Minocycline - Effective defense against HIV ?

We know that Minocycline hydrochloride, also known as minocycline (structure), is a broad spectrum tetracycline antibiotic, and has a broader spectrum than the other members of the group. It is a bacteriostatic antibiotic. It is primarily used to treat acne and other skin infections as well as lyme disease. It may be used to treat certain strains of MRSA infection and disease caused by drug resistant Acinetobacter. Its also used in DMARD (Disease-Modifying Anti-Rheumatic Drug) for RA. 

Now, Johns Hopkins scientists have found that this safe and inexpensive antibiotic (minocycline),   effectively targets infected immune cells in which HIV, the virus that causes AIDS, lies dormant and prevents them from reactivating and replicating. 

As per the claim by the researchers, minocycline, likely will improve on the current treatment regimens of HIV-infected patients if used in combination with a standard drug cocktail known as HAART (Highly Active Antiretroviral Therapy).  Though HART is really effective in keeping down active replication, minocycline is another arm of defense against the virus. 

Dr. Janice Clements lead researcher claims that,  unlike the drugs used in HAART which target the virus, minocycline homes in on, and adjusts T cells, major immune system agents and targets of HIV infection. and  minocycline reduces the ability of T cells to activate and proliferate, both steps crucial to HIV production and progression toward full blown AIDS. 

The idea for using minocycline as an adjunct to HAART resulted when the Hopkins team learned of research by others on rheumatoid arthritis patients showing the anti-inflammatory effects of minocycline on T cells. Interestingly the same researchers earlier found that  minocycline treatment had multiple beneficial effects in monkeys infected with SIV, the primate version of HIV. In monkeys treated with minocycline, the virus load in the cerebrospinal fluid, the viral RNA in the brain and the severity of central nervous system disease were significantly decreased. The drug was also shown to affect T cell activation and proliferation.  

The team used molecular markers to discover that minocycline very selectively interrupts certain specific signaling pathways critical for T cell activation. However, the antibiotic doesn't completely obliterate T cells or diminish their ability to respond to other infections or diseases, which is crucial for individuals with HIV. Researchers conclude that,  this new understanding about minocyline's effects on a T cell  might help to find even more drugs that target its signaling pathways.

At Johns Hopkins and elsewhere, scientists are now testing whether giving HIV patients minocycline benefits them, let us hope for the positive results....

Ref : http://www.usnews.com/science/articles/2010/03/26/existing-antibiotic-might-help-keep-wraps-on-aids-virus.html

UT Southwestern researchers find clues to TB drug resistance.....

In continuation of my update on TB and its challenges...

Now researchers from the University of Texas Southwestern Medical Center at Dallas, have come up with some interesting info. i.e.,  a type of blood pressure medication shows promise at overcoming some drug-resistant tuberculosis, at least in the laboratory. 

Dr. Gumbo (lead researcher) and his colleagues used an experimental apparatus to simulate the way TB bacteria grow in the human lung. When they exposed the bacteria to drugs commonly used to treat the disease (ethambutol and isoniazid),  the bacterial cells activated a cellular mechanism that pumps each drug out of the cells. 

"The pumping action enables the rapid emergence of high-level resistance to the drugs whether administered together as well as individually, Dr. Gumbo said".

As per the claim by the researchers, resistance was drastically reduced  when the researchers gave the blood-pressure drug reserpine – which is known to block this pumping action – to the TB cells before administering ethambutol and isoniazid.

Researchers now want to test all the first-line drug treatments together with the pump blocker in humans. Hope they will come up with positive results.....

Ref  : http://www.utsouthwestern.edu/utsw/cda/dept37389/files/582308.html

Telaprevir-based regimens increase rates of SVR in patients with genotype 1 HCV infection

In continuation of my update on telaprevir-based regimens, I found this article interesting to share with.....

In a clinical trial known as PROVE 3 published in this week's New England Journal of Medicine, treatment with telaprevir-based regimens significantly increased rates of sustained viral response (SVR) in patients with genotype 1 hepatitis C virus (HCV) infection who did not achieve SVR with at least one prior course of pegylated-interferon and ribavirin therapy. In the trial, 51 percent and 53 percent of patients who received telaprevir in combination with pegylated-interferon and ribavirin as part of a 24-week or 48-week regimen, respectively, achieved SVR.   More...

Scientists show carbon nanotubes can be broken down by MPO

Carbon nanotubes were once considered biopersistent in that they did not break down in body tissue or in nature. In recent years, research has shown that laboratory animals exposed to carbon nanotubes via inhalation or through injection into the abdominal cavity develop severe inflammation. A combined study by a team of Swedish and American scientists have come up with an interesting finding, which will be a breakthrough in nanotechnology and nanotoxicology. As per the claim by the researchers, "endogenous MPO can break down carbon nanotubes". This enzyme is expressed in certain types of white blood cell (neutrophils), which use it to neutralise harmful bacteria. Now, however, the researchers have found that the enzyme also works on carbon nanotubes, breaking them down into water and carbon dioxide. The researchers also showed that carbon nanotubes that have been broken down by MPO no longer give rise to inflammation in mice. More....

Scientists show carbon nanotubes can be broken down by MPO

Findings may help devise new strategies for Cryptococcus infections

Findings may help devise new strategies for Cryptococcus infections

Study indicates estrogenic drug could help treat schizophrenia

 

Study indicates estrogenic drug could help treat schizophrenia

New anti-inflammatory drug shows promise for treating inflammatory disorders

In one of my earlier blog, I  did mention about the antiinflammatory activity of H₂S gas. Now interestingly John Wallace, a pharmacologist and director of the Farncombe Family Digestive Health Research Institute at McMaster University, compared naproxen, a commonly used NSAID, to a novel anti-inflammatory drug, ATB-346 (ATB-346 is a derivative of naproxen which releases hydrogen sulfide), which he developed in collaboration with a team of Italian chemists and is now commercializing through his company, Antibe Therapeutics Inc. The basis for this research is by the fact that hydrogen sulphide is an important mediator of gastric mucosal defence. As we all know the ulcerogenecity associated with NSAIDs, there is a need to have NSAIDs with least or no ulcerogenecity.

As per the claim by the researchers, ATB-346, [above, structure : 2-(6-methoxy-napthalen-2-yl)-propionic acid 4-thiocarbamoyl-phenyl ester] acts by inhibiting cyclooxygenase-1 and 2 and  reduces inflammation (in vivo). More interesting out come from their research is  that ATB-346 suppressed gastric prostaglandin E₂ synthesis as effectively as naproxen, but produced negligible damage in the stomach and intestine. 

ATB-346 did not cause significant damage, where as naproxen rendered significant  gastric mucosa damage (e.g. ablation of sensory afferent nerves, inhibition of endogenous nitric oxide or hydrogen sulphide synthesis, co-administration with aspirin, antagonism of K_IR6.x channels). Unlike naproxen and celecoxib, ATB-346 accelerated healing of pre-existing gastric ulcers. In a mouse airpouch model, ATB-346 suppressed cyclooxygenase-2 activity and inhibited leukocyte infiltration more effectively than naproxen. ATB-346 was as effective as naproxen in adjuvant-induced arthritis in rats, with a more rapid onset of activity, but with substantially reduced gastrointestinal toxicity (100 times safer than naproxen). Unlike naproxen, ATB-346 did not elevate blood pressure in hypertensive rats.

The researchers concluded that H2S-releasing NSAIDs appear to represent a promising alternative to existing therapies for the treatment of inflammation and pain. Future research will focus on the potential cardiovascular benefits of these drugs. .....

Ref : John L Wallace et. al., British Journal of Pharmacology, 159(6),  1236 - 1246

Two-drug combination destroys precancerous colon polyps....

A team of scientists at The University of Texas M. D. Anderson Cancer Center lead by Dr. Xiangwei Wu have come up with interesting finding i.e.,  a two-drug combination destroys precancerous colon polyps with no effect on normal tissue, opening a new potential avenue for chemoprevention of colon cancer. 

The regimen, tested so far in mouse models and on human colon cancer tissue in the lab, appears to address a problem with chemopreventive drugs - they must be taken continuously long term to be effective, exposing patients to possible side effects. 

The team found that a combination of Vitamin A acetate (RAc see  structure; source: Wikipedia) and TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), kills precancerous polyps and inhibits tumor growth in mice that have deficiencies in a tumor-suppressor gene. That gene, adenomatous polyposis coli (APC) and its downstream signaling molecules, are mutated or deficient in 80 percent of all human colon cancer.  

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent endogenous activator of the cell death pathway and functions by activating the cell surface death receptors 4 and 5 (DR4 and DR5). TRAIL is nontoxic in vivo and preferentially kills neoplastically transformed cells over normal cells by an undefined mechanism.

Interestingly, early experiments with APC-deficient mice showed that the two drugs combined or separately did not harm normal colon epithelial cells. Separately, they showed no effect on premalignant polyps called adenomas.

RAc and TRAIL together killed adenoma cells, causing programmed cell suicide know as apoptosis. RAc, researchers found, sensitizes polyp cells to TRAIL.

The scientists painstakingly tracked the molecular cascade caused by APC deficiencies, and found that insufficient APC sensitizes cells to TRAIL and RAc by suppressing a protein that blocks TRAIL.

APC-deficient mice were treated with 15 cycles of the RAc/TRAIL combination over six weeks. Others received either RAc or TRAIL and a control group received nothing. One month later, control mice and those treated with one of the drugs averaged between 35 and 42 polyps, while those receiving the combination averaged 10.

To test the combination’s potential as short-term therapy, APC-deficient mice were treated with two cycles of the combination in one week, causing a 69 percent polyp reduction two weeks later. A 10-fold increase in dose left treated mice with only 10 percent of the polyps found in controls.

A longer term test of relative survival using five treatments over four months improved survival from 186 days for controls to beyond 213 days for treated mice, with five of seven treated mice living more than eight months. Next, the researchers treated biopsy samples of normal tissue and tumor regions from patients with familial adenomatous polyposis – an inherited condition that inevitably leads to colon cancer if the colon is not removed. Treatment of normal tissue caused little cell death, while 57 percent of polyp cells were killed via apoptosis.

Targeted therapies today aim at blocking some aspect of the tumor that drives its growth, Wu said, whereas RAc and TRAIL together kill precancerous polyps outright. Since APC is deficient or mutated in other types of cancer, the combination therapy could become a more general drug.

Before human clinical trials can be considered, the team will conduct additional research to understand potential side effects and also will try to develop an injectable version of the combination, which is administered intravenously now..

Ref : http://www.nature.com/nature/journal/vaop/ncurrent/full/nature08871.html

Self-Poisoning of Mycobacterium tuberculosis by targeting GlgE in an a-glucan pathway...

In the past few years, extremely drug resistant strains of TB have arisen that can’t be eliminated by any drugs, so new strategies for attacking TB are urgently needed.

Now, researchers at Albert Einstein College of Medicine of Yeshiva University have found two novel ways of killing the bacteria that cause tuberculosis.

In searching for a new Achilles’ heel for M. tuberculosis, Dr. Jacobs and colleagues focused on an enzyme called GlgE. Previous research had suggested  that GlgE might be essential for the growth of TB bacteria.        (building polysaccharides) GlgE would also be an excellent drug target because there are no enzymes similar to it in humans or in the bacteria of the human gut.

Using genetic and biochemical approaches, William Jacobs and colleagues identified four enzymes involved in a pathway that converts a naturally-occurring sugar compound into polysaccharides called alpha-glucans. The scientists found that inactivating one of these enzymes, TreS, was not lethal to the bacteria, indicating that this pathway is not required for growth. 

However, inactivating GlgE was lethal, causing the buildup of toxic levels of the enzyme's sugar substrate, maltose-1-phosphate. In addition, the scientists found that the combined inactivation of TreS and an enzyme for an alternate alpha-glucan biosynthetic pathway was lethal, highlighting the important roles of alpha-glucan's in M. tuberculosis growth.

Sure enough, when the researchers inhibited GlgE, the bacteria underwent "suicidal self-poisoning": a sugar called maltose 1-phosphate accumulated to toxic levels that damaged bacterial DNA, causing the death of TB bacteria grown in Petri dishes as well as in infected mice.

The researchers discovered a second way of killing TB after observing a crucial connection between their novel alpha glucan pathway and a second pathway that also synthesizes alpha glucans. 

When the researchers knocked out one of the other enzymes in their novel pathway, the pathway's shutdown didn't kill the bacteria; similarly, inactivating an enzyme called Rv3032 in the second alpha glucan pathway failed to kill the microbes. But inactivating both of those enzymes caused what the researchers term synthetic lethality: two inactivations that separately were nonlethal but together cause bacterial death. 

Though the biological role of the GlgE pathway remains to be elucidated, GlgE and the alpha-glucan pathways more generally, are possible drug targets that can now be tested in in vivo models of tuberculosis infection....

"The bacteria that cause TB need to synthesize alpha glucans," notes Dr. Jacobs. "And from the bacterial point of view, you can't knock out both of these alpha glucan pathways simultaneously or you're dead. So if we were to make drugs against GlgE and Rv3032, the combination would be extremely potent. And since TB bacteria need both of those alpha glucan pathways to live, it's very unlikely that this combination therapy would leave behind surviving bacteria that could develop into resistant strains."

Ref :  http://www.nature.com/nchembio/journal/vaop/ncurrent/pdf/nchembio.340.pdf

FDA approves Graceway Pharmaceuticals' NDA for Zyclara

We know that Imiquimod (structure - source -Drug Bank) is an   immune response modifier that acts as a toll-like receptor 7 agonist. Imiquimod is commonly used topically to treat warts on the skin of the genital and anal areas. Imiquimod does not cure warts, and new warts may appear during treatment. Imiquimod does not fight the viruses that cause warts directly, however, it does help to relieve and control wart production.

Graceway® Pharmaceuticals announced recently  that, FDA has approved the New Drug Application (NDA) for Zyclara™, determining it to be safe and effective for the treatment of clinically typical, visible or palpable actinic keratoses (AK).   

The new treatment can be used on large areas of skin, including the full face or balding scalp on a convenient, 6-week dosing cycle.Zyclara shares the same active ingredient as Aldara® (imiquimod) Cream, 5% and while both topicals are FDA-approved for the treatment of AK, there are notable differences between the two.  

Zyclara is indicated for daily use on an accelerated 6-week dosing cycle comprised of two weeks of daily treatment with Zyclara, two weeks of non-treatment, followed by two weeks of daily treatment with Zyclara. Aldara is not approved for daily use and its approved dosing regimen is for a full 16 weeks.  Additionally, Zyclara is indicated for use on larger areas of skin, the full face or balding scalp, while Aldara is restricted to a 25 cm2 area of skin. 

"Because AKs are pre-cancerous and can develop on skin frequently exposed to the sun, such as the face or balding scalp, an effective treatment that can be used on large areas of skin is beneficial," said Darrell Rigel, M.D., clinical professor of dermatology, New York University Medical Center. ....

Ref : http://www.zyclaracream.com/