (enhancer of gastric mobility) (3) /:/ gemtuzumab (8) /:/ genital (infection) (1) /:/ glia (1) /:/ glucagon (2) /:/ gluconeogenesis (1) /:/ glucose (4)
/:/ glycated hemoglobin (1) /:/ glycoproteinIIb/IIIa receptor (1) /:/ gonads (1) /:/ grapefruit (2) /:/ grapefruit juice (1) /:/ grepafloxacin (7) /:/ growth hormone (38) /:/ Guillain-Barré (5) /:/ half-life (8) /:/ hand (ascending paralysis) (1) /:/ hand (bone fracture) (1) /:/ headache (3) /:/ hematopoietic cells (2) /:/ hemolysis (1) /:/ hemolytic anemia (3) /:/ hepatic portal (vein) (2) /:/ hepatitis (1) /:/ hepatocyte growth factor (2) /:/ hepatotoxic (1) /:/ high-density lipoprotein (1) /:/ hippocampus (1)
/:/ Hismanal (1) /:/ histidine-rich lytic peptides (1) /:/ HMG-CoA reductase (1) /:/ homing (4) /:/ hospital admissions (1) /:/ human cardiac valves (1) /:/ human growth hormone (12) /:/ human IgE (1) /:/ human myeloid leukemia (1) /:/ humanized monoclonal antibody (2) /:/ hunger (suppression) (1) /:/ hungry (constantly) (1) /:/ hydromorphone (5) /:/ hyperprolactinemia (1) /:/ hypertension (16) /:/ hypnotic (1) /:/ hypnotic drug (1) /:/ hypothalamic neurons (1) /:/ hypothalamus (8) /:/
hypoxic-ischemic brain injury (1) /:/
I-J-K
idiopathic intracranial hypertension (2) /:/ IgE (immunoglobulin type E) (1) /:/ IGF binding protein (1) /:/ IGF-1 (insulin-like growth factor-1) (43) /:/ IGF1R (receptor for insulin-like growth factor-1) (1) /:/ IGFBP-3 (binding protein for IGF-1) (2) /:/ IgG (immunoglobulin isotype G) (2) /:/ imipramine (1) /:/ immobile patients (1) /:/ immune system (15) /:/ immune system modulator (1) /:/ immunoglobulin (3) /:/ immunological (1) /:/ impair memory (1) /:/ impaired respiration (1) /:/ inappropriate
chemical signals (1) /:/ inappropriate valve cell division (1) /:/ induction of auto-antibodies (1) /:/ infect (1) /:/ inflammation (5) /:/ inflammatory (7) /:/ infliximab (2) /:/ inhalational aerosols (1) /:/ inhaled (drugs) (4) /:/ inhaled insulin (3) /:/ inhibit (8) /:/ inhibitor (9) /:/ inhibitor i-κb (1) /:/ injection (8) /:/ injury (of liver) (11) /:/ innate immunity (2) /:/ insomnia (3) /:/ insulin (25) /:/ insulin resistance (3) /:/ insulin-dependent (1) /:/ insulin-like growth factor-1 (3) /:/ insulin-like growth
factor-1 (IGF-1) (3) /:/ integrin (α4) (3) /:/ interactions with other drugs (1) /:/ interfere (disruption of natural processes or interference with other medicines) (5) /:/ interfering with bone growth (1) /:/ interferon (1) /:/ interferon β-1a (1) /:/ interleukin-2 (inhibition) (1) /:/ intermediate reward (1) /:/ intestinal cytochrome p450 isoform CYP3A4 (1) /:/ intestinal lining (1) /:/ intestine (4) /:/ intracerebro-ventricularly (1) /:/ intramuscular injection (1) /:/ intravenous injection (1) /:/ invasive fungal disease
(1) /:/ inverse agonist (1) /:/ ions (lithium, calcium, or zinc) (3) /:/ iron (transport) (1) /:/ irreversibly inactivates (a liver enzyme) (1) /:/ irritability (1) /:/ irritable bowel syndrome (2) /:/ ischemia (11) /:/ ischemia-induced (1) /:/ ischemia-reperfusion (2) /:/ ischemic (4) /:/ itch (suppression) (1) /:/ JC virus (1) /:/ joint pain (2) /:/ just (restriction of a drug to just one area) (15) /:/ juvenile idiopathic arthritis (1) /:/ kidney (11) /:/ kidney cancer (1) /:/ kidney transplants (1) /:/ kill (bacteria, cancer
cells, etc) (9) /:/
L-M
labile (3) /:/ lactate (buildup) (1) /:/ lactic acidosis (5) /:/ lanreotide (2) /:/ leprosy (1) /:/ leptin (76) /:/ leptin (recombinant) (76) /:/ leptin-resistant (1) /:/ leukemia (3) /:/ leukemic blast cells (1) /:/ leukoencephalopathy (2) /:/ levodopa (3) /:/ levodopa/carbidopa (1) /:/ libido (1) /:/ lidocaine (1) /:/ life-threatening (3) /:/ ligand (1) /:/ Lipobay (1) /:/ lipophilic (1) /:/ liposome (4) /:/ lithium (28) /:/ lithium carbonate (1) /:/ lithium citrate (1) /:/ lithium orotate (1) /:/ lithium sulfate (1)
/:/ liver enzyme (1) /:/ liver injury (1) /:/ long QT syndrome (5) /:/ long-acting analog (1) /:/ long-term (13) /:/ longitudinal axis (of heart) (1) /:/ Lotronex (1) /:/ lower respiratory tract infection (1) /:/ LSD (lysergic acid diethylamide) (2) /:/ lumiracoxib (8) /:/ lung (5) /:/ lupus-like syndrome (1) /:/ lymphatic system (4) /:/ lymphatic vessel (7) /:/ lymphocyte function-associated antigen 1 (1) /:/ lymphoid cells (1) /:/ lymphoma (1) /:/ lysergic acid diethylamide (LSD) (4) /:/ macrophage (2) /:/
macular degeneration (1) /:/ macular edema (2) /:/ malaria (3) maleic anhydride metabolites (1) /:/ mammary epithelial cells (1) /:/ mammary hyperplasia (2) /:/ mania (2) /:/ mast cells (1) /:/ Melleril (1) /:/ memory (1) /:/ menstrual (1) /:/ menstruation (painful) (1) /:/ Merital (1) /:/ mesolimbic reward pathway (1) /:/ metabolite (2) /:/ metastasis (2) /:/ metastasize (3) /:/ metformin (3) /:/ methaqualone (5) /:/ mibefradil (8) /:/ mice (16) /:/ microbial pathogens (1) /:/ microvascular
complication (1) /:/ Micturin (1) /:/ midazolam (1) /:/ mistargeted (immune response) (1) /:/ mitochondria (4) /:/ mitogenic (1) /:/ mitoNEET (2) /:/ mitral heart valve (damage) (1) /:/ monoclonal (antibody or antibodies) (58) /:/ mood (4) /:/ mood stabilizer (1) /:/ mood-stabilizing (1) /:/ morning sickness (1) /:/ morphine (1) /:/ mortality (1) /:/ motility (gastrointestinal) (1) /:/ mouse (2) /:/ mucous membrane (1) /:/ multi-organ hypersensitivity (2) /:/ multidrug-resistant (bacteria) (3) /:/
multifocal leukoencephalopathy (2) /:/ multiple myeloma (2) /:/ multiple sclerosis (5) /:/ muscle atrophy (1) /:/ muscle relaxant (4) /:/ myalgia (1) /:/ Mycobacterium tuberculosis (1) /:/ myelin (1) /:/ myeloid leukemia (3) /:/ Mylotarg (1) /:/ myoglobin (1) /:/
N-O-P
narcolepsy (2) /:/ nasal septum (1) /:/ natalizumab (24) /:/ neovascularization (3) /:/ nerve (1) /:/ nervous system (22) /:/ nervousness (1) /:/ neuritis (peripheral) (1) /:/ neuroleptic malignant syndrome (1) /:/ neurological (disorder) (2) /:/ neurons (8) /:/ neuropeptide Y (2) /:/ neurotransmitter (3) /:/ NF-κB (1) /:/ nitric oxide (17) /:/ nodular skin eruption (UV-induced) (1) /:/ nomifensine (11) /:/ non-alcoholic fatty liver (1) /:/ non-competitively (modify liver enzymes) (1) /:/ non-metastatic
colon cancer (1) /:/ non-opioid analgesic (1) /:/ non-shivering thermogenesis (1) /:/ non-small cell lung cancer (5) /:/ non-steroidal anti-inflammatory drugs (1) /:/ non-target (tissues, organs, or sites) (7) /:/ norepinephrine (7) /:/ norfenfluramine (1) /:/ Norkotral (1) /:/ Normison (1) /:/ nuclear factor NF-κB (1) /:/ nursing infants (1) /:/ obese (6) /:/ obesity (8) /:/ octreotide (7) /:/ oligopeptide (1) /:/ omalizumab (1) /:/ Omniflox (1) /:/ opioid (1) /:/ opportunistic fungal infections (1) /:/
opportunistic infection (1) /:/ oral (7) /:/ oral (administration of a drug) (7) /:/ organ (7) /:/ osmotic damage (1) /:/ osteoarthritis (2) /:/ ovaries (1) /:/ overeating (prevention) (1) /:/ overgrowth (of blood vessels in the eye) (1) /:/ oxygen (3) /:/ ozogamicin (3) /:/ p450 (cytochrome, liver enzyme) (3) /:/ p53 (protein that opposes cell division) (1) /:/ painful (2) /:/ Palladone (1) /:/ pancreas (2) /:/ pancreatic (5) /:/ pancreatic enzymes (1) /:/ pancreatic insufficiency (3) /:/ parallel (lymph and blood
vessels run parallel) (2) /:/ paralysis (2) /:/ parenteral (administration) (1) /:/ Parkinson’s (2) /:/ pasireotide (3) /:/ pemoline (9) /:/ perforations (in the stomach, intestines, nasal septum) (1) /:/ pergolide (10) /:/ peripheral artery disease (1) /:/ peripheral edema (1) /:/ peripheral ischemia (2) /:/ peripheral nervous system (1) /:/ peripheral neuritis (1) /:/ Permax (1) /:/ peroxisome proliferator-activated receptors (ppars) (1) /:/ phenacetin (9) /:/ phenformin (11) /:/ phentermine (3) /:/
phenylpropanolamine (7) /:/ phocomelia (1) /:/ photocoagulation therapy (1) /:/ phototoxicity (1) /:/ pioglitazone (11) /:/ pituitary gland (7) /:/ placenta (2) /:/ plasma (blood) (3) /:/ platelets (3) /:/ polyneuropathy (1) /:/ polyps (colon and rectum) (1) /:/ Posicor (1) /:/ posterior reversible encephalopathy syndrome (1) /:/ potential for abuse (2) /:/ pregnant women (3) /:/ preprosomatostatin (1) /:/ presystemic (metabolism of drugs) (1) /:/ Prexige (1) /:/ prodrug (3) /:/ progressive multifocal
leukoencephalopathy (pml) (2) /:/ prohormone (1) /:/ prolactin (2) /:/ proliferative valve disease (1) /:/ Propagest (1) /:/ propranolol (1) /:/ Propulsid (1) /:/ prosomatostatin (1) /:/ prostaglandin (3) /:/ prostate cancer (2) /:/ prostatitis (1) /:/ protease (1) /:/ psoriatic arthritis (1) /:/ psychiatric (4) /:/ psychosis (1) /:/ psychostimulant (1) /:/ pulmonary arterial hypertension (1) /:/ pulmonary arteries (2) /:/ pulmonary emphysema (1) /:/ pulmonary hypertension (9) /:/
Q-R-S
QT interval (2) /:/ Quaaludes (1) /:/ radiation treatment (1) /:/ radioisotope (1) /:/ rapacuronium (6) /:/ Raplon (1) /:/ Raptiva (efalizumab) (1) /:/ Raxar (grepafloxacin) (1) /:/ re-uptake (inhibitors) (7) /:/ reactive oxygen species (1) /:/ receptor (12) /:/ receptor (blocking of) (12) /:/ recreational drug (1) /:/ rectal suppositories (1) /:/ red-brown urine (1) /:/ Reductil (1) /:/ rejuvenation (Repnumi) (5) /:/ Remestan (1) /:/ remission (2) /:/ renal failure (1) /:/ renal pelvis (1) /:/ renal thrombotic
microangiopathy (1) /:/ reperfusion damage (1) /:/ Repnumi (rejuvenation) (5) /:/ respiration (impaired) (1) /:/ restless leg syndrome (2) /:/ Restoril (1) /:/ retina (3) /:/ retinopathy (diabetic) (23) /:/ reverse-metabolized (aciretin to etretinate) (1) /:/ Rezulin (2) /:/ rhabdomyolysis (5) /:/ rheumatoid arthritis (4) /:/ rimonabant (7) /:/ rofecoxib (11) /:/ rosiglitazone (7) /:/ salivary gland (inflamed) (1) /:/ satiety (3) /:/ schizophrenia (1) /:/ seborrhoeic dermatitis (2) /:/ secreted (human growth
hormone) (2) /:/ 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
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Revised August 19, 2014, 2:10 PM