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Treatment Overview What is a Drug?

Last update: 06/29/2013

 

ON NATURAL MEDICINES 

Andrew Dodds writes:

"It isn't very surprising that plants contain anti-cancer chemicals; they have being fighting a biochemical war against the world's animals for approximately 300 million years (land plants, anyway..) and have hence evolved chemicals that probably interfere with virtually every biochemical pathway that exists. Hence it is very likely that there are chemicals out there that interfere with those chemical pathways crucial to the survival and proliferation of cancer cells.

However, this does NOT mean that 'natural is best'. First, the compound in question will only fight cancer as a secondary effect to it's primary purpose (killing an insect that feeds on the plant, for instance). Hence a synthetic derivative may be far more effective.

Second, the [natural] compound may be too unstable in vivo, so again a synthetic derivatives will be more successful.

Thirdly, useful dose ranges (between ' no effect' and 'killing the patient') may be quite narrow, making direct consumption of leaves/bark/etc either ineffective or highly dangerous or both.

In short, the 'big pharma' versions of these 'natural' drugs are going to be more effective.

That does not mean that all information from these companies should be taken uncritically at face value - you should always look closely and critically at the real data supporting the claims made. However, at least this is possible. With alternative 'cures', all you get is the marketing."

posted by Andrew Dodds to

scienceblogs.com 

 

HETEROGENEITY:

One reason cancers are challenging to treat is the molecular processes and mutations within the cells can vary, even within the same types of lymphoma, sometimes partly nullifying how well a drug works, even in different patients with the same diagnosis. 

Still another challenge of determining safe and effective drug dosage is related to inherited  differences in patients known as normal genetic variations or genotypes.  These normal individual variations, similar to what determines our eye color, can affect the clearance rates of drugs. 

To deal with these variations (the heterogeneity of the disease and the patient), a personalized approach to medicine is evolving. 

Advanced tests, such as molecular profiling, is slowly becoming the basis for therapies tailored for individual patients.  Investigators are actively designing and validating the new tools that are essential  realizing this goal. (See for details NBN)

Accelerating progress also requires adopting common standards and platforms for sharing data across trials. We need more coordination and research to account for the variables underlying the myriad molecular pathways of disease. We may need to protect or increase incentives to achieve these goals …and more aggressive leadership in this area.

Preclinical research must be better able to predict active and toxic agents before the human phase of development as in the FDA's Critical Path. Studies that incorporate molecular profiling and less toxic immunotherapies may  be more reasonable as treatment decisions to patients concerned about the risks of new investigational  therapies. 

In addition to answering important clinical questions, studies must be reasonable as treatment decisions both to the participant and their physicians - not as an afterthought, but at the outset. This should hold true for the first line, relapsed and refractory settings.

It seems also that we should give community doctors incentives to refer patients to trials, perhaps recognition awards could be 

Finally, we need to educate about the process and the importance of participating in credible medical research. We must address misinformation and wishful thinking about some alternative practices, which by definition have not been evaluated objectively.

 

SPECIFICITY

For cancer therapy the state of the art is still mainly chemotherapy, which has some degree of specificity ... because most chemo agents are selectively  toxic to dividing cells. Thankfully!, blood cell cancers are typically  highly sensitive to chemo- and radio-therapies. But we need to improve on  this. 

The big improvement in recent years has been from antibody therapy: Rituxan  and RIT. Here the specificity is improved: The range of cells affected by  therapy are reduced dramatically to one type: mature b-cells that express  cd20 - normal and malignant. Importantly, immature normal b-cells are not  effected, because they do not have cd20, allowing new mature b-cells to replace those eliminated by treatment.

Anyone trying to get rid of dandelions understands the concept of  specificity. You can spray the entire lawn with chemical - a systemic approach. The chemical sticks mainly on broad leaf plants. But this method  also does harm to the living soil, the ground water, and to beneficial plants and  critters.

(For the record, I hand pick them ... highly specific, but this approach is  unrealistic on a large lawn!)

The way our immune systems works to remove infection and cancers is highly  specific. 

You get the mumps once, because your immune system recognizes the unique antigens of the mumps virus. Once eliminated, memory cells remain on guard and will execute a fast and furious assault on the virus should it ever try to reenter the premises. It's so efficient that you'll not even know that the battle occurred.

Both the positive and negative impact of immunity on lymphomas is not fully understood (not nearly so), but knowledge about it is accelerating, and a consensus is emerging that immunity against lymphoma plays a significant part in clinical outcomes ... in how fast or slow the lymphoma progresses; in spontaneous regressions; and even in the durability of the response to standard therapy.

Progress is accelerating in immunotherapy, because of recent breakthroughs, such as  how to target immune checkpoint blockade - how cancers cells put the immune Effector cells to sleep, and because of adoptive t-cell therapy - the development of living drugs that are designed to target cancer cell molecules on the cell surface, such as cd19 (CART 19)

See also Agents that target disease pathways

We are entering an exciting and promising era in cancer therapeutics.  Our goal is to foster a general understanding of how agents (standard and targeted) for lymphoma are thought to work - as an aid to informed consent.  

A little History

Our ancestors have used plants, minerals and animal parts as medicines to relieve pain and suffering from disease.  Today the endeavor continues, aided by insights into how drugs act against disease, and, of course, a much better understanding of disease processes, but also the ability to modify drug compounds in order to better target disease processes or reduce toxicities. 

Still the answers cannot come quickly enough, and people continue to die and suffer from cancers and other diseases.  The process of drug discovery and testing is not fast enough, or efficient enough.  "The patients are waiting."

(See sidebar on NATURAL MEDICINES.) 

The objective here is to answer some basic questions about drugs:

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What is a drug?  

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What makes a drug active?  

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What makes it effective?  

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How do drugs work?

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Terms like:  affinity, specificity, pathway, PK, mechanism of action, synergy ...

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Why does it take so long to develop and test new drugs for cancers? 

What is a Drug?

The first question is the easier to answer.  A drug is a compound used (ingested, infused, or applied)  to correct, slow down, or relieve a medical condition.  A definition that could apply to chicken soup for the common cold, or to Cytoxan for a cancer.   For the first example, the mechanism is lacking and the evidence is thin.

A distinction should be made between a food and a drug.  Foods provide energy and nutrients to support health and functions. Most drugsmust be absorbed into the blood at sufficient levels to affect the disease process.   

Notably, FDA oversight begins when medical claims are made for the intervention. 

Chicken soup is a food, of course, but if promoted as a cancer cure, it could then be regulated as a drug, and the sponsor would have to prove it first before being able to market it as such.  

Is the drug active?  Is it effective? 
What's the difference?

An active drug stops or interrupt a disease process, such as cell division in cancer. However, an active drug is not necessarily an effective drug, because the side effects might offset the positive effects.

For example, you might shrink a tumor with a new compound, but also do greater harm to bone marrow function. That is, an active drug may not help the patient to live better or longer, even if it's active against the disease.

An effective drug is one that has been proven to provide a net benefit: the positive effects exceed the negative and the patients are better off to use the intervention than to let the condition run untreated, or treated with another drug.

In other words, an effective drug is one that provides clinical benefit, and the most convincing measure of clinical benefit is when the drug improves survival compared to another effective drug.  This assessment is made possible by randomized clinical trials that test the new drug with the standard of care.  

Note: Sometimes surrogate measures of benefit (surrogate endpoints) are used when it's not feasible to measure survival, such as comparing time to progression in each arm of the study comparing two treatments.

So an effective drug provides clinical benefit, which is best measured by an improvement in survival, but also if it can stop or reverse a disease process when no other therapy can.  An effective drug might also provide relief from symptoms, without impairing survival, or quality of life.

The search for effective drugs starts with agents that seem active in pre-clinical experiments.  

Active drugs interfere with a disease processes. The mechanisms of action (how they work) are many.  It may be useful to think about drugs that are very familiar to us. 

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Aspirin, for example, can help to reduce the sensation of pain by inhibiting inflammatory enzymes in our body.  

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Other painkillers put locks on neural receptors to reduce the sensation of pain.  

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Antibiotics, such as the well-known penicillins,  work by killing bacteria. 
They do this by interfering with the formation of the cell walls or cell 
contents of the bacteria. Other antibiotics work by stopping bacteria from
multiplying.  

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Chemotherapy agents damage rapidly dividing cells, causing the cells 
to self-destruct ... not unlike skin cells do when exposed to too much sun. 

Before aspirin there was willow bark. Opium and cocaine relieved pain. Early scientists extracted and purified the active ingredients from such early natural compounds. Clever organic chemists delighted in fragmenting these molecules in order to find their structures. 

Aspirin and penicillin have been around for a long time, but the drugs that stop and kill cancer cells are among the newest drugs being discovered and fine-tuned. 

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How do scientists develop them?

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How do we know what happens when a drug is received in the body,
introduced by mouth, IV drip, or by patch?   

Drug Discovery or Design

Briefly, the investigation is done in phases: preclinical, clinical (human testing), and regulatory assessment. 

The first task in in the preclinical phase is to find by screening or design a promising compound and then to determine how much of the drug is needed to do the job. The necessary concentration is determined in preclinical experiments involving cell cultures as in the well-known Petrie dish, or with animals.  

(NOTE: This phase is essential to credible drug research. Sometimes herbal products are inappropriately hyped as cancer treatments based on cell culture experiments, without accounting for the concentration needed in the blood to achieve the cell-culture effect, or if that concentration would be toxic.)

Increasingly for cancer and other diseases new compounds are designed to bind to parts of cell that are driving cell survival or proliferation. These abnormal working parts of the cell are called disease pathways

See also Agents that target disease pathways

In the body the drug interacts with, binds to, or disrupts, some process underlying the disease. Targets of the compound can be cell membranes; enzymes, structures or carriers - all proteins - or any one of the cellular chemicals or processes that have been hijacked to keep the disease going. 

The fit between a drug and a body molecule or diseased cell structure is known as affinity

One important goal of therapy related to affinity is specificity ... that the compound binds as exclusively as possible to the target of treatment and minimally impairs normal processes. 

The interaction between drug and disease is known as mechanism of action - how the drug works. 

However, even well-targeted drugs, such as the cancer drug Gleevec, can have off-target effects:  significant side effects, emphasizing the need for caution in the testing of new drugs in human subjects, particularly classes of drugs that work by new mechanisms of action or even when approved agents are combined for the first time.  

A relatively new drug target is found on the surface of cancer cells. These are molecular binding sites. One binding site, known as CD20, is targeted by the drug Rituxan.  Here a mouse/man-made antibody binds to the CD20 receptor which can cause the cell to self destruct, or leads to killing of the tumor cell by immune cells. 

Mab-apoptosis.jpg (24354 bytes)   mab-nk.jpg (38897 bytes)  
          Click antibody engaging b-cell tumor images to enlarge

The field of identifying new potential drug targets is accelerating.  Drug targets may be within the cell, such proteins or genes that prevent cell death, on the cell surface as described above, or the target may be other "normal" cells that contribute to the survival and expansion of the malignant cells in the tumor microenvironment.

Many chemotherapy drugs exploit the overt behavior of cancerous cells - rapid cell division.  The dividing cell more readily takes up the drug, which leads to damage of its DNA (the vital information that determine cell behavior and functions) which is more vulnerable during cell division.  ...


Source: http://www.nih.gov/sigs/aig/ 

... The cell, detecting the damage to its DNA , self destructs in a process called apoptosis, similar to when diminishing light triggers leaves to fall from trees.  

Abnormal cells, being living parts of the body, can adapt to drugs leading to drug resistance.  Here getting the dose right and the rationale combination of drugs can minimize the ability of the cells to adapt and survive.    Combining drugs can have an ad

There can be an additive or synergistic effects when combing drugs agents.  Also it's possible that one active agent can work against the mechanism of another active agent (as an agonist) - such as when the second agent causes cell cycle arrest, which is needed for first agent to work.

Additive:      1+1 equals 2
Synergistic:  1+1 equals 3
Agonistic:     1+1 is less than 2 

Researches will also study the mechanisms of resistance. To do this they will need tumor sample from the participants of studies - samples before and after resistance to identify what pathways are turned on in the cells that survive the targeted agent - that may also be targeted. ... As was done with Gleevec.

Identifying the Right Dose: the therapeutic window

The dose differentiates a remedy and a poison. ~ Paracelsus

That a compound is active is just the starting point in the drug development process. 

The agent might be highly toxic at the concentration needed be active in a test tube (In vitro).  Or it may not be absorbed well if taken orally, or it may be cleared too quickly to have a meaningful treatment effect in the body (in vivo).

Thus, pharmacokinetics (PK) is an essential part of new drug development and assessment in the clinical phase.  It's the study of what your body does to a drug. The initial PK research is carried out on animals and then ever-so-slowly and carefully in humans.  See also Wikipedia.org

How long the drug remains in the bloodstream, and at what concentration, are vital to the safety and effectiveness of drug, which are determined by

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Absorption

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Distribution

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Metabolism and 

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Excretion 

(ADME for short). 

The organs that have a major impact on ADME are the liver and the kidneys and therefore liver and kidney function are monitored very closely when new drugs are first administered in humans.

Individual differences in ADME can result in faster or slower clearance of the drug from the body.. Differences in clearance rates can affect the course of treatment and severity of side effects. 

(See also the side bar on HETEROGENEITY.)


If the drug remains in the blood too long it can increase side effects. Conversely, a drug that's excreted or cleared too rapidly will not be around long enough, or at the proper concentration, to do its job well. 

Moreover, interaction with other drugs or herbs can affect how drugs are absorbed or cleared from the body. 

Yet another vital aspect of the drug development and testing is the called pharmacodynamics, or PD, which is the study of the effects of drugs on the body or on disease processes within the body and the mechanisms of drug action and the relationship between drug concentration and effect.  See also Wikipedia.org

The objective of PD studies is to identify the therapeutic window:  the dose needed to achieve sufficient levels of the agent in the blood at acceptable toxicity. 

The larger the therapeutic window the more likely the drug can be administered in a safe and effective protocol. 

If the new drugs shows reasonable safety and activity in early phases of clinical trials, it is then tested against approved therapies in large randomized controlled clinical trials.  The goal of phase III studies is to objectively determine the safety and efficacy in a way that minimizes bias.  

Notably, failures outnumber successes in the drug development process.  Only 1 in 5,000 new compounds evaluated in the preclinical stage makes it to the clinic ... and about 1 in 5 new therapies that reach phase III clinical testing. 

The regulatory evaluation of the data submitted by the sponsor for marketing approval does not take very long ... about 6 to 9 months; while the preclinical and clinical testing phase can take ten years or longer.  The cost to the sponsor can exceed 1 billion dollars.  

Because the financial risks of cancer drug development are high and most new drugs fail to win approval, incentives (primarily in the form of marketing exclusivity) are granted to new drugs that win approval.  

See also Patent  http://en.wikipedia.org/wiki/Patent 

See also Treatment mechanisms | Treatment types 

 
Disclaimer:  The information on Lymphomation.org is not intended to be a substitute for 
professional medical advice or to replace your relationship with a physician.
For all medical concerns,  you should always consult your doctor. 
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