Browsing Pathways

Zidovudine is a nucleoside reverse transcriptase inhibitor (NRTI) used in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV) infections. When HIV infects a cell, the virus first binds and fuses with the cell, releasing its nucleocapsid containing its RNA and reverse transcriptase into the cytosol of the cell. The reverse transcriptase converts the viral RNA into viral DNA in the cytosol. The viral DNA goes to the nucleus through the nuclear pore complex where it undergoes the process of transcription. The new viral RNA formed from transcription is transported back to the cytosol through the nuclear pore complex and translation occurs to produce viral proteins. These viral proteins are assembled and new HIV viruses bud from the cell. Zidovudine enters the cell via solute carrier family 22 member 6 and is converted into zidovudine monophosphate by thymidine kinase. Thymidylate kinase then converts zidovudine monophosphate into zidovudine diphosphate. Zidovudine diphosphate is metabolized to zidovudine triphosphate via nucleoside diphosphate kinase A. Zidovudine triphosphate is an analog of deoxyguanosine triphosphate (dGTP). Zidovudine diphosphate inhibits the activity of HIV-1 reverse transcriptase by competing with its substrate, dGTP and by incorporation into viral DNA. Zidovudine triphosphate lacks the 3'-OH group which is needed to form the 5′ to 3′ phosphodiester linkage essential for DNA chain elongation, therefore, once Zidovudine triphosphate gets incorporated into DNA, this causes DNA chain termination, preventing the growth of viral DNA. Less viral proteins are therefore produced, and there is a reduction in new viruses being formed. Zidovudine has a high frequency of side effects that limits its use. Side effects of taking zidovudine may include nausea, vomiting, diarrhea, headaches, myalgia, insomnia, bone marrow suppression, peripheral myopathy, elevated liver enzyme, lactic acidosis and hepatotoxicity.

The discovery of AIDS prompted the search for agents that block the HIV replication process. Zidovudine (AZT) is a nucleoside analogue of thymidine, and was shown to reduce considerably the mortality of patients with AIDS. Zidovudine is toxic to the hemtopoietic system, causing anemia and neutropenia. It is clear, however, that disease progression can occur during continued administration of zidovudine. Moreover, zidovudine is not effective in treating Kaposi sarcoma, a common complication of HIV infection. Zidovudine therapy is also associated with a high incidence of toxicity, primarily bone marrow suppression, that requires dosage reduction or discontinuation of the therapy.

Ziconotide, also known as SNX-111, is an N-type calcium channel antagonist used to manage patients with severe chronic pain who cannot tolerate, or who have not responded adequately to other treatments such as intrathecal morphine and systemic analgesics. Ziconotide is a neurotoxic peptide derived from the cone snail Conus magus comprising 25 amino acids with three disulphide bonds. It is used to manage severe chronic pain through the inhibition of N-type calcium channels involved in nociceptive signalling.Ziconotide was granted FDA approval on December 28, 2004 under the brand name Prialt. To date, ziconotide is the only calcium channel blocking peptide approved for use by the FDA. Nociceptive pain signalling is a complex processing pathway involving peripheral nociceptors, primary afferent nerve fibres, and downstream CNS neurons located in the spinal cord such as the dorsal root ganglion. Voltage-gated calcium channels (VGCCs) are important regulatory components of neural signalling, including type-N voltage-gated calcium channels. N-type channel activate lightly myelinated Aδ- and C-fibres, which mediate the release of neurotransmitters substance P, calcitonin gene-related peptide (CGRP), and glutamate. This causes downstream nociceptive neuronal activity and pain perception. Substance P and CGRP both also induce inflammation, further exasperating chronic pain. Ziconotide inhibits Voltage-dependent N-type calcium channels in presynaptic neurons. This prevents calcium from entering the neuron which prevents neurotransmitter release from the dorsal root ganglion as well as other nociceptive neurons. Therefore substance P, CGRP, and glutamate are not released into the synapse and cannot activate the substance P receptors, CGRP receptors, or the N-Methyl-D-aspartic acid receptors on the post-synaptic neuron. This causes hyperpolarization, with a down-stream effect of hyperalgesia, a prevention of pain signalling.

Ziconotide, also known as SNX-111, is an N-type calcium channel antagonist used to manage patients with severe chronic pain who cannot tolerate, or who have not responded adequately to other treatments such as intrathecal morphine and systemic analgesics. Ziconotide is a neurotoxic peptide derived from the cone snail Conus magus comprising 25 amino acids with three disulphide bonds. It is used to manage severe chronic pain through the inhibition of N-type calcium channels involved in nociceptive signalling.Ziconotide was granted FDA approval on December 28, 2004 under the brand name Prialt. To date, ziconotide is the only calcium channel blocking peptide approved for use by the FDA. Nociceptive pain signalling is a complex processing pathway involving peripheral nociceptors, primary afferent nerve fibres, and downstream CNS neurons located in the spinal cord such as the dorsal root ganglion. Voltage-gated calcium channels (VGCCs) are important regulatory components of neural signalling, including type-N voltage-gated calcium channels. N-type channel activate lightly myelinated Aδ- and C-fibres, which mediate the release of neurotransmitters substance P, calcitonin gene-related peptide (CGRP), and glutamate. This causes downstream nociceptive neuronal activity and pain perception. Substance P and CGRP both also induce inflammation, further exasperating chronic pain. Ziconotide inhibits Voltage-dependent N-type calcium channels in presynaptic neurons. This prevents calcium from entering the neuron which prevents neurotransmitter release from the dorsal root ganglion as well as other nociceptive neurons. Therefore substance P, CGRP, and glutamate are not released into the synapse and cannot activate the substance P receptors, CGRP receptors, or the N-Methyl-D-aspartic acid receptors on the post-synaptic neuron. This causes hyperpolarization, with a down-stream effect of hyperalgesia, a prevention of pain signalling.