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Tuesday, May 27, 2008

Newer drugs in Treatment of Type 2 Diabetes

Incretins
Incretins are gastrointestinally secreted insulinotropic hormones that play an important role in glucose homeostasis as they are involved in augmentation of -cell secretion of insulin and in suppression of glucagon secretion by the cell. The incretin effect refers to the augmented release of insulin that is observed from oral ingestion of glucose when compared with intravenous glucose challenge, even though the glucose concentration achieved in plasma may be equivalent. There are two different gut hormones that are mainly responsible for the incretin effect, which may include glucose-dependent insulinotropic peptide and GLP-1. In contrast to glucose-dependent insulinotropic peptide, GLP-1 maintains a glucoregulatory function in individuals both with and without diabetes. For this reason, GLP-1 was identified as a potential therapeutic agent for diabetes treatment.
One of the major concerns for GLP-1 that limited clinical applicability is the rapid enzymatic degradation by DPP-4 and as such, requires continuous intravenous or subcutaneous infusion. To address the problem, two research approaches have been attempted. One is to modify the molecule to resist or delay degradation. Agents such as exenatide and liraglutide are GLP-1 receptor agonists that are resistant to DPP-4 inhibition. A second approach has been to inhibit endogenous DPP-4 activity, thus prolonging the circulating half-life of native GLP-1. Agents in the DPP-4 inhibitor class are represented by vildagliptin and sitagliptin

Treatment of Type 2 Diabetes

Type 2 diabetes, the most common form of diabetes, is characterized by abnormalities in hepatic glucose production, insulin resistance, and a progressive decline in -cell function over time. To treat effectively the individual with type 2 diabetes, the provider must have a thorough understanding of the underlying pathophysiology to provide treatment that precisely addresses the metabolic abnormalities. Currently, the provider who cares for subjects with type 2 diabetes can choose an antidiabetic agent from no less than eight pharmacologic classes. These classes include agents that increase insulin secretion, improve insulin action, and delay absorption of carbohydrates. The newer treatments available, specifically incretin therapy, address a previously unmet need in diabetes by modulating glucose supply. The currently available agents can be combined and combination therapy markedly improves glycemic control. This allows the provider to design regimens to specifically address underlying abnormalities.
Goals
A1c goal recommended by the American Diabetes Association (ADA) is a A1c value <7%. This is not a value considered in the normal range, as an A1c level of 4.0–6.0% is considered as the non-diabetic range. However, this level was selected on the basis of practicality and the projected reduction in complications over time. The ADA guidelines also suggest that for "the individual patient," the A1c should be "as close to normal (<6%) as possible without significant hypoglycemia". The most recent glycemic goal set by both the American Association of Clinical Endocrinologists and the European Union–International Diabetes Federation is an A1c level <6.5%.

Tuesday, May 20, 2008

Therapeutic Angiogenesis

strategy is designed to promote the development of supplemental collateral blood vessels that will act as endogenous bypass conduits
Promotion of coronary collateral growth has many attractive features, particularly in
patients with angina who are not indicated for percutaneous coronary intervention or coronary artery
bypass grafting surgery.
Two major avenues:
1. gene therapy (the introduction of new genetic material into somatic cells to synthesize proteins that are
missing, defective, or desired for specific therapeutic purposes)
2. protein-based therapy
(administration of the growth factors, instead of the genes encoding for the growth factors responsible for angiogenesis).

Delivery of angiogenic factors (Protein-based therapy with cytokines including vascular endothelial growth factor and fibroblast growth factor) demonstrated functionally significant angiogenesis in several animal models.
Delivery of gene encoding for the respective protein product has been shown to induce angiogenesis in numerous
animal models, and expression of a functioning product has been demonstrated with evidence of
neovascularization and improved perfusion in the target myocardium.

Various early clinical
trials of therapeutic angiogenesis have shown reduction in anginal symptoms and increases in exercise
time, as well as objective evidence of improved perfusion, left ventricular function and angiographic
appearance following such angiogenic treatments.

Patients with chronic critical limb ischemia
who are not candidate for surgical or percutaneous revascularization- Therapeutic angiogenesis, which has the goal to achieve the process of new
blood vessel formation via the administration of growth factors, has become a new promising hope. The
discovery of the possibility of inducing sprouting of new vessels from preexisting vasa (angiogenesis) or
the in situ differentiation of endothelial cells from stem cell precursors (vasculogenesis) have open new
lease on life. In experimental studies therapeutic angiogenesis has been produced by
recombinant growth-factor protein application as well as by growth factor gene therapy. Most widely
studied factors belong to vascular endothelial growth factor (VEGF) or fibroblast growth factor (FGF)
families. Studies have also shown that, angiogenic growth factors stimulate endothelial cell migration
and accelerate endothelial repair by enhancing post-injury re-endothelization.

Angiostatic Approach to Cancer Therapy

Various inhibitors of angiogenesis are under investigation in patients with
advanced cancer:


Drugs that block matrix breakdown:
1. Marimastat

against
pancreas,
non-small
cell lung,
breast
cancers
Synthetic inhibitor of
matrix
metalloproteinases
(MMPs)
2. Bay 12-9566

against lung,
ovary, and
pancreatic
cancers
Synthetic inhibitor of
tumor growth
3. AG3340

against
non-small
cell lung;
against
prostate
cancer
Synthetic MMP
inhibitor



4. CGS
27023A

Synthetic MMP inhibitor
5. COL-3

Synthetic MMP
inihibitor.
Tetracycline derivative
6. Neovastat

against
non-small
cell lung
cancer
Naturally occurring
MMP inhibitor
7. BMS-275291

Synthetic MMP
Inhibitor
8. Dalteparin
9. Suramin



Drugs that inhibit endothelial cells directly:

1. TNP-470

against
advanced
cancer for
adults with
solid tumors;
against
pediatric solid
tumors,
lymphomas,
and acute
leukemias
Synthetic
analogue of
fumagillin; inhibits
endothelial cell
growth
2. Thalidomide

against
Kaposi's
sarcoma,
glioblastoma,
prostate, lung,
and breast
cancers
Mech. unknown
3. Squalamine

Extract from
dogfish shark liver;
inhibits
sodium-hydrogen
exchanger, NHE3
4. Combretastatin

Induction of
apoptosis in
proliferating
endothelial cells
5. Endostatin

solid
tumor
Inhibition of
endothelial cells

6. 2-methoxyestradiol
(2-ME)
7. CC-5013 (Thalidomide Analog)
8. LY317615 (Protein Kinase C Beta Inhibitor)
9.Soy Isoflavone (Genistein; Soy Protein Isolate)

Drugs that block activators of angiogenesis:

1. Anti-VEGF Antibody
against lung,
breast,
prostate,
colorectal, and
renal cancers
Monoclonal
antibody to
vascular
endothelial
growth factor
(VEGF)



2. SU5416

against
Kaposi's
sarcoma,
against
metastatic
colorectal
cancer, and
against
advanced
malignancies
Blocks VEGF
receptor
signaling
3. SU6668

against
advanced
tumors
Blocks VEGF,
FGF, and EGF
receptor
signaling





4. PTK787/ZK
22584

against
advanced
cancers
against
glioblastoma
and Kaposi's
sarcoma;
against Von
Hippel Lindau
disease
Blocks VEGF
receptor
signaling
5. Interferon-alpha
Commercially
Available

Inhibition of
bFGF and
VEGF
production



Drugs that inhibit endothelial-specific integrin/survival signaling:

1. Vitaxin

Antibody to
integrin present
on endothelial
cell surface
2. EMD121974

against Kaposi's
sarcoma, brain
tumors, and
solid tumors
Small molecule
blocker of integrin
present on
endothelial cell
surface

Drugs with non-specific mechanism of action:
1. CAI

against ovarian,
non-small cell
lung, and renal
cell cancers
Inhibitor of
calcium influx
2. Interleukin-12
against Kaposi's
sarcoma and
solid tumors
Up-regulation of
interferon gamma
and IP-10
3. IM862
Against AIDS-related
Kaposi's
sarcoma
Unknown
mechanism

Antiangiogenic therapy combined with conventional anticancer therapies may represent an useful tool in the future care of patients with cancer.

Tuesday, May 13, 2008

Process of Angiogenesis

In physiological conditions, angiogenesis occurs primarily in embryo development, during wound healing and in response to ovulation.

However, pathological angiogenesis, or the abnormal rapid proliferation of blood vessels,is implicated in over 20 diseases, including cancer, psoriasis and age-related macular degeneration.
The angiogenic sequence
A cell activated by a lack of oxygen releases angiogenic molecules that attract inflammatory and endothelial cells and promote their proliferation.

During their migration, inflammatory cells also secrete molecules that intensify the
angiogenic stimuli.

The endothelial cells that form the blood vessels respond to the angiogenic call by
differentiating and by secreting matrix metalloproteases (MMP), which digest the
blood-vessel walls to enable them to escape and migrate toward the site of the angiogenic stimuli.

Several protein fragments produced by the digestion of the blood-vessel walls intensify the proliferative and migratory activity of endothelial cells, which then form a capillary tube by altering the arrangement of their adherence-membrane proteins.

Finally, through the process of anastomosis, the capillaries emanating from the arterioles and the venules will join, thus resulting in a continuous blood flow.

Normal regulation of angiogenesis is governed by a fine balance between factors that
induce the formation of blood vessels and those that inhibit the process.
When this balance is destroyed, it usually results in pathological angiogenesis which causes increased blood-vessel formation in diseases that depend on angiogenesis.

More than 20 endogenous positive regulators of angiogenesis have been described,
1. growth factors, can induce the division of cultured endothelial cells thus indicating a direct action on these cells.
vascular endothelial growth factor (VEGF),
transforming growth factors (TGF-beta),
fibroblast growth factors (FGF),
epidermal growth factor (EGF),
angiogenin
Other factors have virtually no effect on the division of cultured endothelial cells indicating that their angiogenic action is indirect.

2. Matrix metalloproteinases,
3.Cytokines
4. Integrins

How Does Acupuncture Work?

Nerve-Reflex Theory
This theory was developed by Japanese doctors of physiology (Ishikawa and Fujita et al ) who were deeply involved in acupuncture research in 1950s. It holds that when an abnormal condition occurs in an internal organ, alterations take place in the skin and muscles related to that organ by means of the autonomic nervous system. The autonomic nervous system extending through the internal organs, skin, subcutaneous tissues and muscles, constantly transmit information about the physical condition to the spinal cord and the brain. These information impulses set up a reflex action that cause symptoms of internal organ's disorders to manifest themselves on the surface area as hyper or hyposensitivity, spasm, contraction, tightness or lumping of the muscles, discolouration, dryness or oiliness of the skin,etc. This phenomena is called "Viscera-Cutanous Refelx". At the same time, this intimate relation can exert the reverse effects too. That is, stimulation of the skin and muscles can cause dilation or contraction of the vessels to change the blood and lymph flow of the internal organs, activate the endocrine (hormone) and immune system,etc. This phase is called "Cutanous -Viscera Reflex". According to this theory, Acupuncture is defined as the most effective systematized stimulation therapy to utilize these reflexes for restoring the homeostasis of the body and acceralate the healing process.
The Gate Control Theory of Pain
In the west, especially in the USA, media has popularized the amazing effect of acupuncture for pain relief, therefore, it is understandable that most scientific research has been focussed on the mechanism of acupuncture for pain relief In 1965 Drs. Melzack and Wall won scientific acclaim by proposing a theory called "Gate Control Theory of Pain", which was eventually hailed to be the best model to explain the mechanism of acupuncture for pain relief. This theory was the first serious attempt to unify the many ideas that existed about the mechanism that perceives and transmits pain through the nervous system. It holds that there are some specific nerve fibres that transmit pain to the spinal cord, while the input of other nerve fibres inhibits the transmission of pain. Both of these groups of fibres meet at an area called the "substantia gelatinous" in the spinal cord. The substantia gelatinous controls the integration of pain and pain inhibitory stimuli. If the pain input is excessive, then it is transmitted up the spinal cord to the brain to be perceived as pain. This theory proposes a balance between stimulation of the pain fibres and inhibition of that stimulus, so that pain is perceived only if the pain input overrides the inhibition of pain. The problem with this theory is that it does not explain the full spectrum of the effects of acupuncture. Acupuncture excites the pain inhibitory nerve fibres for a short period of time, thereby blocking pain, but the effects of acupuncture can last much longer than that, quite often for some months after the acupuncture needle has been removed, and nothing in the Gate Control Theory really explains this prolonged effect. The mechanism of pain perception and transmission has not been clearly and completely defined, and in the light of the current state of knowledge about the basic mechanism of pain, it is a little unreasonable to expect an explanation of the effects of acupuncture on pain.
Endorphin
The worsening problem of drug addiction in the West has provided a great impetus for research into the mechanism of morphine action and addiction. (Morphine, heroin and opium are all related chemicals, collectively called opiates.) Morphine-like substances have recently been discovered in the central nervous system (the brain and the spinal cord). These substances are called endorphin, or naturally-occurring morphine,, and they have been found to be very effective in blocking pain. It is also verified that acupuncture stimulation can trigger the release of endorphin into the central nervous system, and the effects of acupuncture anaesthesia can be reversed by the use of anti-morphine drugs. However, recent research shows that not all types of acupuncture anaesthesia can be blocked by anti-morphine. e.g. If a patient has a painful arthritic knee, and acupuncture provides relief for the knee pain, then anti-morphine do not usually block the effects of this type of acupuncture therapy. The effects of acupuncture can be very swift (in terms of seconds) and it seems that the release of chemicals might possibly be too slow a process to have such a swift action. The endorphin theory again only deals with pain and makes little attempt to explain the use and effects of acupuncture in non-painful diseases. Implicit Order of "X-Signal System"
This is one of the latest theories proposed by Dr. Yoshio Manaka (1911-1989), an internationally renowned MD (surgeon & acupuncturist) who had made great contribution in both clinical applications and research of Japanese acupuncture for almost 40 years. This theory holds that acupuncture works not only on physiological systems of the body but also would work on bio-informational system or "X-Signal System" with a primary regulatory function; primarily hemostatic functions, regulating the overall energetic condition and the overall physiological condition. This information system is essentially not anatomical (though in microscopic structures it may have some physical expression), just as the various theories of the "Qi", meridian (energy channel), yin-yang, and the five phases are not clearly anatomical. This information system can be described as being hidden or enfolded or implicit order of primitive biological properties which might arose through various stages of evolution and were then masked by the development of the more efficient automation systems such as the nervous and endocrine systems. This process of enfoldment probably involves their being absorbed into the body of information stored, for example, in the genetic information of DNA. These potential information could be unfolded only with the correct internal and external stimulus, and in that process we can see manifestations of the clinical laws of acupuncture that were classically formulated as "Qi", meridian, ying-yang, five phase, and biorythmic theories. Treatment that takes advantage of, and activate changes in this system, can produce diverse effects because potentially the whole biological system can be affected. If the function of this information system stays in the ideal condition, then the body will function optimally. Since Dr.Manaka was a remarkable figure equipped with profound, diverse knowledge and experiences of both traditional oriental medicine and modern scientific medicine, this model is very convincing and useful to explain various phenomena surrounding acupuncture. However, we still do not have scientific means to prove this model. We might have to wait until much more sophisticated high-tech machines or instruments will prove this theory in the future, like Einstein's "General Theory of Relativity" was finally confirmed many years later after its publication.
Other Ideas
Some research workers, particularly in Russia, have suggested that fields of biological activity exist around all living objects, which is often described as "Kirlian phenomena". The concept of 'biofields' has little hard scientific evidence to support it, but there are people in many countries now who are suggesting that acupuncture may work through these fields. At present there are no good grounds for accepting or rejecting these theories.

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