RESEARCHERS DISCOVER POTENTIAL DRUG TARGET FOR EARLY ONSET OF GLAUCOMA

Using a novel high-throughput screening process, scientists have for the first time identified molecules with the potential to block the accumulation of a toxic eye protein that can lead to early onset of glaucoma. Researchers have implicated a mutant form of a protein called myocilin as a possible root cause of this increased eye pressure. Mutant myocilin is toxic to the cells in the part of the eye that regulates pressure. These genetically inherited mutants of myocilin clump together in the front of the eye, preventing fluid flow out of the eye, which then raises eye pressure. This cascade of events can lead to early onset-glaucoma, which affects several million people from childhood to age 35.

To find molecules that bind to mutant myocilin and block its aggregation, researchers designed a simple, high-throughput assay and then screened a library of compounds. They identified two molecules with potential for future drug development to treat early onset glaucoma.

"These are really the first potential drug targets for glaucoma," said Raquel Lieberman, an associate professor in the School of Chemistry and Biochemistry at the Georgia Institute of Technology in Atlanta, whose lab led the research.

Lieberman presented her findings on January 20 at the Society for Laboratory Automation and Screening conference in San Diego, Calif.

The study was published on Nov. 26, 2013, in the journal ACS Chemical Biology. The National Institutes of Health and the Pew Scholar in Biomedical Sciences program provided support for the research. The work was a collaboration involving Georgia Tech, Emory University and the University of South Florida.

At the heart of the study was an assay that Lieberman’s lab created to take advantage of the fundamental principles of ligand binding. In their assay, mutant myocilin is mixed with a fluorescent compound that emits more light when the protein is unwound. When a molecule from the library screen binds to myocilin, the pair becomes highly stable - tightly wound - and the fluorescent light emitted decreases. By measuring fluorescence, researchers were able to identify molecules that bound tightly to mutant myocilin.

The researchers then added these molecules to cultured human cells that were making the toxic aggregating myocilin. Treating the cells with the newly identified molecules blocked the aggregation and caused the mutated version of myocilin to be released from the cells, reducing toxicity.

"We found two molecules from that initial screen that bound to our protein and also inhibited the aggregation," Lieberman said. "When we saw that these compounds inhibited aggregation then we knew we were onto something good because aggregation underlies the pathogenesis of this form of glaucoma."

In a separate study, Lieberman's lab characterized the toxic myocilin aggregates. That study was published in December 2013 in the Journal of Molecular Biology. The study found that myocilin aggregates are similar to the protein deposits called amyloid, which are responsible for Alzheimer’s disease and other neurodegenerative diseases.

"In Alzheimer's disease, the deposits are extracellular and kill neurons. In glaucoma the aggregates are not directly killing neurons in the retina to cause vision loss, but they are cytotoxic in the pressure-regulating region of the eye," Lieberman said. "It's parallel to all these other amyloids that are out there in neurodegenerative disease."

The researchers are now focusing on mapping the structure of myocilin to learn more about what myocilin does and why it is in the eye in the first place.

"The underlying problem with myocilin is that for 14 years it has been studied and still nobody really knows what its biological role is inside the eye," Lieberman said.

CLEVER CHEMISTRY AND A NEW CLASS OF ANTIBIOTICS

As concerns about bacterial resistance to antibiotics grow, researchers are racing to find new kinds of drugs to replace ones that are no longer effective. One promising new class of molecules called acyldepsipeptides - ADEPs - kills bacteria in a way that no marketed antibacterial drug does - by altering the pathway through which cells rid themselves of harmful proteins.

Now, researchers from Brown University and the Massachusetts Institute of Technology have shown that giving the ADEPs more backbone can dramatically increase their biological potency. By modifying the structure of the ADEPs in ways that make them more rigid, the team prepared new ADEP analogs that are up to 1,200 times more potent than the naturally occurring molecule.

A paper describing the research was released on-line by the Journal of the American Chemical Society.

"The work is significant because we have outlined and validated a strategy for the enhancing the potency of this promising class of antibacterial drug leads," said Jason Sello, professor of chemistry at Brown and the paper's senior author. "The molecules that we have synthesized are among the most potent antibacterial agents ever reported in the literature."

ADEPs kill bacteria by a mechanism by that is distinct from all clinically available anti-bacterial drugs. They work by binding to a protein in bacterial cells that acts as a "cellular garbage disposal," as Sello describes it. This barrel-shaped protein, called ClpP, breaks down proteins that are misfolded or damaged and could be harmful to the cell. However, when ClpP is bound by an ADEP, it's no longer so selective about the proteins it degrades In essence, the binding by ADEP causes the garbage disposal to run amok and devour healthy proteins throughout the cell. For bacteria, a runaway ClpP is deadly.

ADEPs have been shown to kill bacteria that cause staph infections, some kinds of pneumonia, tuberculosis, and other types of infection in the lab. The molecules have also been reported to cure bacterial infections in mice and rats.

ADEPs were first discovered as naturally occurring compounds. Certain bacteria produce them for chemical defense. But for the last few years, scientists including Sello's group have been making synthetic ADEP analogs, in the hope of identifying compounds with potential as new drugs.

One approach the researchers thought might work involves making the ADEP molecule more rigid. Compared to the ClpP molecule to which it binds, the ADEP molecule is a bit "floppy," Sello said. "We often use the expression 'lock and key' to describe how a small molecule binds to a protein. One can imagine that it is easier to fit a rigid key into a lock rather than a floppy key. In the same sense, rigid molecules often bind to their protein targets more tightly."

Sello and his team synthesized several new ADEP molecules. They swapped out certain amino acids in the naturally occurring molecule with ones they thought might increase the molecule's rigidity. To find out if the new molecules were indeed more rigid, the team performed experiments that tested the strength of hydrogen bonds within the molecule. Stronger hydrogen bonds would indicate a more rigid molecule.

The researchers placed ADEP molecules in a solution rich in deuterium, a hydrogen atom that has an extra neutron. Over time, the deuterium atoms in the solution will swap places with the hydrogen atoms in the ADEP molecules. The deuterium swap happens more slowly, however, when hydrogen atoms are involved with strong bonds. So if the modified ADEPs exchanged deuterium more slowly, it would be an indication of strong bonds and a more rigid molecule.

The experiments showed that the modified ADEPs exchanged deuterium as much as 380 times more slowly than the natural molecule, a clear indication that the molecules were more rigid.

"It was exciting to see how rather simple modifications to the ADEP structure could affect their rigidity in such a profound manner," said Daniel Carney, a graduate student in Sello's group. "More importantly, the results were in line with our ADEP design principle. It is always rewarding when a sophisticated chemical theory can be applied and validated by laboratory experiments."

To follow up on the prediction that the rigid ADEPs would bind ClpP more tightly, Robert Sauer and Karl Schmitz at MIT measured the capacity of the ADEP analogs and the parent compound to produce the "runaway garbage disposal" phenomenon in solutions containing the ClpP protein. The experiments showed that the modified ADEPs produced the effect at much lower concentrations, indicating a higher binding efficiency. The results implied that the modified molecules were about seven times better than the standard ones at binding to ClpP.

The final step was testing whether the rigid ADEPs were better at killing bacteria in a test tube. Those tests showed that, compared to published reports for standard ADEPs, the modified compounds were much more potent against three different dangerous bacteria - 32 times more potent against S. aureus, 600 times more potent against E. faecalis, and 1,200 times more potent against S. pneumoniae.

Sello was a bit surprised by the dramatic increase in ADEP potency compared to the much more modest improvement in ClpP binding.

"We found that the most potent ADEP analog binds ClpP seven-fold better than the parent compound, yet it has 1,200-fold better antibacterial activity," Sello said. "We believe that some of the increase in potency may stem from the fact that the rigidified ADEPs bind ClpP more tightly and have an enhanced capacity to cross the cell membrane. The improved cell permeability of the ADEP analogs is consistent with reports in the literature that molecules with strong intramolecular hydrogen bonds are particularly good at penetrating cells."

Antibacterial Soaps Don’t Work and May Cause Harm Says the FDA

“Now a Days There is recently no evidence that they are any more effective at preventing illness than washing with plain soap and water.”
Anti-bacterial soaps make kill your hands of germs easy, right? Just a few squirts and you’re germ-free … well, at least that is what the makers of these soaps tell us.
According to the Food and Drug Administration (FDA), anti-bacterial soaps make some pretty lofty claims but may not be all that they are marketed to be. The federal agency that monitors the safety of food and drugs in our country released a statement noting that they have seen no evidence that antibacterial soaps perform better at arresting the spread of germs than non-antibacterial soaps that make no germ-fighting power claims. This release comes out of an ongoing review into the safety and efficacy of the active ingredients in the soap.
Dangers of Triclosan
Studies have been revealing the dangers of antibacterial soap for years now. In 2005, research found that the antibacterial agent triclosan reacts with chlorinated water to produce chloroform, a known carcinogen.
 FDA even published a draft stating that triclosan was “not generally recognized as safe and effective.”
Yet the ingredient is included in a wide range of consumer products, most commonly in soaps, but also in everything from toothpastes and cosmetics to kitchenware, apparel and even toys.
Just some of the other dangers of triclosan include:

• Muscle function impairment
• Contribution to heart disease and heart failure
• Alteration of levels of thyroid hormones and reproductive hormones like testosterone and estrogen
• Increased risk of infertility
• Early puberty

Even the typically conservative American Medical Association slammed antibacterial soaps years earlier, stating that there was “undisputed evidence that nothing works better when it comes to hand washing than plain soap and water, without the unnecessary toxic antibacterial chemicals.”
Despite the numerous studies and massive amount of evidence, in 2010 the FDA claimed that it “did not have sufficient safety evidence” to recommend changing consumer use of products that contain triclosan.
Earlier this year: After four decades since its first use, the FDA has decided they would make the determination as to whether or not antibacterial soaps, and specifically triclosan, are doing more harm than good. Government researchers stated that they plan to deliver a review this year of the chemical that has been used for cleaning kitchens and the human body.
A spokesperson for the FDA noted that it is now one of their highest priorities, but the fact that it has taken this long to review something so potentially harmful should make one take notice.
Now, They See It (or at least part of it)
In addition to the agency finding no super powers in antibacterial soaps they claim that they could even cause harm by increasing antibiotic resistance and disrupting hormones. Antibiotic-resistant diseases have greatly increased since the use of products with triclosan, posing an even a greater threat than some plagues.
Starting immediately, the FDA requires that antibacterial soap makers prove that their soaps have some clinical benefit that outweighs the risks of regular contact with antibiotics.
Janet Woodcock, director of the FDA Center for Drug Evaluation and Research, noted
“Due to consumers’ extensive exposure to the ingredients in antibacterial soaps, we believe there should be a clearly demonstrated benefit from using antibacterial soap to balance any potential risk.”
This new requirement comes on the heels of agency plans to buckle down on the use of antibiotics in industrial meat farming and is directly related to the escalation of antibiotic resistance.
The FDA wants to be sure that if Americans are going to spray, pump, wipe and squirt millions of gallons of antibacterial soap on their hands and body each day, that the benefits better outweigh the risks.
Strangely, Hospitals are Exempt
One strange twist to this new regulation is the fact that hospitals are exempt. The FDA explains this exemption by noting that there is a higher risk of disease being spread in a hospital than in other settings.
Their point, odd as it may be, is that these antibacterial soaps, which they claim do not work and can increase the risk of antibiotic resistance, deserve a place not among the healthy but among the sick.
According to the CDC, over one million Americans pick up infections at hospitals, medical offices, outpatient surgery centers and nursing homes every year. Approximately 100,000 of these people die as a result of their infections.
Just Wash the Old Fashioned Way
Often times, in our rush to save time, we compromise our health, as in the case of choosing fast and processed food over whole and nutritious food. Handwashing it seems is no different.
There is really no good replacement for a thorough hand wash using soap and warm water, even it it does take a little more time than a quick rinse with an antibacterial soap. Be sure to wash both the back and front of your hands, as well as between your fingers, for at least 20 seconds and rinse well. Parents can encourage their children to wash for as long as it takes them to sing their ABC’s.

WORLDS TINIEST DRUG CABINETS COULD BE ATTACHED TO CANCEROUS CELLS FOR LONG TERM TREATMENT

Reservoirs of pharmaceuticals could be manufactured to bind specifically to infected tissue such as cancer cells for slow, concentrated delivery of drug treatments, according to new research published in ACS Macro Letters. The findings, from the University of Copenhagen and the Institut Laue-Langevin (ILL), came as a result of neutron reflectometry studies at the world's leading neutron source in Grenoble, France. They could provide a way to reduce dosages and the frequency of injections administered to patients undergoing a wide variety of treatments, as well as minimising side effects of over-dosing.

The attachment of reservoirs of therapeutic drugs to cell membranes for slow diffusion and continuous delivery inside the cells is a major aim in drug R&D. A promising candidate for packaging and carrying concoctions of drugs is a group of self-assembled liquid crystalline particles. Composed of fatty molecules - phospholipids - and tree-like macromolecules called dendrimers, the particles form spontaneously and have the capacity to soak up and carry large quantities of drug molecules for prolonged diffusion. They are also known for their ability to bind to cellular membranes.

The first treatments using such particles are close to market through products incorporating a similar formulation called Cubosomes (cubic phase nanoparticles). Developed and commercialized by Swedish start-up Camarus Ab, its FluidCrystal® nanoparticles promise months of drug delivery from a single injection and the possibility of tuning the delivery to intervals of anything from once a day to once a month. However, a key requirement for optimal application of these formulations is a detailed understanding of how they interact with cellular membranes.

This was the focus of a collaboration between Dr Marité Cárdenas (Copenhagen) and Dr Richard Campbell and Dr Erik Watkins (ILL). In this experiment the team used neutrons to analyse the interaction of the liquid crystalline particles with a model cellular membrane whilst varying two parameters:

Gravity - to see how the interaction changed if the aggregates attacked the cell membrane from below as opposed to above

Electrostatics - to see how the balance between positive and negative charges of the aggregate and membrane affect the interaction

The team utilised a technique known as neutron reflectometry whereby beams of neutrons are skimmed off a surface. The reflectivity is measured and used to infer detailed information about the surface, including the thickness, detailed structure and composition of any layers beneath. These experiments were carried out on the FIGARO instrument at the ILL in Grenoble which offers unique reflection up vs. down modes that allowed the team to examine the top and bottom surfaces, alternating the samples on a two hourly basis during a 30 hour sampling period.

The interaction of the liquid crystalline particles with the membrane was shown to be driven by the charge on the model cell membrane. Subtle changes in the degree of negative charge on the membrane encouraged the tree-like dendrimer molecules to penetrate, allowing the rest of the molecule to bind to the surface, forming an attached reservoir. The sensitivity of the interaction to small changes in charge suggests that simple adjustments to the proportion of charged lipids and macromolecules could optimise this attachment. In the future this characteristic could also provide a mechanism to focus the treatment at targeted cells such as those infected by cancer, which are thought to be more negatively charge than healthy cells.

In terms of gravitational effects, the analysis also showed that aggregates interacted more strongly with membranes when located above the sample. Similar effects caused by differences in density and buoyancy of solutions are already exploited in some stomach treatments and the researchers would encourage future studies into how gravitational effects could be used to optimise these interactions for drug delivery.

"Cancerous cells have an imbalance that gives them a different molecular composition and overall different physical properties to normal healthy cells," explains Dr Cardenas. "Whilst all cells are negative, cancerous cells tend to be more negatively charged than healthy ones due to a different composition of fatty molecules on their surface. This is a property that we believe could be exploited in future research into delivery mechanisms involving the attachment of lamellar liquid crystalline particles. Our next step is to introduce the drug itself into the reservoirs and make sure it can move across the membrane. This work paves the way for cell tests and clinical trials in the future exploiting our methodology."

"Of course it's not new that particles in formulations can sink or float, but such dramatically different specific interactions of these nanocarriers with model membranes of different orientations took us completely by surprise" said Dr Campbell. "Very small sample volumes are often used in biomedical investigations so the effects of phase separation cannot be seen. Our findings suggest that laboratory researchers may need to re-evaluate the way in which they examine the effectiveness of newly developed formulations to account for strong gravitational effects."

Dr Watkins further commented: "This study is a perfect illustration of FIGARO’s unique capability to take data from above and below horizontal interfaces in the same experiment. Not only are neutrons uniquely sensitive to the lighter elements found in organic chemistry but the ability to take all the data at once in situ without disturbing the sample is vital. These biological samples are always subtlety changing throughout the time you are analysing them so it's vital that you can take this data as quickly as possible."

RESEARCHERS DEVELOP ARTIFICIAL BONE MARROW

Artificial bone marrow may be used to reproduce hematopoietic stem cells. A prototype has now been developed by scientists of KIT, the Max Planck Institute for Intelligent Systems, Stuttgart, and Tübingen University (Germany). The porous structure possesses essential properties of natural bone marrow and can be used for the reproduction of stem cells at the laboratory. This might facilitate the treatment of leukemia in a few years.

Blood cells, such as erythrocytes or immune cells, are continuously replaced by new ones supplied by hematopoietic stem cells located in a specialized niche of the bone marrow. Hematopoietic stem cells can be used for the treatment of blood diseases, such as leukemia. The affected cells of the patient are replaced by healthy hematopoietic stem cells of an eligible donor.

However, not every leukemia patient can be treated in this way, as the number of appropriate transplants is not sufficient. This problem might be solved by the reproduction of hematopoietic stem cells. So far, this has been impossible, as these cells retain their stem cell properties in their natural environment only, i.e. in their niche of the bone marrow. Outside of this niche, the properties are modified. Stem cell reproduction therefore requires an environment similar to the stem cell niche in the bone marrow.

The stem cell niche is a complex microscopic environment having specific properties. The relevant areas in the bone are highly porous and similar to a sponge. This three-dimensional environment does not only accommodate bone cells and hematopoietic stem cells but also various other cell types with which signal substances are exchanged. Moreover, the space among the cells has a matrix that ensures a certain stability and provides the cells with points to anchor. In the stem cell niche, the cells are also supplied with nutrients and oxygen.

The Young Investigators Group "Stem Cell–Material Interactions" headed by Dr. Cornelia Lee-Thedieck consists of scientists of the KIT Institute of Functional Interfaces (IFG), the Max Planck Institute for Intelligent Systems, Stuttgart, and Tübingen University. It artificially reproduced major properties of natural bone marrow at the laboratory. With the help of synthetic polymers, the scientists created a porous structure simulating the sponge-like structure of the bone in the area of the blood-forming bone marrow. In addition, they added protein building blocks similar to those existing in the matrix of the bone marrow for the cells to anchor. The scientists also inserted other cell types from the stem cell niche into the structure in order to ensure substance exchange.

Then, the researchers introduced hematopoietic stem cells isolated from cord blood into this artificial bone marrow. Subsequent breeding of the cells took several days. Analyses with various methods revealed that the cells really reproduce in the newly developed artificial bone marrow. Compared to standard cell cultivation methods, more stem cells retain their specific properties in the artificial bone marrow.

The newly developed artificial bone marrow that possesses major properties of natural bone marrow can now be used by the scientists to study the interactions between materials and stem cells in detail at the laboratory. This will help to find out how the behavior of stem cells can be influenced and controlled by synthetic materials. This knowledge might contribute to producing an artificial stem cell niche for the specific reproduction of stem cells and the treatment of leukemia in ten to fifteen years from now.

NEW TECHNIQUE TARGET SPECIFIC AREA OF CANCER CELL WITH DIFFERENT DRUGS

Researchers have developed a technique for creating nanoparticles that carry two different cancer-killing drugs into the body and deliver those drugs to separate parts of the cancer cell where they will be most effective. The technique was developed by researchers at North Carolina State University and the University of North Carolina at Chapel Hill.

"In testing on laboratory mice, our technique resulted in significant improvement in breast cancer tumor reduction as compared to conventional treatment techniques," says Dr. Zhen Gu, senior author of a paper on the research and an assistant professor in the joint biomedical engineering program at NC State and UNC-Chapel Hill.

"Cancer cells can develop resistance to chemotherapy drugs, but are less likely to develop resistance when multiple drugs are delivered simultaneously," Gu says. "However, different drugs target different parts of the cancer cell. For example, the protein drug TRAIL is most effective against the cell membrane, while doxorubicin (Dox) is most effective when delivered to the nucleus. We've come up with a sequential and site-specific delivery technique that first delivers TRAIL to cancer cell membranes and then penetrates the membrane to deliver Dox to the nucleus."

Gu's research team developed nanoparticles with an outer shell made of hyaluronic acid (HA) woven together with TRAIL. The HA interacts with receptors on cancer cell membranes, which "grab" the nanoparticle. Enzymes in the cancer cell environment break down the HA, releasing TRAIL onto the cell membrane and ultimately triggering cell death.

When the HA shell breaks down, it also reveals the core of the nanoparticle, which is made of Dox that is embedded with peptides that allow the core to penetrate into the cancer cell. The cancer cell encases the core in a protective bubble called an endosome, but the peptides on the core cause the endosome to begin breaking apart. This spills the Dox into the cell where it can penetrate the nucleus and trigger cell death.

"We designed this drug delivery vehicle using a 'programmed' strategy," says Tianyue Jiang, a lead author in Dr. Gu's lab. "Different drugs can be released at the right time in their right places," adds Dr. Ran Mo, a postdoctoral researcher in Gu's lab and the other lead author.

"This research is our first proof of concept, and we will continue to optimize the technique to make it even more efficient," Gu says. "The early results are very promising, and we think this could be scaled up for large-scale manufacturing."

Food and drug Interaction

Introduction:

Drugs are frequently taken with food, and patients often use mealtime to remind them to take their medication. However, food can have a significant effect on the bioavailability of drugs. Food or certain dietary items influence the activity of a drug e. g. Food-Drug interaction. Food may influence drug absorption indirectly, through physiological changes in the GI tract produced by food, and/or directly, through physical or chemical interactions between the drug molecules and food components.

When a food is ingested, stomach emptying is delayed, gastric secretions are increased, stomach pH is altered and splanchnic blood flow may increase. These may all affect bioavailability of drugs. Food may also interact directly with drugs, either chemically (e. g. chelation), or physically, by adsorbing the drug, or acting as a barrier to absorption. In general GI absorption of drug is favoured by an empty stomach. However, some drugs have to be taken with or after a meal in order to avoid gastric irritation or to reduce the side effect. Food often may affect the rate and extant of absorption of drugs from GI tract. For exp. Many antibiotics should be given at least one hr before or two hr after meal to achieve optimal absorption.  

Food will reduce the rate and/or extant of absorption by virtue of reduced gastric emptying time, which particularly important for the drug unstable in gastric fluid and for dosage form designed to release drug slowly. Food provides rather viscous environment which will reduce the rate of drug dissolution and drug diffusion to absorbing membrane. Drug may also bind with to food particles or react with the gastrointestinal fluids secreted in response to the presence of food. The absorption of a few is actually promoted when administered after a meal. For example, the absorption of riboflavin is greater when administered after meal. The absorption of griseofulvin is doubled when administered after a meal containing high fat content. The bioavailability of chlorthiazide is increased when taken immediately following a meal compared to that found in fasting subjects. Exact mechanism of food-drug interaction is complex and unpredictable. Drug absorption may bereduced, delayed, enhanced or unaffected by the presence of food.

Why Food-Drug interaction is important?

          Food may influence drug bioavailability by means of the following mechanisms.

1.   Increased viscosity of GI contents: The presence of food in the GIT will provide a viscous media which may result in reduction in the rate of dissolution in the GI contents. In addition, the rate of diffusion may be reduced by an increased viscosity. Both phenomenons will tend to reduce the absorption of drug and ultimately decrease the bioavailability of drug.

2. Alteration in the rate of gastric emptying: Larger and bulk of meals, longer the gastric emptying time. Liquid meal takes less hr than solid meal to empty. High or low temperature of ingested food (in comparison to body temperature) reduces the gastric imptying rate. Thereby delay the onset of drug action.

3.      Stimulation of GIT secretions: The secretion of GIT is stimulated by food. The gastric secretion includes hydrochloric acid and pepsin where as intestinal secretion includes bail salts, bail acids enzymes etc. They influence the drug stability and the absorption rate. Degradation of drugs takes place in GIT due to chemical hydrolysis and enzymatic metabolism and leads to reduce bioavailability of such sensitive drugs. While bail acid increases the absorption of certain drug by increasing their rate of dissolution in GIT fluids. However bail salt is found to form insoluble, non-absorbable complexes with such drugs as kanamycin, neomycin and nystatin.

4.      Competitive inhibition of drug absorption by food component: There certain specialized absorption mechanism for absorption of certain nutrients. The drugs which have structural similarity with these nutrients are also absorbed by same mechanism. Therefore, there are a competition between drugs and nutrients. Exp. Absorption of levodopa is inhibited by certain amino acid which comes from the breakdown of ingested food containing protein.

5.      Non-absorbable complex formation of drug with food components: In general, reduction in bioavailability due to complexation is observed only when drug forms an irreversible or non-absorbable complexes with food components. For example:

(a)   Tetracycline- metals: Tetracycline can combine with metal ions such as Ca⁺², Mg⁺², Zn⁺², Fe⁺² etc. in GIT to form complex that are absorbed poorly. Thus the simultaneous administration of certain dietary item containing these metal ions (e.g. milk, other product containing Ca⁺²) with tetracycline could result in significant absorption of tetracyclines.

(b)    Fluroquinolons-Metals: Certain dietary items (milk, yogurt), have been reported to reduce markedly the absorption and serum concentration of fluroquinolons, probably as a result of metal ion complexing with fluroquinolons.

(c)    Penicilamine-Metal: Food also will decrease the absorption of penicilamine by chelation and/or adsorption mechanisms.

6.      Blood flow to the liver: Blood flow to the GIT and liver increases shortly after a meal. This increased blood flow to the liver will increase the rate at which drugs are presented to the liver. Thus first-pass metabolism of some drugs (e.g.propranolol, hydralazine, and dextropropoxyphen etc.) is reduced because metabolism of such drugs is sensitive to their rate of presentation to liver, greater the rate of presentation of such drugs to the liver the larger the fraction of the drug that escapes first-pass metabolism. This is due to the enzyme systems responsible for their metabolisms become saturated at that rate of presentation of drugs to the liver.                   

Mechanisms by which absorption of drugs following meal could be increased: Increased drug absorption following a meal could be due to one or more of the under mentioned reasons:

1.      Increased time for dissolution of a poorly soluble drug.

2.      Enhanced solubility due to GIT secretion like bile.

3.      Prolonged residence time and absorption site contact of drug e.g. water soluble vitamins.

4.      Increased lymphatic absorption e.g. acitretin.

Table 1: Effect of Food on Drug Absorption

Reduced	Delayed	Increased	Unaffected
Ethanol Tetracycline Erythromycin Levodopa Captopril Atenolol Aspirin Ampicillin	Aspirin Digoxin Diclofenac Acetaminophen Furosemide Sulfadiazine Sulfixazole Nitrofurantoin	Griseofulvin Diazepam Vitamins Propranolol Metaprolol Chlorthiazide Hydralazine Lebetalol	Mehyldopa Sulfasomidine Propylthiouracil

What should be remembered about food-drug interaction?

• Read the prescription label on the container. If you do not understand something, or think you need more information, ask your physician or pharmacist.

• Read directions, warnings, and interaction precautions printed on all medication labels and package inserts. Even over-the-counter medications can cause problems.

• Take medication with a full glass of water.

• Do not stir medication into your food or take capsules apart (unless directed by your physician). This may change the way the drug works.

• Do not take vitamin pills at the same time you take medication - vitamins and minerals can interact with some drugs.
• Do not mix medication into hot drinks, because the heat from the drink may destroy the effectiveness of the drug.

• Never take medication with alcoholic drinks.

• Be sure to tell your physician and pharmacist about all medications you are taking, both prescription and non-prescription.

What happens during a food- drug interaction?

A food-drug interaction can occur when the food you eat affects the ingredients in a medication you are taking, preventing the medicine from working the way it should. Food-drug interactions can happen with both prescription and over-the-counter medications, including antacids, vitamins, and iron pills.

Some nutrients can affect the way you metabolize certain drugs by binding with drug ingredients, thus reducing their absorption or speeding their elimination. For example, the acidity of fruit juice may decrease the effectiveness of antibiotics such as penicillin. Dairy products may blunt the infection-fighting effects of tetracycline. Antidepressants (called MAO inhibitors) are dangerous when mixed with foods or drinks that contain tyramine (i.e., beer, red wine, and some cheeses).

Not all medications are affected by food, but many can be affected by what you eat and when you eat it. Sometimes, taking medications at the same time you eat may interfere with the way your stomach and intestines absorb medication. Other medications are recommended to be taken with food. Be sure to ask your physician or pharmacist for specific directions on eating prior to or after taking any medication.

Table 2: Medications which should be taken on an empty stomach

Alendronate	Ampicillin	Astemizole	Bethanechol
Bisacodyl	Captopril	Cefibuten	Cilostazol
Demeclocycline	Dicloxacillin	Didanosine	Etidronate
Felodipine	Indinavir	Lansoprazole	Levothyroxine
loratadine	loracarbef	Methotrexate	Moexipril
Mycophenolate	Omeprazole	Oxacillin	Penicillamine
Perindopril	Repaglinide	Rifampin	Rifabutin
Riluzole	Roxithromycin	Sucralfate	Sulfamethoxazole - trimethoprim
Sulfadiazine	Zalcitabine	Tolcapone	Zafirlukast

Table 3: Medications which should be taken with Food

Allopurinol	Atovaquone	Augmentin	Aspirin
Amiodarone	Baclofen	Bromocriptine	clofazimine
Carvedilol	Naproxen	Chloroquine	Cimetidine
Cefpodoxime	Diclofenac	Divalproex	Doxycycline
Felbamate	fenofibrate	Fiorinal	Fludrocortisone
fenoprofen	Griseofulvin	glyburide	Hydrocortisone
Sulindac	Indomethacin	Valproic acid	Itraconazole
Ketorolac	Lithium	Metronidazole	Misoprostol
methanamine	mebendazole	Prednisone	Naltrexone
Ticlopidine	Tolmetin	Trazodone	Troglitazone
Ritonavir	Nelfinavir	Nitrofurantoin	Niacin

The Effect of Food:

Anti-infective agents-Food: The presence of food in GIT will reduce the absorption of many anti-infective agents (e.g. Penicillin and tetracycline derivatives). Erythromycin stearate formulation should be administered at least 1 hr before meal or 2 hr after meal. Although there are many anti-infective agents (e.g. Penicillin V, Amoxicillin, Doxycycline minocycline etc.)  which absorption is not affected by food.

Theophylline-Food: Generally food does not alter the activity of theophylline significantly when the drug is administered in an immediate release formulation. However, variation is seen with the controlled release formulation of theophylline.

Captopril-Food: The presence of food in GIT has been reported to reduce the absorption of captopril by 30% to 40%. It is advisable to administer the drug 1 hr before the meal.

Alendronate & Risedronate-Food: Food and even coffee, orange juice and mineral water may markedly reduce the bioavailability of these drugs. It is recommended that these drugs be administered soon after arising at least half hr before any food, medication, with plan water.

MAOIs-Tyramine: There have been reports of serious hypertensive crisis reactions occurring in people being treated with MAOIs (e.g. Isocarboxazid, Phenelzine etc.) following ingestion of food with a  high content of tyramine (e.g. aged cheese, wine, pickled fish, concentrated yeast extracts, broad-been pods). The interaction can cause a potentially fatal rise in blood pressure.

Grapefruit Juice: Grapefruit juice reduces the activity of cytochrome P-450 enzyme in the gut wall that are involved in the metabolism of certain calcium channel blockers (e.g. Amlodipine, feloidipine, nisoldipine Varapamil etc.), HMG-CoA reductase inhibitors (e.g. Lovastatin) and cyclosporine As a result, larger amounts of unmetabolized drug is absorbed, and serum concentrations are increased.

Orange juice shouldn't be consumed with antacids containing aluminum. 'The juice increases the absorption of the aluminum. Orange Juice and milk should be avoided when taking antibiotics. The juice's acidity decreases the effectiveness of antibiotics, as doe’s milk.

Laxatives-Milk: Milk also doesn't mix with laxatives containing bisacodyl (Correctol and Dulcolax). You might find the laxative works a little "too well" in the morning.

Digoxin-Oatmeal: Large amounts of oatmeal and other high-fiber cereals should not be eaten when taking digoxin. The fiber can interfere with the absorption of the drug, making the act of swallowing the pill a waste of time.

Coumadin-Food: Leafy green Vegetables high in vitamin K should not be taken in great quantities while taking Coumadin. These vegetables could totally negate the affects of the drug and cause blood clotting.

Caffeinated beverages and asthma drugs taken together can cause excessive excitability. Those taking Tagament (Simetidine), quinolone antibiotics (Cipro, Penetrex, Noroxin) and even oral contraceptives should be aware these drugs may cause their cup of coffee to give them more of a Java jolt than they expected.

Theophylline-Grilled meat: Grilled meat can lead to problems for those on asthma medications containing theophyllines. The chemical compounds formed when meat is grilled somehow prevent this type of medication from working effectively, increasing the possibility of an unmanageable asthma attack.

NSAIDs-Food: Regularly consuming a diet high in fat while taking anti-inflammatory, arthritis medications can cause kidney damage and can leave the patient feeling, drowsy and sedated.

Tomato contains small quantities of a toxic substance known as solanine that may trigger headaches in susceptible people. They are also a relatively common cause of allergies. An unidentified substance in tomatoes and tomato-based products can cause acid reflux, leading to indigestion and heartburn. Individuals who often have digestive upsets should try eliminating tomatoes for 2 to 3 weeks to see if there is any improvement

Raspberries: Raspberries contain a natural salicylate that can cause an allergic reaction in aspirin sensitive people.

Horseradish Very high doses of horseradish can cause vomiting or excessive sweating. Avoid if you have hypothyroidism.

Drugs	Effects and Precautions
Antibiotics:
Cephalosporins, penicillin:	Take on an empty stomach to speed absorption of the drugs.
Erythromycin:	Don't take with fruit juice or wine, which decrease the drug's effectiveness.
Tetracycline:	Dairy products reduce the drug's effectiveness. Lowers Vitamin C absorption.
Antidepressants:
Lithium:	A low-salt diet increases the risk of lithium toxicity; excessive salt reduces the drug's efficacy
MAO Inhibitors:	Foods high in tyramine (aged cheeses, processed meats, legumes, wine, beer, among others) can bring on a hypertensive crisis.
Tricyclics:	Many foods, especially legumes, meat, fish, and foods high in Vitamin C, reduce absorption of the drugs.
Antihypertensive, Heart Medications:
Alpha blockers:	Take with liquid or food to avoid excessive drop in blood pressure.
Antiarrhythmic drugs:	Avoid caffeine, which increases the risk of irregular heartbeat.
Beta blockers:	Take on an empty stomach; food, especially meat, increases the drug's effects and can cause dizziness and low blood pressure.
Digitalis:	Avoid taking with milk and high fiber foods, which reduce absorption, increases potassium loss.
Antiasthmatic Drugs:
Pseudoephedrine:	Avoid caffeine, which increase feelings of anxiety and nervousness.
Theophylline:	Charbroiled foods and high protein diet reduce absorption. Caffeine increases the risk of drug toxicity.
Cholesterol Lowering Drugs:
Gemfibrozil:	Avoid fatty foods, which decrease the drug's efficacy in lowering cholesterol.
Antiulcer Medications:
Antacids:	Interfere with the absorption of many minerals; for maximum benefit, take medication 1 hour after eating.
Cimetidine, Fanotidine, Sucralfate:	Avoid high protein foods, caffeine, and other items that increase stomach acidity.
Hormonal Preparations:
Oral contraceptives:	Salty foods increase fluid retention. Drugs reduce the absorption of folate, vitamin B-6, and other nutrients; increase intake of foods high in these nutrients to avoid deficiencies.
Steroids:	Salty foods increase fluid retention. Increase intake of foods high in calcium, vitamin K, potassium, and protein to avoid deficiencies.
Thyroid drugs:	Iodine-rich foods lower the drug’s efficacy.
NSAIDs:
Aspirin and stronger non-steroidal anti-inflammatory drugs:	Always take with food to lower the risk of gastrointestinal irritation; avoid taking with alcohol, which increases the risk of bleeding. Frequent use of these drugs lowers the absorption of folate and vitamin C.
Codeine:	Increase fiber and water intake to avoid constipation.
Sedatives, Tranquilizers:
Benzodiazepines:	Never take with alcohol. Caffeine increases anxiety and reduce drug's effectiveness.