Conventional combination treatments for HIV/AIDS cost $22 000 per patient per
year in the US. Do cheaper and less toxic drugs exist?
Sam Burcher and Dr Mae-Wan Ho report
A quintet of older drugs could make a cheap and safe alternative to current anti-HIV drug cocktails, claim Drs Aldar Bourinbaiar and Vichai Jirathitikal of Immunitor Corporation in Thailand, which created the V1 AIDS vaccine (see Pink Panacea, an AIDS vaccine? this series).
In a paper published in Current Pharmaceutical Design in 2003, the two scientists review evidence suggesting that these old, widely available conventional drugs may have anti-retroviral and immune modulating properties, which could help recover the immune system of HIV/AIDS patients.
Warfarin is a synthetic drug derived from the naturally occurring coumarins found in a wide variety of plants 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, courmarins were synthesised in the laboratory to make perfumes and flavouring. When combined with glucose they produce glycosides, which are anti-cancer, anti-fungus and anti-coagulant. All structurally related courmarins 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 is 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 2mg
of warfarin do not affect the "prothrombin-time", a lab test to
monitor blood coagulation in HIV patients, but does significantly lower viral
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 PI (protease inhibitor) used in triple-drug treatments of HIV cost
between $10-$20 per day, in contrast to a daily dose of 2 mg warfarin which
costs as little as 10 cents.
Reverse transcriptase (RT) inhibitors are also essential in the successful
treatment of HIV/AIDS. By far the most prescribed RT is AZT, which has side
effects in up 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 the full-blown AIDS disease.
Bourinbair and Jirathitikal found that a combination of warfarin with anti-HIV compounds discovered by them, such as cimetidine and lavamisole seem to enhance the beneficial immune effect.
Cimetidine is an over the counter ant-acid or anti-ulcer drug otherwise known as Tagamet, 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 FDA (Food and Drug Administration) in 1977. On account of its excellent safety record, it 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 cells leukaemia 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, and to discover that
cimetidine has broad anti-retroviral activity.
Further studies revealed that cimeditine, unlike AZT, which was used as a control,
produced no cytotoxicity even at the highest dose tested (1mM). According to
the authors, 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 200mg
of cimetidine will suffice to provide steady IC50 levels (concentration producing
50% inhibition) for HIV replication.
It appears that the success of H2 antagonists tested for anti-viral activity
depends on the imidazole nucleus. Some, though not all non-nucleoside reverse
transcriptase inhibitors (NNRTIs) possess imidazole rings. 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
The combination of warfarin and cimeditine was previously thought to be incompatible,
but there have been no reports of adverse reactions at low doses of cimetidine
and 2mg of warfarin in more than a hundred available references in the TOXLINE
database. In fact, the cases of anaemia caused by cimetidine is 2.3 per 100
000 as opposed to 70% in patients treated with AZT.
In trials, cimeditine 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.
Cimeditine sells over the counter for 20 cents per 400mg pill, while in China bulk buying the pills may cost as little as $18 per kilo.
Levamisole was synthesised in the early 1960s and used primarily for the treatment of intestinal worms in animals. In the 1990s, Levamisole was approved for human medicinal use to provide immune support for colon cancer patients. Bourinbair and colleagues, aware that it contained the same imidazole ring as cimeditine surmised that it might also have anti-HIV activity. They found that the IC50 of Levamisole to be around 0.1mM, and there was no toxicity at the highest dose of 1mM. The drug was effective against several lab strains and primary isolates of HIV-1.
However, chronic daily doses of Levamisole appeared to have an accumulated
toxic effect, usually severe nausea and granulocytopenia (a reduction of granulocytes,
a kind of white blood cells in the blood). In general, once weekly low doses
of the drug are well tolerated.
Interestingly, levamisole can either enhance or suppress the immune system
depending on the administered dose. Many studies have found beneficial effects
of levamisole in various immune deficiency disorders. Similarly, the drug used
alone, or in combination with interferon and other anti-inflammatory drugs significantly
improves the healing of eye and skin lesions caused by herpes simplex and zoster
virus. Levamisole is also strikingly effective against auto-immune diseases
such as rheumatoid arthritis and systemic lupus erythematosus.
Other studies, however, have found no benefit from levamisole.
Since 1985, Levamisole has undergone sporadic tests with AIDS patients with
conflicting results. Some trials report no effect, while others found beneficial
Bourinbair and Jirathitikal conclude that levamisole may have both immune modulating
and antiviral activities. But caution must be exercised in using this drug because
"the dosage, administration schedule, gender and many other variables
seem to have a serious influence on the outcome of the therapy."
For human use, it cost $6 per pill, but the same pill for animal use costs just 6 cents. So the cost for treating a sheep for one year is $1, but treating a human for one year would cost $1,200.
Acetaminophen was first synthesised in 1878 as an intermediary compound in the manufacture of synthetic aniline dyes. Some fifteen years later, its analgesic or pain- killing property was identified. But its clinical application did not come until 1949 when a study by Nobel laureates Brodie and Axelrod was published, and by the 1960s, it was made available as an over the counter drug. Brand names ascribed to acetaminophen are Paracetamol, Panadol, and Tylenol etc, as a non-toxic broad-spectrum pain reliever with few or no side effects at therapeutic doses. It is thought to cause fewer side effects than aspirin, a non-common non-steroidal, anti-inflammatory (NSAID) drug.
It is not fully understood how acetaminophen works, but it is believed to inhibit
prostaglandin synthesis or the actions of chemical mediators or other substances
that sensitise the pain receptors to mechanical or chemical stimulation. During
a study by Bourinbair & Jirantikal to identify a serine protease for use
in contraceptive creams, they discovered that acetaminophen displayed significant
anti-HIV activity while it was used as a negative control. The anti-viral effect
was specific and almost 100% inhibition was observed at 1mM (150mg/ml), while
IC50 was 20mg/ml, which is satisfied by the standard dosage of a 650mg pill
every six hours.
Studies of acetaminophen have shown it to be non-toxic even in the highest
dose of 1mM tested, and it has been used to counteract toxicity in AIDS patients
treated with AZT. No further toxicity occurred in these patients, but the anti-HIV
activity in acetaminophen was not studied in these cases.
It is not yet clear how acetaminophen affects HIV replication, but it its thought
to behave in a similar way to reverse transcriptase inhibitors (RT) that inhibit
the synthesis of DNA from RNA.
As far as cost is concerned, these familiar painkillers may well turn out to be the cheapest of all currently available reverse transcriptase (RT) drugs.
Gramicidin D was the first ever clinically identified antibiotic predating penicillin by one year. It was isolated from the soil bacterium Bacillis brevis by Rene Dubois, hence "D", in 1939. Gramicidins are short peptides of 15 alternating L- and D- amino acids that are synthesized outside the genetic coding route. The D-amino acids are unnatural in that they do not occur in proteins encoded in the genome of organisms. There are several kinds of gramicidins, differing in the amino acid sequence. They usually exist as molecular complexes of two peptides. These linear gramicidins are related to the cyclic (ring-shaped) gramicidin S discovered later in the former Soviet Union.
Gramicidin acts by causing potassium to flow out from the target cell, thus
killing it. And because of its unique construction it has never been implicated
in the emergence of resistant bacteria like so many younger antibiotics.
It was first used in the USA for the treatment of gram-positive infections
and was also widely used in over the counter throat lozenges, dentifrices and
mouthwashes. Nowadays, it is available by prescriptions only as a treatment
for skin and eye infections. In Russia Gramicidin S is available over the counter
as a prophylactic spermicide, which can be used in combination with condoms
and diaphragms. It can be applied topically as an anti-microbial to treat skin
infections caused by other viral or fungal sexually transmitted diseases and
Gramicidin has been in clinical use for over 60 years and it is non-toxic when
administered topically or orally. However, some medical opinions suggest toxicity
in systemic use. This may have been because gramicidin was used in combination
with other drugs, which caused side effects. More recent studies have shown
that systemic doses of gramicidin are well tolerated and efficacious in the
treatment of experimental malaria in mice. Gramicidin injections cleared the
malaria parasite in mice in four days. It is hoped that gramicidin can be a
potent treatment for both AIDS and malaria particularly in Africa where both
diseases are endemic.
Due to the presence of unnatural D-amino acids, gramicidin has a remarkable
resistance to peptide cleaving proteases found in the body, such as blood, pus,
urine and saliva. It has a broad PH range (acid to alkaline) and remains active
for ten years at room temperature.
Bourinbaiar and Jirathitikal have shown that gramicidin is highly effective
against HIV and herpes simplex viruses at non-toxic nanogram doses. The IC50
of gramicidin against 3 herpes simplex isolates was 0.3mg/ml. At an even lower
dose of 10ng/ml, it was active against both lab strains of HIV and clinical
isolates. When gramicidin was compared with the most popular anti-HIV spermicide
"N9", it was found to be 1000 times more effective. "N9"
could only display anti-viral activity in doses that were toxic to cells. Despite
N9's equivalence to household bleach, a toxic substance not normally topically
applied to skin, it continues to be evaluated as a spermicide in clinical trials.
Thus, gramicidin may be a safe and more efficient microbicide and spermicide
than N9. Its use as a vaginal suppository would make an extremely cheap and
efficient prophylactic or "barrier method" against HIV and other
STDs. A supply of 3kg would be sufficient for one year's use, and the
cost is negligible. Gramicidin D already has US FDA (Food and Drug Administration)
approval for topical use, and cyclic gramicidin S has been used in Russia as
a spermicidal preparation.
Gramicidin possesses a formidable list of attractive properties, all of which
are relevant against emerging diseases. It is anti-STD, anti-fungal, anti-protozoan
(malaria) and is poorly absorbed by the skin, reducing the risk of irritation.
It enhances skin tissue healing and resists and inhibits proteolytic enzymes,
which break down proteins in the body.
This 60 year-old drug has now come of age and its anti-viral properties need
to be confirmed in clinical trials.
Article first published 02/04/04
Bourinbaiar AS and Jirathitikal V. Low-cost anti-HIV compounds: Potential application for AIDS therapy in developing countries. Current Pharmaceutical Design 2003, 9,1419-31.
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