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Timothy Clark
Medicinal Chemistry
• Human immunodeficiency virus (HIV) is a lentivirus (a member of the
retrovirus family) that causes acquired immunodeficiency syndrome
(AIDS), a condition in humans in which the immune system begins to fail,
leading to life-threatening opportunistic infections. Infection with HIV
occurs by the transfer of blood, semen, vaginal fluid, pre-ejaculate, or
breast milk. Within these bodily fluids, HIV is present as both free virus
particles and virus within infected immune cells. The four major routes of
transmission are unsafe sex, contaminated needles, breast milk, and
transmission from an infected mother to her baby at birth
• Lentivirus (lenti-, Latin for "slow") is a genus of slow viruses of the
Retroviridae family, characterized by a long incubation period. Lentiviruses
can deliver a significant amount of genetic information into the DNA of the
host cell and have the unique ability among retroviruses of being able to
replicate in non-dividing cells, so they are one of the most efficient
methods of a gene delivery vector.
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HIV infects primarily vital cells in the human immune system such as helper T cells (to be
specific, CD4+ T cells), macrophages, and dendritic cells. HIV infection leads to low levels of
CD4+ T cells through three main mechanisms: First, direct viral killing of infected cells; second,
increased rates of apoptosis in infected cells; and third, killing of infected CD4 + T cells by CD8
cytotoxic lymphocytes that recognize infected cells. When CD4+ T cell numbers decline below a
critical level, cell-mediated immunity is lost, and the body becomes progressively more
susceptible to opportunistic infections.
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T helper cells (also known as Th cells) are a sub-group of lymphocytes (a type of white blood
cell or leukocyte) that play an important role in establishing and maximizing the capabilities of
the immune system. These cells are unusual in that they have no cytotoxic or phagocytic
activity; they cannot kill infected host cells or pathogens, and without other immune cells they
would usually be considered useless against an infection. Th cells are involved in activating and
directing other immune cells, and are particularly important in the immune system. They are
essential in determining B cell antibody class switching, in the activation and growth of
cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages. It
is this diversity in function and their role in influencing other cells that gives T helper cells their
name. Mature Th cells are believed to always express the surface protein CD4. T cells expressing
CD4 are also known as CD4+ T cells.
• Early Symptoms of HIV
The earliest symptoms of HIV
infection occur while your body begins
to form antibodies to the virus (known
as seroconversion) between six weeks
and three months after infection with
the HIV virus. Those who do show
early HIV symptoms will develop flulike symptoms. This can include: fever,
rash, muscles aches and swollen lymph
nodes and glands. However, for most
people, the first symptoms of HIV will
not be apparent.
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Although the infection is slowly taking hold of your body, the majority of those infected with HIV
will be asymptomatic. Only by being tested for HIV can you know for sure if you have been infected.
Yet, despite the absence of HIV symptoms, you are still highly contagious during this time making it
very much a possibility to infect others
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Without treatment, people infected with HIV can expect to develop AIDS eight to ten years after
HIV infection. Taking HIV medications, however, can slow down this progression. With treatment, it
can take ten to 15 years or more before you develop AIDS. In the later stages of HIV, before it
progresses to full blown AIDS, signs of HIV infection can involve more severe symptoms
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chronic yeast infections or thrush
Fever and/or night sweats
Easy bruising
Bouts of extreme exhaustion
Unexplained body rashes
Appearance of purplish lesions on the skin or inside mouth
Sudden unexplained weight loss
Chronic diarrhea lasting for a month or more
Symptoms of AIDS
To be diagnosed with AIDS, your T4 cell count must drop
to below 200 per cubic millimeter (in healthy adults, a T4
cell count of 1,000 or more per millimeter is normal) or be
infected with an opportunistic infection. Opportunistic
infections are so named because they take advantage of
your weakened immune system. The Centers for Disease
Control and Prevention maintains a list of those illnesses
that are deemed to be opportunistic infections and lead to
an AIDS diagnosis.
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Kaposi's Sarcoma
Pulmonary tuberculosis
Candidiasis of the esophagus, trachea, bronchi or lungs
Toxoplasmosis of the brain
Severe bacterial infections
Invasive cervical cancer
Recurrent pneumonia
Additionally, vision loss, nerve damage and
brain impairment can also occur. Signs of
brain deterioration include troubles thinking,
loss of co-ordination and balance and
behavioral changes.
• HIV is found in blood and other body fluids such as semen and
vaginal fluids. It cannot live for long outside the body, so to be
infected with HIV you need to allow some body fluid from an
infected person to get inside your body. The virus can enter the body
via contact with the bloodstream or by passing through delicate
mucous membranes, such as inside the vagina, rectum or urethra.
• The most common ways that people become infected with HIV are:
• having sexual intercourse with an infected partner.
• injecting drugs using a needle or syringe that has been used by
someone who is infected.
• as a baby of an infected mother, during pregnancy, labour or
delivery, or through breastfeeding.
• In virology, superinfection is the process by
which a cell, that has previously been infected
by one virus, gets coinfected with a different
strain of the virus, or another virus at a later
point in time. Viral superinfections of serious
conditions can lead to resistant strains of the
virus, which may prompt a change of treatment.
For example, an individual superinfected with
two separate strains of the HIV virus may
contract a strain that is resistant to antiretroviral
treatment. The combined infection has also
been shown to reduce the overall effectiveness
of the immune response.
• In medicine, superinfection is an infection
following a previous infection, especially when
caused by microorganisms that are resistant or
have become resistant to the antibiotics used
earlier.
The rate of superinfection — re-infection
of an HIV-positive person with a second
strain of the virus — appears to be higher
than previously thought, at least among
gay men not on treatment.
HIV/AIDs Treatment
• antiretroviral drug treatment
• The aim of antiretroviral treatment is to keep the amount
of HIV in the body at a low level. This stops any
weakening of the immune system and allows it to recover
from any damage that HIV might have caused already.
• Taking two or more antiretroviral drugs at a time is called
combination therapy. Taking a combination of three or
more anti-HIV drugs is sometimes referred to as Highly
Active Antiretroviral Therapy (HAART).
• If only one drug was taken, HIV would quickly become
resistant to it and the drug would stop working. Taking
two or more antiretroviral at the same time vastly reduces
the rate at which resistance would develop, making
treatment more effective in the long term.
Groups of Antiretroviral Drugs
• Nucleoside/Nucleotide Reverse Transcriptase
Inhibitors NRTIs- NRTIs interfere with the action
of an HIV protein called reverse transcriptase,
which the virus needs to make new copies of itself.
• Non-Nucleoside Reverse Transcriptase InhibitorsNNRTIs also stop HIV from replicating within
cells by inhibiting the reverse transcriptase protein.
• Protease Inhibitors- PIs inhibit protease, which is
another protein involved in the HIV replication
process.
• Fusion or Entry Inhibitors- Fusion or entry
inhibitors prevent HIV from binding to or entering
human immune cells.
• Integrase Inhibitors- Integrase inhibitors interfere
with the integrase enzyme, which HIV needs to
insert its genetic material into human cells.
Nucleoside/Nucleotide Reverse
Transcriptase Inhibitors
Treating HIV Link
Nucleoside/Nucleotide Reverse
Transcriptase Inhibitors Drugs
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Lamivudine, Epivir
Abacavir, Ziagen
Zidovudine, Retrovir
Stavudine, Zerit
Didanosine, Videx EC
emtricitabine, Emtriva
Tenofovir, Viread
Nucleoside/Nucleotide Reverse
Transcriptase Inhibitors Drugs
Lamivudine, Epivir
Zidovudine, Retrovir
Non-Nucleoside Reverse Transcriptase
Inhibitors
Non-Nucleoside Reverse Transcriptase
Inhibitors Drugs
• Delavirdine,
Rescriptor
• Efavirenz,
Sustiva
• Etravirine,
Intelence
• Nevirapine,
Viramune
Non-Nucleoside Reverse Transcriptase
Inhibitors Drugs
Efavirenz, Sustiva
Delavirdine, Rescriptor
Protease Inhibitors Drugs
•Saquinavir, Fortovase
•Ritonavir, Norvir
•Indinavir, Crixivan
•Nelfinavir, Viracept
•Amprenavir, Agenerase
Protease Inhibitors Drugs
Ritonavir
Fusion or Entry Inhibitors
Fusion or Entry Inhibitors Drugs
• Enfuvirtide, Fuzeon
Requires extensive patient
counseling on injection
technique, adherence, and
management of possible
side effects.
• Maraviroc Many drug-drug
interactions; dose
adjustment needed with
many other antiretrovirals
and/or other medications.
Consult current information
before prescribing.
Fusion or Entry Inhibitors Drugs
Maraviroc
Enfuvirtide, Fuzeon
Integrase Inhibitors
• are a class of antiretroviral drug designed to block the action of
integrase, a viral enzyme that inserts the viral genome into the
DNA of the host cell. Since integration is a vital step in retroviral
replication, blocking it can halt further spread of the virus.
Integrase inhibitors were initially developed for the treatment of
HIV infection, but they could be applied to other retroviruses.
• Elvitegravir (GS 9137 or JTK-303), licensed by Gilead Sciences from
Japan Tobacco, is currently undergoing Phase 2 clinical trials. GS
9137 is a low-molecular-weight, highly selective integrase inhibitor
that shares the core structure of quinolone antibiotics.
• MK-2048, a second generation integrase inhibitor, that appears to
have a duration of action up to 4 times longer than raltegravir
Clinical Trials Link
Journal Article
• 1. Describe the differences between the HIV 1
type and HIV 2?
• Draw a structure from each of the five antiHIV drugs. (NRTIs, NNRTIs, Fusion Inhibitors,
Integrase Inhibitors, and Protease Inhibitors.)
• Describe the mechanism of action of NRTIs
and NNRTIs, explain the similarities and
differences between the two.
• What is a Superinfection?
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Divisions of HIV/AIDS Prevention (2003). "HIV and Its Transmission". Centers for Disease
Control & Prevention. http://www.cdc.gov/HIV/pubs/facts/transmission.htm.
UNAIDS, WHO (December 2007). "2007 AIDS epidemic update" (PDF).
http://data.unaids.org/pub/EPISlides/2007/2007_epiupdate_en.pdf. Retrieved 201004-12.
"HIV/ AIDs." EMedicineHealth (2010): 1-3. WebMD. Web. 6 Apr. 2010.
<www.avert.org/new-aids-drugs.hmt>.
“HIV/ AIDs” EMedicineHealth (2010): 1-5. WebMD. Web. 6 Apr. 2010
www.avert.org/aids-drugs-table.hmt
Douek DC, Roederer M, Koup RA (2009). "Emerging concepts in the
immunopathogenesis of AIDS". Annu. Rev. Med. 60: 471–84.
Schneider MF, Gange SJ, Williams CM, Anastos K, Greenblatt RM, Kingsley L, Detels R,
Munoz A (2005). "Patterns of the hazard of death after AIDS through the evolution of
antiretroviral therapy: 1984–2004". AIDS 19 (17): 2009–18.
Department of Health and Human Services Panel on Clinical Practices for Treatment of
HIV Infection (October 6, 2005). "Guidelines for the Use of Antiretroviral Agents in HIV1-Infected
National Institutes of Health (October 15, 2006) “The HIV/ AIDs Fact Sheet”.