AIDS therapy from cheap generics

Townsend Letter for Doctors and Patients, June, 2006 by Mae Wan Ho, Veljko Veljkovic, Sam Burcher, Rhea Gala

New Uses for Cheap, Well-Known Drugs

A quintet of older drugs could make a cheap and safe alternative to current anti-HIV drug cocktails, claim Dr. Aldar Bourinbaiar and Dr. Vichai Jirathitikal of Immunitor Corporation in Thailand, which created the VI AIDS vaccine. In a paper published in Current Pharmaceutical Design in 2003, the two scientists reviewed evidence suggesting that these old, widely available conventional drugs might have antiretroviral and immune modulating properties, which could help recover the immune system of HIV/AIDS patients. (1)

Warfarin

Warfarin is a synthetic drug derived from the naturally occurring coumarins found in a wide variety of plant species worldwide. Coumarins are the parent organic compounds that work as natural pesticides in plants such as lavender, grasses like sweet clover, and food plants like strawberries and lemons. In 1868, coumarins were synthesized in the laboratory to make perfumes and flavoring. When combined with glucose, they produce glycosides, which are anticancer, anti-fungus, and anti-coagulant. All structurally related coumarins show potent anti-HIV activity. The use of coumarins as an immune support accompanying standard chemotherapy treatment has significantly improved survival rates of colon-cancer patients. More recently, warfarin has been used as an anti-coagulating drug in the treatment of heart disease and stroke. There is some anecdotal evidence suggesting that a small daily dose of 2 mg of warfarin does not affect prothrombin time, a lab test to monitor blood coagulation in HIV patients, but does significantly lower viral loads.

Warfarin possesses four essential properties for fighting HIV: inhibition of serine protease, aspartyl protease, reverse transcriptase, and integrase, all of which are central to the virus's ability to replicate. An average protease inhibitor used in triple-drug treatments of HIV costs between $10 and $20 per day, in contrast to a daily dose of 2 mg warfarin, which costs as little as ten cents. Reverse transcriptase (RT) inhibitors are also essential in the successful treatment of HIV/AIDS. By far the most prescribed RT inhibitor is AZT, which has side effects in up to 75% of patients with HIV/AIDS.

Warfarin is of further value in the treatment of cognitive functions in HIV/ AIDS patients. A daily dose of warfarin appears to improve the fluency of speech and mental aptitude of patients suffering from progressive dementia associated with full-blown AIDS disease. Bourinbaiar and Jirathitikal found that a combination of warfarin with compounds whose anti-HIV effects they had discovered, such as cimetidine and levamisole, seem to enhance the beneficial immune effect.

Cimetidine

Cimetidine (Tagamet) is an over-the-counter antacid or anti-ulcer drug and, as such, inhibits gastric acid secretion via histamine type (H2) receptors on parietal cells (in the stomach). Cimetidine was developed as part of a research effort led by Nobel laureate Sir James Black and was the first H2-antagonist to receive approval from the Food and Drug Administration (FDA) in 1977. Because of its excellent safety record, cimetidine is now widely available as an over-the-counter drug.

Cimetidine first came to the attention of Bourinbaiar and Jirathitikal when they observed the inhibition of human T-cell leukemia virus (HTLV-1) secretion from chronically infected cells. This led them to the idea that viral release is regulated in the same way as gastric acid secretion. They discovered that cimetidine has broad antiretroviral activity. Further studies revealed that cimetidine, unlike AZT, which was used as a control, produced no cytotoxicity even at the highest dose tested (1mM). According to the researchers, this is an exceptional drug index that cannot be matched by any drugs currently used in the treatment of HIV/AIDS. Twice-daily doses of 200 mg of cimetidine provide steady IC50 levels (concentration producing 50% inhibition) for HIV replication.

It appears that the success of H2 antagonists tested for antiviral activity depends on the imidazole nucleus. Some, although not all, non-nucleoside reverse transcriptase inhibitors (NNRTIs) possess the special chemical structures, called imidazole rings, that are present in cimetidine. It is thus likely that cimetidine acts like an NNRTI and has the ability to treat HIV infection. NNRTIs have a reputation for rapidly eliciting resistance due to mutations of the amino acids surrounding the NNRTIs' binding site. So emerging strains of resistant HIV can be confronted if the NNRTIs are combined with other anti-HIV agents such as cimetidine.

The combination of warfarin and cimetidine was previously thought to be incompatible, but there have been no reports of adverse reactions at low doses of cimetidine with 2 mg of warfarin in more than 100 available references in the TOXLINE database. In fact, cimetidine has caused anemia in only 2.3 per 100,000 people, as opposed to 70% of HIV patients treated with AZT. (2) In trials, cimetidine significantly enhanced a variety of immune functions both in vivo and in vitro and was successful in partially restoring the immune function in 33 AIDS patients. (3) Cimetidine sells over-the-counter for 20 cents per 400 mg pill; in China, the pills may be purchased in bulk for as little as $18 per kilogram.