Advances in Clinical Pharmacology
The fields of medicine, biotechnology and pharmacology are all involved in the design of new drugs and their production. Historically, drugs were formed by taking the active ingredient from traditional remedies or by serendipitous discovery. Early examples of this are morphine, which is isolated from opium, still used today in pain treatment; another is digoxin which originates from Digitalis latana and is used to stimulate the heart. Advances in molecular biosciences and biotechnology have led to new approaches to drug design.
The main basis of drug action is that a compound (a ligand) will bind to a target in the body and alter it's structure and or function. This leads to a physiological change which is the therapeutic consequence in treating a disease. If the ligand can bind to more than the specific target this can cause unwanted side effects. An effective drug will need to have minimal adverse effects, or at least, side effects that are less dangerous to the patient than leaving them untreated. The more specific the ligand is, the more specific the therapeutic response will be and thus the better the drug.
Modern Drug Design
Despite many advances in the field of pharmaceutics and many revolutionary drugs being brought into wide clinical use, the process is still lengthy, expensive and in many cases not very effective. The process of designing a drug involves the identification of candidates, synthesis, characterization, screening, and assays for therapeutic efficacy. Once a compound has been shown to be successful in these areas, it is developed into a drug and then progresses to clinical trials.
There are two main types of drug design currently used in pharmaceutics. The first is ligand based drug design. This relies on the knowledge of molecules that bind to the target site of interest. These can then be modified to form a pharmacophore which is the minimum structural form that the ligand must have in order to interact with the target. These can then be developed into new molecular entities.
The second main type of drug design is structure based. This relies on the knowledge of the precise 3D structure of the biological target. This involves finding the active site and then the precise structure is found using techniques such as X-ray crystallography or NMR spectroscopy. Using this structure, drugs can be predicted to bind with high affinity and specificity. It is the advances in the imaging techniques of the 3D structures that have lead to an increase in the effectiveness of this type of drug design. The ligands can be found in two main ways. The first is by screening a database of known ligands for one that is a possible match for the structure found by imaging. The second, is a more lengthy process as it involves building the ligands within the constraints of the binding pocket from either atoms or fragments. This method has led to some exciting results as the ligands formed are completely novel.
As part of the investigation as to the effects of a drug in the body pharmacokinetics must also be considered. This involves finding out the pathway and effects on the molecule as it passes through the body. This starts with the absorption of the drug which affects what the most effective administration will be, whether oral, injected, topical etc. The next stage to be considered is the distribution around the body. Depending on the volume of distribution that reaches the target tissue, this will affect the optimal dose given. The drug is then metabolised, a process which normally occurs in the liver. The rate of metabolism and the molecules that are produced need to be considered in the dosage as there needs to be sufficient time for action of the drug and also the production of toxic metabolites needs to be avoided. Finally the drug is eliminated from the body and this mainly involves the kidneys. The effect on the kidneys needs to be investigated; many potential drugs have been removed from clinical trials due to their damaging effect on the kidneys. Much of the investigation of the pharmacokinetics will lead to the rational prescribing of the drug.
This involves studying the drugs for any adverse effects they may have on humans. It includes investigating the symptoms, mechanisms, detection and treatment of poisoning of people. The toxicity of a substance is related to the dose at which it is administered. The LD50 of a drug is the dose at which 50% of the test population are killed. Finding the correct dose is and important part of clinical trials and must be kept well below the toxic level.
There are many instances whereby particular substances can interact with drugs. This can lead to very dangerous consequences or it could just reduce the effectiveness of the drugs in use. These interactions can involve enzyme induction, enzyme inhibition or affect the bioavailability. There are many known dangerous interactions of substances and these are carefully avoided by the prescribing physician.
Current Drug Developments
The company GlycoMimetics, Inc. have made some some very recent advances in the development of new targets and compounds with potentially extensive therapeutic use. All of their drugs are based on carbohydrate compounds. Despite the importance of carbohydrates in biological processes of both health and disease, they have previously been unused in the design of drugs, due to the poor pharmaceutical properties of naturally occurring molecules. The company have taken a new, successful, approach to the development of new compounds that mimic carbohydrates. They are capable of targeting carbohydrate processes involved in disease.
GMI-1070 is one of the compounds that has been developed by GlycoMimetic, Inc. It is an inhibitor of E-, P- and L-selectins which are involved in the process of recruiting neutrophils forming a key stage in the inflammatory process. This has been shown in animal studies to restore the blood flow to occluded arteries in animals with a vaso-occlusive crisis as a result of sickle cell disease. GMI-1070 has successfully passed Phase 1 clinical trials and is now moving into Phase 2 trials.
In areas of advancing medical research such as this, global communication is an inevitable part of the development of new drugs. At TJC Global, our experienced linguists can offer translation services for documents, research, histories and records and interpreting for conferences, clinical meetings, consultations, symposiums and other settings to ensure that language is not a barrier.