Use of NSAIDs--An Update

The articles for this week deal with the positive and negative actions of NSAIDs. This particular article primarily addressed a popular news topic: the increase in risk for cardiovascular and cerebrovascular events due to selective COX-2 inhibitors. These drugs looked promising for pain relief without the unwanted side affect of GI bleeding that occurs with COX-1 inhibition. However, in September 2004, Merck withdrew its product, Vioxx, from the market and the concerns for COX-2 inhibitors increased significantly.

The American Heart Association released this article as an update on the safety of using NSAIDs. An FDA joint meeting came to the conclusion that celecoxib (Celebrex), valdecoxib (Bextra) and rofecoxib (Vioxx), all selective COX-2 inhibitors, “significantly increase the risk of cardiovascular events in a dose-dependent manner.” Although celecoxib is still on the U.S. market, it comes with a strict “black box” warning.

The article by Antman et al. stated the hypothesis that the increased risk for CV events is due to a shift in the prothrombotic/antithrombotic balance on endothelial cells. The shift leans toward thrombosis. It is believed this occurs because platelet aggregation is COX-1-dependent and so this mechanism would still work. In addition, COX enzymes catalyze the production of prostacyclin in endothelial cells which can disrupt platelet aggregation. So selective COX-2 inhibition would keep COX-1 activated while decreasing prostacyclin production and thus decreasing antithrombotic activity. The hypothesis also includes the fact that COX-2 inhibition increases sodium and thus water reabsorption (which can cause edema) and can increase risk for heart failure and hypertension (since activation of COX ultimately causes “local smooth muscle cell relaxation and vasodilation” and this would be inhibited).

The article concludes basically by saying that patients who must have NSAID treatment should first try acetaminophen or aspirin, the least risky NSAIDs. If this doesn’t work, then they should be prescribed nonselective NSAIDs. Selective COX-2 inhibitors should only be prescribed if absolutely necessary, and in the lowest dose and for the shortest duration possible. Any patients with a medical history of CV problems should seriously weigh the risks and benefits.

Warfarin or the generic form Coumadin is a commonly used prescription drug that is used to prevent stroke in patient suffering from chronic atrial fibrillation, a heart valve replacement, and/or a recent heart attack. Warfarin is usually referred to as a "blood thinner" or anticoagulant because it keeps blood flowing smoothly throughout the body by decreasing the amount of clotting proteins in the blood. This medication is classified has having a low therapeutic index(i.e. there is a small margin between a normal recommended dose and a potentially lethal dose).
Since the topic this week is Anti-inflammatories and warfarin has a extremely high level of protein binding, there is a possibility that Warfarin may interact with NSAIDs. Along with the affinity for protein binding, it also can cause partial metabolic inactivation by prehepatic and hepatic CYP2C9. The medications that can cause adverse reactions include aspirin, ibuprofen, naproxen, and celecoxib(Celebrex). The complications start because the NSAID's and the COX-2 inhibitor are also extremely prone to bind to proteins in the blood(~99%) and can therefore displace the protein binding for warfarin. This can then lead to free blood levels of non-binded warfarin which can lead to the increased risk of GI or other types of hemorrhagic diseases.
Another factor that could lead to the increased GI bleeding is that each of these drugs can have an effect of the clotting profile of the blood such as inhibition of potassium dependent clotting factors suppressed by the Warfarin and the inhibition of the COX-1 in the platelets and GI mucosa caused by the NSAID's. It could be recommended then that NSAIDs should be avoided while taking anticoagulants such as Warfarin and Coumadin and to use a mild pain reliever such as Acetaminophen or Tramadol as the alternative.

Mechanism of Action of Aspirin-Like Drugs

The Cyclooxygenase enzyme, also known as COX, is responsible for prostaglandin synthesis. There are two isoforms that were studied in this paper, COX-1 and COX-2. COX-1 is constitutively expressed; whereas, COX-2 is known as the inducible isoform. These enzymes serve a variety of functions in several vital regions of the body, but for time sake I will just discuss a few examples of their functions, and some things I found interesting.

COX-1 is known for its importance in maintaining normal physiological function in the body, and to perform the housekeeping job in synthesis of protective prostaglandins, particularly important in the stomach. PGs are cytoprotective in the sense that they work to prevent gastric erosion and ulceration. For example, in the GI tract, COX-1 activation leads to the production of prostacyclin, which reduces secretions of gastric acid and causes vasodilation at the mucosa. Furthermore, the prostanoids stimulate the secretion of viscous mucus, gastric fluid, and duodenal bicarbonate. The mucus acts as a protective barrier in combination with the alkaline environment that helps neutralize any excess acid. Also, COX-1 in platelets causes thromboxane A2 production, leading to platelet aggregation (a clotting factor.) COX-2, on the other hand, is induced by inflammatory stimuli and cytokines, and functions more in inflammation situations. It is highly expressed in human and animal colon cancer cells, and in human colorectal adenocarcinomas. The increase in PG synthesis can be controlled by nonsteroid anti-inflammatory drugs selective to the particular COX enzyme.

Nonsteroid antiinflammatory drugs (NSAIDs) are aspirin-like drugs that inhibit the activity of the COX enzyme. Since the two isoforms are found at different levels of concentration at different sites in the body, and have various functions, inhibition of them also has different effects. Different NSAIDs are selective to the different isoforms. Among other functions, COX-2 inhibitors are used as anti-inflammatory agents, and have been used in the treatment of rheumatoid arthritis and osteoarthritis. They are also show promise in the inhibition of colorectal tumor cell growth and in delaying premature labor! COX-1 inhibitors are thought to cause some side effects, including GI and renal toxicity. NSAIDs that are selective to COX-2 may have less side effects that current ones used.

The COX enzymes serve a variety of functions and are found all over the body; they are especially important in the GI tract(as discussed), kidney, brain and spinal cord. To discuss all of these in detail would take up a ton of space, but if you have any questions regarding one of these areas, do not hesitate to ask….I have read all about it! =) However, here’s a brief description of some interesting info from some areas of study.

Kidney-"Prostaglandins are important for normal kidney function in both animal models of disease states and in patients with CHF, liver cirrhosis and renal insufficiency." Thus, when NSAIDs reduce PG synthesis, it can cause problems(e.g. increased risk for renal ischemia.) Kidney cells that produce PGs contain mostly COX-1.
Brain & SC- COX-1 is abundant in the forbrain, where PGs might be involved in complex integrative functions, like control of the ANS!
Gestation/Parturition-PGs are important for inducing uterine contraction, which is why NSAIDs are used to delay labor. COX-1 in the amnion may be essential for pregnancy maintenance via PG synthesis. COX-1 and COX-2 are expressed in the uterine epithelium at different times in early pregnancy and could be important during implantation of the ovum AND significant in angiogenesis important for the placenta!

Parkinson's, Nicotine and Caffeine

Since we learned in PSIO 480 that caffeine may play a role in decreasing the incidence of Parkinson’s Disease (PD), I wondered if there was any more recent research on this. I found this study by Singh et al published this past February in the journal Brain Research.

Although previous studies have shown neuroprotective effects of caffeine and nicotine against PD (see article’s references), no conclusion of the exact mechanism has been made. This study attempted to determine the effect of caffeine and nicotine on toxicant responsive enzymes and vesicular monoamine transporter-2 (VMAT-2), which are involved in chemically-induced PD. Since decreased expression of toxicant responsive genes such as CYP1A1 and VMAT-2 result in cellular damage and since this altered expression is seen in chemically-induced PD, the authors hypothesized that caffeine and nicotine may have an effect on these genes and proteins.

The study used an accepted model of chemically-induced PD that includes giving animals a chemical called MPTP, which is “a contaminant in synthetic heroin.” The study pre-treated mice with caffeine, nicotine, or saline (control) for 8 weeks. Then the animals were divided into subgroups, where some did not receive MPTP and other groups were co-treated with MPTP and caffeine or nicotine for 1 day to 4 weeks.

Biochemical analysis was performed on the striatum of the mice. Results showed that MPTP decreased dopamine in mice, but mice co-treated with MPTP and caffeine or nicotine had less of a decrease in dopamine compared to controls. Also, MPTP decreased CYP1A1 and VMAT-2 expression, while mice pre-treated with either caffeine or nicotine showed significant reversal of this decrease. All in all, caffeine and nicotine showed a reduction in toxicity of chemically-induced PD.

BUT, I am definitely not endorsing smoking or excessive caffeine-drinking!


Here's the journal article citation:
Singh S et al: Nicotine and caffeine-mediated modulation in the expression of toxicant responsive genes and vesicular monoamine transporter-2 in 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's Disease phenotype in mouse. Brain Research, Feb. 2008

Alzheimer's and Neurofibrillary Tangles

The articles we have read about Alzheimer's have focused on the amyloid-beta pathology. The other part of Alzheimer's disease is the formation of neurofibrillary tangles. Neurofibrillary tangles are composed of tau proteins that have abnormally formed because of overactive enzymes. Tau proteins are a microtubule associated protein. Tau proteins are important for assembling tubulin monomers into microtubules. Tau proteins also serve a structural purpose by maintaining the cytoskeleton and helping axonal transport. Neurofibrillary tangles form when there is a hyper-phosphorylation of tau protein and it becomes insoluble and forms aggregates. The tangles result in the death of cells and this is the role is plays in Alzheimer's disease.

Drink Apple Juice Now Before You Forget

I found this article of a study done.  It says that eating aple related product could help with memory loss and alzheimer like symptoms.

Here the link to it

www.brightsurf.com/news/headlines/22731/Age-related_memory_improvement_linked_with_consumption_of_apple_products.html

For other neurological degenerative news here's another link

www.molecularneurodegeneration.com/news

Apitherapy

I was really interested in the Bee sting therapy of Multiple sclerosis which is also known as apitherapy. According to A Randomized Crossover Study of bee sting therapy for Multiple sclerosis, apitherapy has no significant affect on M.S. patients. So I tried to see if there were any other studies out there that say otherwise. Most of what is out there is proposed studies; very little research has already been done. What I found out was that apitherapy may be affective in treating other health problems such as tendonitis, fibromyositis and rheumatoid arthritis. These health problems appear ideal for this anti-inflammatory treatment. For the most part I found testimonials of those who swore by apitherapy. I noticed that those who swore by it would never have met the criteria that would allow them to participate in any study not being well enough to participate. If such people where allowed, I wonder how it would affect future studies.

Leprosy and Neurodegeneration

In Anura Rambukkana's study, published in Nature Medicine, showed that the leprosy bacteria, Mycobacterium leprae, attaches to myelinated Schwann cells and induces rapid demyelination. This demyelination can occur in the absence of immune cells, which is the cause of demyelination in neurodegenerative diseases, but the process is chronic and relatively slow despite high levels of the M. Leprae.

Type-1 leprosy reactions are idiopathic episodes of strongly increased inflammation and cell-mediated immune reactivity which are frequently accompanied by acute inflammation of peripheral nerves. This peripheral inflammation often leads to extensive and irreversible nerve damage. Immunosuppressive drugs are often a treatment to prevent further nerve damage.

This information suggests that inflammatory immune reactions play an important role in leprosy nerve damage and that the mere presence of M. leprae does not explain the full extent of leprosy nerve damage. Inflammatory responses seem to be necessary for the complete manifestation of demyelination, like in other neurodegenerative diseases.

Though the mechanismas are not entirely clear, it is believed that there are two phases of M. leprae actions. The early phase consists of specific targeting of peripheral nerves and contact dependent demyelination. The other phase consists of increase immunity and inflammation, where acute and extensive nerve damage happens, mostly contributed by cytokines and immune effector cells.

The human immune response plays an important role in the full expression of leprosy nerve damage.

http://www.sciencemag.org/cgi/content/full/296/5569/927?ck=nck

Randomized Cross Over Study For Bee Sting Therapy in MS

MS is a demyelinating disorder of the CNS (these axons unlike in the PNS cannot regenerate themselves) Treatment of MS does not invlove ridding the patient of the disease. Medical limitations allow only to alleviate the symptoms in hopes of the patient leading as normal a life as possible. Because of this, many people suffering with MS are open to trying alternative therapy, one includes bee sting venom. Bee sting venom contains anti inflammatory substances. Esentially, disease progression is characterized by an abnormal immune response in the central nervous system.
In relapse-remitting MS (85-90% of all cases) and secondary progressive MS. It showed no delay in disease progression and no improvement in bettering the quality of life.
Knowing how MS affects patients, it would be wise to experiment with different methods to somehow insert Na+ channels in areas of axons that have been demyelinated. Only then will action potentials propagate.
By stopping inflammation, I don't see how this would better the patient, they would remain diabled. What do you guys thinks???

Fibrin Deposition Accelerates Neurovascular Damage and Neuroinflammation in Mouse Models of AD

A characterisitc of Alzheimer's Disease in neurofibrillary tangles and amyloid plaques. It is these amyloid plaques that are beleived to be the reason for neurodegenitive degradation by acting either as a neurotoxin or an inflammatory response. Fibrinogen (a precursor to and the inactive form of Fibrin) is a stabilizing component of blood clots. Typically it is not seen in the central nervous system because of its inability to penetrate the blood brain barrier. However, with neurological damage, fibrinogen in able to enter the brain's vascular system. In patients and mouse models with AD, researchers have noticed an increased deposition of fibrinogen. In those with an increase in the protein, wound healing is impaired and there seems to be a higher mortality rate. Because inflammation is seen in those patients with fibrinogen, it is beleived that fibrinogen either initiates or augments the degree of inflammation.
Paul et al. set out to examine this hypothesis by determining the blood brain barrier's permeability to fibrinogen in three mouse models. In mice with AD, they found both damage to the blood brain barrier (BBB) and fibrin, the active form of fibrinogen.
Paul et. al are confident that fibrin plays a role in AD progression. This is evident because they used a mouse model with AD to induce fibrin deposition and reduce fibrinolysis and the pathology worsened.
Paul et. al used Evan's Blue Dye (which binds to albumin; a protein found in the blood) to track the permeability of the blood brain barrier. Each of the three mice had different strains of AD which display different characteristics as far as disease progression and age of onset. It was consistent with each model that the BBB was comprimised due to the movement of this dye across the BBB. They biopsied portions of the cortex to determine endothelial cell health as well as its ability to repair itself upon inflicted damage. Endothelial cells showed reduced response to signaling indicating an inability to become aware of damage. The BBB showed to be permeable to albumin so it was assume that macromolecules such as fibrinogen would have access as well. So overtime, fibrinogen/fibrin would accumulate thereby increasing disease progression.
So based on this evidence, wouldn't it make sense to encourage fibrinolysis in the models to determine whether or not this slowed or halted disease progression? Paul et. al used this information to devise another experiment to test whether or not this would work. In the case of fibrinogen inhibition, the models seemed to have reduced inflammation and protected from degradation by plasmin (a protease). Plasmin works to destroy blood clots before the dislodge and become an embolism.
The only thing I found conclusive of the article was that fibrinogen/fibrin is an upstream mediator of inflammation. Does anyone know plasmin's role in AD. In this article it mentions that plasmin has damaging effects to the BBB as well.