       TreatmentUpdate56, Vol 7, No. 2 - February 1995
       *************************************************************
       published by Community AIDS Treatment Information Exchange,
       Suite 420 - 517 College St., Toronto, Ontario, Canada M6G 4A2
       *************************************************************

       HIV/AIDS THEORY

       A. HIV and cytokines-testing the theory

       * BACKGROUND

       There are two types of responses the immune system can make
when it senses an infection. One response is called CMI
(cell-mediated immunity, also known as a type 1 response). Very
simply, CMI involves T cells that fight invading microbes and
destroy infected cells. To boost CMI the immune system makes
cytokines such as:

       - interferon-gamma
       - interleukin-2
       - interleukin-12

       As a general rule, CMI is needed to fight infections caused
by viruses and other microbes that infect and 'hide' inside cells.

       The other type of response is called humoral immunity or a
type 2 response. Here the immune system relies largely on antibodies
made by B cells. To strengthen this response the immune system
releases cytokines such as:

       - IL-4
       - IL-6
       - IL-10

       Interestingly, these cytokines cause cells to make less of
the cytokines needed for CMI. As well, interferon gamma can cause
cells to decrease production of the cytokines needed for humoral
immunity. Some researchers think that, over time, the immune systems
of HIV-infected patients make less of the chemicals needed to boost
CMI while making more of the chemicals that help humoral immunity.
This 'shift' may be one reason people with HIV/AIDS (PHAs) develop
life-threatening infections. Researchers have also found cells that
release both types of cytokines, and their role in the loss of CMI
is not clear.

       * CYTOKINE THERAPY

       Some researchers suggest that PHAs ought to be treated with
cytokines that can boost CMI. This idea is being tested; subjects in
Vancouver, California and New York are receiving IL-2 and/or IL-12.
Intravenous cytokine therapy may not work because cytokines:

       - quickly break down
       - are needed at very small and particular sites
       - can be toxic when taken in large doses

       Some researchers are beginning to suspect that there will not
be any single 'magic' cytokine for treatment of HIV/AIDS. Leading
immunologists suspect this is the case because there is usually a
'mix' of cytokines that cause certain effects. In TreatmentUpdate 55
we reported data from several experiments with cytokines or
anti-cytokines for treating arthritis and cancer. In the section on
immunomodulators in this issue of TreatmentUpdate, we report results
from a study using interferon-gamma to boost the immune systems of
subjects with HIV/AIDS

       REFERENCES:

              1. Clerici M and Shearer G. The Th1-Th2 hypothesis of
       HIV infection: new insights. Immunology Today 1994;15(12):
       575-581.

              2. Mossmann TR. Cytokine patterns during progression
       to AIDS. Science 1994;265:193-194.

              3. Meyaard B, Otto SA, Keet IPM, et al. Changes in
       cytokine patterns of CD4+ cell clones in Human
       Immunodeficiency Virus infection. Blood
       1994;84(12):4262-4268.

              4. Autran B, Legac E, Blanc C and Debre P. A
       ThO/Th2-like function of CD4+ CD7 - T helper cells from
       normal donors and HIV- infected patients. Journal of
       Immunology 1995;154(3):1408-1417.

       II ANTI-HIV AGENTS

       A. Cholesterol drug for HIV?

       * BACKGROUND

       AZT and related drugs are supposed to work by interfering
with an enzyme needed to make new viruses. HIV can become resistant
to these drugs, so researchers are testing drugs that can affect
other parts of the viral life cycle such as protease (or proteinase)
inhibitors and tat inhibitors.

       The outer part of a cell has a layer of lipids (fat-like
substances) that helps to hold the cell together. This outer layer
is called a membrane. The shell protecting the virus is also made of
lipids. Several research teams have found that when cells become
infected with HIV the types of lipids in the membrane change. Drugs
that interfere with the type and amount of lipids in the cell
membrane could be used to damage HIV and infected cells.

       * LOVASTATIN

       Lovastatin is a drug that causes cells to make less
cholesterol. Researchers in France have been conducting experiments
on HIV-infected cells with lovastatin. They found that lovastatin
reduces production of lipids by 60% to 70%. HIV-infected cells
treated with lovastatin survived longer than HIV-infected cells not
treated with the drug. As well, the level of the essential viral
enzyme RT (reverse transcriptase) fell to 10% of its normal value in
cells treated with lovastatin.

       * TOXICITY

       The researchers stated that lovastatin is well tolerated by
patients who use the drug to reduce their production of cholesterol.
The concentration of lovastatin used in these experiments can be
reached by patients taking 40 mg/day. The researchers suggested
lovastatin and 'related' drugs should be considered as potential
anti-HIV therapy. Lovastatin (Zocor(R)) is licensed in North
America to reduce production of cholesterol.

       * LOVASTATIN IN MONTRAL

       Researchers in Montral have been studying the effect of
lovastatin on the immune system. This is because white blood cells
need to make cholesterol to build their cell membranes. This is
particularly important when the immune system is under attack and
needs to make many cells to fight back. If cells cannot make enough
cholesterol then production of white blood cells may not be enough
to contain the infection. In some laboratory experiments using
lovastatin at concentrations 10 times above the normal value, the
ability of cells of the immune system to respond to infection (in
simulated tests) fell between 25% and 50%. The Montral researchers
gave 52 adult (non-HIV-infected) subjects 40 mg/day of lovastatin
for 8 weeks. During the 8 weeks no significant decline in the
performance of white blood cells occurred. There were no decreases
in numbers of T cells. The researchers did not provide any
information on CD4+ and CD8+ cell numbers. Researchers noted a
slight decrease in production of antibodies. It is possible that
there may have been other effects on the immune system that this
research team did not detect.

       REFERENCES:

              1. Maziere JC, Landureau JC, Gird P, et al. Lovastatin
       inhibits HIV-1 expression in HIV infected-human T lymphocytes
       cultured in cholesterol-poor medium. Biomedicine and
       Pharmacotherapy 1994;48:63-67

              2. McPherson R, Tsoukas C, Baines MG, et al. Effects
       of lovastatin on natural killer cell function and other
       immunological parameters in man. Journal of Clinical
       Immunology 1993;13(6):439-444.

       III IMMUNOMODULATORS

       A. Interferon-gamma for HIV/AIDS

       * STUDY DETAILS

       In the late 1980s researchers in California conducted a small
study on the effect of interferon-gamma (INF-y) in 12 subjects with
AIDS who also had Kaposi's sarcoma. The average CD4+ cell count was
56 cells and the average CD8+ cell count was 511 cells. The
researchers did not provide details about the gender of subjects.
Subjects received various doses of INF-y (up to 20 million units)
"three times per week [either intravenously] or five times per week
[via injections into muscles] for up to 8 weeks." Subjects received
INF-y on one of two schedules; either on Monday/ Wednesday/Friday or
Monday through Friday.

       * RESULTS

       No subject had increased blood levels of CD4+ or CD8+ cells
while in the study. Despite receiving high doses of INF-y several
subjects developed life-threatening lung infections after the
study.

       REFERENCES:

              1. Martinez-Maza O, Mitsuyasu RT, Miles SA, et al.
       Gamma-interferon-induced major histocompatibility complex
       class II antigen expression in individuals with Acquired
       Immunodeficiency Syndrome. Cellular Immunology
       1989;123:316-324.

       B. Interferon-gamma in the eye?

       * INTERFERON-GAMMA

       Researchers in the USA have been conducting experiments with
one herpes virus (HSV) in the eyes of mice. These researchers
injected interferon-gamma (INF-y) into the eyes of mice. They found
that injections of that immune booster protected the eye from attack
by HSV. In some mice, injection of INF-y into one eye protected the
other eye from infection. There is a direct connection between the
brain and eye. Infection of those connecting nerves can allow the
virus to enter the brain. In these experiments, although the eye was
protected, treatment with INF-y "did not prevent the virus from
spreading to the brain."

       * PROTECTION

       The researchers conducting these experiments could not
explain why the eye recovered from the viral infection but the brain
did not. Nor did they understand why the untreated eye could resist
viral infection. This is especially interesting because in a recent
study on CMV retinitis in HIV-infected humans, researchers expected
"90% of untreated eyes ...would [develop CMV retinitis] within 6
weeks". The researchers suggested that interferon may have restored
the ability of the local immune system (in the eye) to alert other
cells about the infection. Once alerted, CD8+ cells may have been
able to control the infection in the eye but not its spread to the
brain. If other researchers can confirm the protective effect of
INF-y against herpes viruses, including CMV, then perhaps
experiments on the eyes of CMV-infected humans may be considered.

       REFERENCES

              1. Mossman TR. Cytokine patterns during progression to
       AIDS. Science 1994;265:193-194.

              2. Geiger K, Howes EL and Sarvetnick N. Etopic
       expression of gamma interferon in the eye protects transgenic
       mice against intraocular herpes simplex virus type 1
       infections. Journal of Virology 1994;68(9):5556-5567.

              3. Martin DF, Parks DJ, Mellow SD, et al. Treatment of
       cytomegalovirus retinitis with an intraocular
       sustained-release ganciclovir implant. Archives of
       Ophthalmology 1994;112(12):1531-1539.

       IV INFECTION FIGHTERS

       A. CMV in the eye

       * BACKGROUND

       CMV (cytomegalovirus) infection is common in North American
patients who are also infected with HIV. Interestingly, CMV
infection does not always "result [in symptoms]" in HIV-infected
patients. CMV can cause the sight-threatening infection CMV
retinitis. As well, this virus can attack the intestines, lungs and
nerves. Nearly all cases of CMV infection occur in patients with
less than 100 CD4+ cells. Indeed, 75% of serious complications
caused by CMV happen in patients with less than 75 CD4+ cells.

       * CMV

       In North America, patients who have access to medical care
and who are able to get preventative doses of antimicrobial drugs
appear to be living longer compared to patients with AIDS at the
beginning of the epidemic. Although these patients can survive PCP,
their immune systems continue to weaken, placing them at risk for
other infections such as CMV and MAC (Mycobacterium avium complex).
In one study subjects with AIDS/ARC had a 15% chance of developing
complications due to CMV over a 2-year period. In subjects with less
than 100 CD4+ cells the risk was 21%. In another study, where
subjects received drugs to prevent PCP, 40% of subjects eventually
developed symptoms of CMV infection.

       * TREATMENT

       Standard treatment for CMV infection consists of either
ganciclovir (Cytovene(R), DHPG) or foscarnet (Foscavir(R), sodium
phosphonoformate). Ganciclovir can damage the bone marrow and
appears to affect the immune system, particularly CMI (cell-mediated
immunity). Based on results from a controlled study, HIV-infected
patients treated with foscarnet tend to survive about 4 months
longer than similar patients getting ganciclovir. Foscarnet can
cause kidney problems which can then result in seizures. Doctors and
their patients are looking for alternative ways to deliver anti-CMV
drugs to the eye. Some doctors inject anti-CMV drugs directly into
the eye. Patients will need to get twice weekly eye injections once
the retinitis clears and may be at high risk of developing
complications such as detached retinae. One new method of delivery
is to place a slow-release form of ganciclovir directly into the
eye. One problem with all of these therapies is that they do not
deal with the underlying cause of these infections; the loss of CMI
(cell-mediated immunity).

       REFERENCES:

              1. Jacobson MA. Current management of cytomegalovirus
       disease in patients with AIDS. AIDS Research and Human
       Retroviruses 1994;10(8):917-923

       B. Eye implant for CMV

       * STUDY DETAILS

       Researchers in the USA enrolled 26 adult HIV-infected
subjects of whom 25 were male and 1 female. Overall, their CD4+ cell
counts were below 25 cells. Potential subjects for this study had
never received anti-CMV drugs (ganciclovir or foscarnet) or had any
complications due to CMV infection. As well, subjects were well
enough to undergo the eye surgery necessary for this study. At the
time they entered the study, all subjects had been newly diagnosed
with CMV retinitis which was not yet sight-threatening. Doctors
randomly assigned subjects to one of two groups in this study.
Within 48 hours of entering the study, subjects in group 1 had
surgeons open and insert a small device--the implant--which slowly
released ganciclovir. Subjects in group 2 were closely monitored for
worsening retinitis. Should doctors decide that the retinitis was
becoming worse, or that CMV was infecting some other part of the
body, they recommended intravenous ganciclovir or foscarnet. Those
subjects with worsening retinitis but no other indication of CMV
infection could choose between intravenous ganciclovir/foscarnet or
the implant.

       * RESULTS

       Researchers inserted implants into 39 eyes during the study
(some eyes had their implants replaced). Fourteen eyes had implants
inserted within 48 hours of entering the study and researchers
monitored 16 other eyes for signs of worsening retinitis. Another 11
eyes entered the study free from retinitis, but later developed this
infection.

       * 226 DAYS

       About half the eyes that received the implant were protected
from worsening retinitis for at least 226 days. At first, the
implant gave all 39 eyes protection against retinitis. Indeed 30 of
39 eyes did not have retinitis that became worse.

       * THE OTHER EYE

       Twenty-one subjects entered the study with only 1 eye having
retinitis. In 14 of those subjects, the other eye became infected
with CMV during the study. By the 203rd day at least half of the 21
subjects had retinitis develop in the previously uninfected eye.

       * SURVIVAL

       About 1/3 of subjects eventually had CMV attack parts of the
body other than the eye, usually "lungs and [intestines]". Half of
the subjects died about 10 months after entering the study. Data
from a controlled study comparing foscarnet against ganciclovir
(both given intravenously) suggested that half of subjects receiving
foscarnet survived 12.5 months and those receiving ganciclovir 8.5
months.

       * EFFECTIVENESS

       Results from this trial suggests that the implant is clearly
effective in treating CMV retinitis. About half the subjects whom
the doctors assigned to be monitored (group 2) developed retinitis
within 15 days of diagnosis. By contrast, half the subjects whom the
doctors assigned to receive the implant immediately were free from
retinitis for 295 days. This difference between the two groups was
statistically significant; that is, not likely due to chance alone.
Researchers did not detect any retinitis that was resistant to
treatment with the implant. In theory the implant was supposed to be
empty "between 32 and 38 weeks". Some implants ran out of
ganciclovir before 32 weeks (because they released the drug faster
than others). This faster release may have been why 9 subjects
developed retinitis before the 32nd week. Clearly, the implant is
not perfect and the manufacturer needs to take action so that future
versions have a more reliable performance.

       * ACCESS AND COST

       In June 1994, doctors in Vancouver first inserted the implant
in a Canadian patient with CMV retinitis. Eye surgeons in Canada who
have patients newly diagnosed with CMV retinitis may call the
Emergency Drug Release Programme in Ottawa and request that their
patient be considered for receiving an implant. Chiron Vision Canada
may then decide to send the implant. The cost of an implant is
currently $5,000 (CND) and this is paid for by the patient. Canadian
doctors who want further information can call the company at
1-800-263-3557. Doctors in the USA may call Chiron Vision at their
office in Irvine, California. That number is 1-800-553-3354.

       REFERENCES:

              1.  Martin DF, Parks DJ, Mellow SD, et al. Treatment
       of cytomegalovirus retinitis with an intraocular
       sustained-release ganciclovir implant: a randomized
       controlled clinical trial. Archives of Ophthalmology
       1994;112:1531-1539.

       C. Issues about the implant

       * FIFTY PERCENT

       Given low doses of antimicrobial drugs, some patients with
AIDS in North America are living longer. While these drugs may delay
or prevent the appearance of life-threatening infections, they do
not help the immune system recover. Thus more patients are living
longer despite low CD4+ cell counts. Some researchers think that as
many as 50% of patients with AIDS in North America will develop the
sight-threatening infection CMV retinitis. Doctors in the USA
estimate that it costs about $70,000 US to treat one patient with
retinitis with intravenous ganciclovir or foscarnet for 1 year. In
relation to the cost of the implant this may be cheaper. But the
fight against CMV carries with it more than it seems. According to
one San Francisco doctor, those who care for patients with AIDS know
that blindness from CMV is what many fear most. It is all too often
the final insult that leads a patient to decide either to commit
suicide or stop all medical support.

       * A "CLUMSY DEVICE"

       One of the advantages of the implant is that concentrations
of anti-CMV drugs 4 to 5 times higher than can be achieved with
intravenous therapy can get into the eye. The device is not perfect.
Indeed, one doctor describes it as "clumsy", but it is a start in
the direction of better quality of life for patients. Hopefully,
over time, the manufacturer will create more sophisticated devices.
Perhaps more importantly, they might reduce the cost of an implant
to a level that most patients and/or health care plans can afford.

       REFERENCES:

              1. Irvine AR. Intraocular sustained release devices.
       Editorial. Archives of Ophthalmology 1995;113:25-26.

       D. A virus for Kaposi's sarcoma?

       * BACKGROUND

       At the start of the AIDS epidemic in North America doctors
noticed the appearance of formerly rare "purple blotches" or lesions
on the skin of their gay/bisexual patients. Ordinarily seen in
elderly men living in Mediterranean countries, Kaposi's sarcoma (KS)
was not usually fatal. The KS seen with the AIDS epidemic often
caused complications that killed patients. Although there are many
theories about what causes KS, none have been proven. Whatever
causes the aggressive KS in HIV-infected gay/bisexual men appears to
be spread through sex. The most recent theory suggests that a new
herpes virus may be the cause of KS. The research team that put
forward this theory has not found a virus, just traces of one. Even
if the team found a virus, they would still have to prove it causes
KS. The research team is working on a simple blood test that could
then allow them to screen patients with HIV/AIDS to see if they are
infected with the new herpes virus. If KS is caused by a herpes
virus then doctors and their HIV-infected patients with KS may wish
to experiment with anti-herpes drugs. Researchers in Sweden have
been conducting such experiments and we now report their results in
the section below.

       REFERENCES:

              1. Cohen J. Is a new virus the cause of KS? Science
       1994;266:1803-1804.

              2. Schulz TF and Weiss RA. Kaposi's sarcoma: a finger
       on the culprit. Nature 1995;373:17-18.

              3. Chang Y, Cesar E, Pessin MS, et al. Identification
       of herpes virus-like DNA sequences in AIDS-associated
       Kaposi's sarcoma. Science 1994;266:1865-1869.

       E. Foscarnet for KS?

       * BACKGROUND

       Doctors in Stockholm noticed that 2 HIV/AIDS patients who had
CMV infection and who received the anti-herpes drug foscarnet also
had their KS lesions shrink. The doctors then did a pilot study on 5
male adult subjects with AIDS who had "recently developed" KS and
gave them foscarnet.

       * STUDY DETAILS

       Four of the 5 subjects had CD4+ cell counts below 30 cells.
Testing samples of their lesions confirmed that they were indeed KS.
The subjects received foscarnet in the following schedule:

       - 60 mg/kg every 8 hours for the first 5 days
       - 90 mg/kg every 12 hours for the next 5 days

       * SUBJECT 1

       Over a period of months the lesions changed, became thinner
and nearly disappeared 12 months after receiving foscarnet.
Seventeen months after entering the study all the former lesions
reappeared.

       * SUBJECT 2

       This subject had all 15 of his lesions clear and 20 months
after receiving foscarnet he remained free from lesions.

       * SUBJECT 3

       He received 2 courses of foscarnet and his 29 lesions faded
and he remained free from lesions 15 months after receiving
foscarnet.

       * SUBJECT 4

       One subject with 6 CD4+ cells had lesions that continued to
grow despite 2 courses of foscarnet within three months and his
overall condition became worse.

       * SUBJECT 5

       The final subject had only a partial course of foscarnet and
his overall health also became worse as did the size and spread of
his lesions.

       It is interesting that in the first 3 subjects lesions on the
skin as well as others inside the body shrank. In the last 2
subjects whose overall health was also declining, foscarnet therapy
had little, if any, effect. Based on these results, foscarnet may
not work in every case of KS. It may be that some parts of the
immune system need to be intact if the drug is to work. Larger,
controlled studies testing foscarnet and other anti-herpes drugs
may confirm these promising results.

       ACKNOWLEDGEMENTS

       1. We thank Steve Johnston for access to research papers.

       REFERENCES:

              1. Morfeldt L and Torssand J. Long-term remission of
       Kaposi's sarcoma following foscarnet treatment in
       HIV-infected patients. Scandinavian Journal of Infectious
       Diseases 1994;26;749-752.

       F. Vancouver: Complications from PCP

       * BACKGROUND

       In North America, the most common life-threatening lung
infection is PCP (Pneumocystis carinii pneumonia). What can kill
patients even if they receive antibiotics is the inflammation and
fluid build up in the lungs which can then cause the patient to stop
breathing (ARF; acute respiratory failure). When patients develop
ARF they can sometimes be saved by being taken to an intensive care
unit (ICU) and connected to a respirator. To try and reduce these
complications doctors sometimes prescribe corticosteroids. Doctors
in Vancouver have been looking at hospital records to note the
effect of complications from PCP and patient survival.

       * RESULTS-SURVIVAL FALLS

       Over a 4 year period (1987-1991) doctors diagnosed 456
episodes of PCP, 9% (42 patients) developed ARF. Twenty-seven of the
42 patients had to be put on a respirator so that they could
continue breathing. Despite help from the respirator, 24 of the 27
patients died. The 3 patients who survived because of their care in
the ICU later died within 6 months of leaving the ICU. During the
years between 1987 and 1991, deaths from "PCP-related ARF" climbed
from 75 % to 100%. The researchers compared records from 1981 to
1987. During those early years of the AIDS epidemic, doctors
diagnosed "127 episodes of PCP". Twenty-seven of those patients
were sent to the ICU and hooked up to a respirator. Fifty percent of
the 27 patients survived and could leave the ICU. This huge
difference in survival rates between the early and later years of
the AIDS epidemic was statistically significant. In the period after
1987 more patients began to receive corticosteroids in addition to
anti-PCP therapy.

       * CHANGES IN CARE

       The Vancouver researchers suggest that patients who develop
ARF despite treatment with antibiotics and low-dose steroids may
have a poor chance of survival. Their review of hospital records
shows that overall, death due to PCP remained relatively the same
between 1981-1991. The researchers suggest that between 1981 and
1987 increased use of steroids resulted in fewer deaths from
PCP-related ARF. After 1987, even more doctors began to use
corticosteroids and they also used them earlier in the course of
PCP. As a result there were fewer cases of ARF related to PCP.
However, the few patients who developed ARF despite use of
corticosteroids all died.

       REFERENCES:

              1. Hawley PH, Ronco IJ, Guillemi SA, et al. Decreasing
       frequency but worsening mortality of acute respiratory
       failure secondary to AIDS-related Pneumocystis carinii
       pneumonia. Chest 1994;106(5):1456-1459.

       V TESTING

       A. Predicting eye damage from CMV

       * BACKGROUND

       In the USA, more patients with AIDS are surviving despite low
CD4+ cell counts. Researchers estimate that as many as 50% of these
patients will eventually develop the sight-threatening infection CMV
retinitis. Doctors cannot yet precisely predict when patients will
develop CMV retinitis. Currently, regular eye exams are the only way
doctors can diagnose retinitis. Although some patients report
'floaters' across their vision this does not always mean that
retinitis has begun. Indeed, healthy, non-HIV-infected people can
also have 'floaters' and this does not mean that they have eye
diseases. Current anti-CMV treatments are costly and have side
effects. If doctors could predict when retinitis will appear then
patients could begin anti-CMV therapy only when necessary.

       * BLOOD TESTS

       Researchers in San Francisco have been experimenting with
white blood cells taken from subjects with and without HIV/AIDS and
CMV retinitis. Technicians looked at the amount of CMV in white
blood cells from those subjects. Using PCR (polymerase chain
reaction) the researchers found that subjects without HIV infection
had the lowest level of CMV in their blood cells. The next highest
were subjects having between 100 and 800 CD4+ cells. They were
followed by subjects with less than 100 CD4+ cells. On average, the
subjects with the highest level of CMV were those with retinitis.
Only 50% of samples from subjects with retinitis had high levels of
CMV.

       * ONLY 50%

       That laboratory tests could not detect high levels of CMV in
nearly 50% of patients with retinitis suggests that these tests will
not be useful for every patient. One possible reason for this result
is that some subjects had the infection restricted to their eyes. In
the other cases the infection had spread beyond the eyes. According
to the researchers, "[nearly] 80% of patients in any given year with
CD4+ cell counts below 100 cells remain free from [symptoms of CMV]
infection." The researchers will continue to try and improve their
tests. According to their preliminary results, patients who have
high blood levels of CMV infection but do not have retinitis develop
this condition within 4 months of being tested.

       REFERENCES:

              1. Rasmussen L, Morris S, Zopeto D, et al.
       Quantitation of Human Cytomegalovirus DNA from peripheral
       blood cells from Human Immunodeficiency Virus-infected
       patients could predict Cytomegalovirus retinitis. Journal of
       Infectious Diseases 1995;171-182.

       B. AZT-rate of release affected by hormones and other drugs?

       * GETTING RID OF DRUGS

       When patients take a drug, the body processes it and it is
eventually released, usually into the urine or feces. The body can
also get rid of substances by releasing them into a number of
fluids, including sweat, tears and breath.

       * STUDY DETAILS

       Doctors in Amsterdam studied 63 men and 5 women to see how
the body processes and gets rid of AZT. As well, they also looked at
the interaction(s) of other drugs with AZT. The doctors collected
data from 68 subjects some of whom had symptoms of AIDS and others
who were symptom-free. Subjects were not supposed to eat overnight
nor in the morning and their blood was collected before the subjects
ate breakfast. Samples were taken both before and after subjects
took their morning dose of AZT.

       * RESULTS-SEX

       According to their results, the researchers reported that
women's bodies appear to get rid of AZT about 42% slower than men's.
The doctors checked "other possible [factors]" such as weight,
severity of illness, drug use and liver dysfunction to see if they
could by themselves affect the results. The researchers stated that
none of those factors appeared to be the cause of the difference in
"clearing" AZT. This difference between men and women was
statistically significant, that is, not likely due to chance alone.
There were only 5 women used in this experiment and perhaps a study
with more women might have found different results. However, some of
the researchers were not surprised at the different rate of
clearance of AZT. They noted that several other drugs such as
"codeine, [Tylenol(R), Valiums and related compounds]", are
processed in a similar manner to AZT and are released more slowly by
women than men. This difference in the clearing rates of drugs may
be caused by hormones.

       * OTHER DRUGS

       The researchers did not find age or liver/kidney dysfunction
to affect the rate at which the body released AZT. The researchers
also noted that many patients with HIV/AIDS take a variety of other
medications and they tried to find any interactions. Patients taking
methadone had a 45% decrease in the rate at which they got rid of
AZT. This difference was statistically significant and may mean that
patients given both AZT and methadone may need careful monitoring
for AZT toxicity. Ganciclovir and rifampin appeared to increase the
rate at which AZT is released from the body. Other drugs tested
which did not have any significant effect on the release of AZT
included: ddI, fluconazole, Bactrim/Septra(R), pyrimethamine,
acyclovir, ketoconazole, cimetidine and related drugs.

       REFERENCES:

              1. Burger DM, Meenhorst PL, ten Nopel CHH, et al.
       Pharmacokinetic variability of Zidovudine in HIV-infected
       individuals: subgroup analysis and drug interactions. AIDS
       1994;8(12):1683-1688.

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