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Preclinical investigation of analgesic drug candidates in combination
thesisposted on 09.02.2017, 05:14 by Kolosov, Anton
Many millions of people suffer from pain that persists for months or years. These include the pain from inflammatory diseases such as arthritis, or from degenerative diseases e.g. chronic back pain, or from nerve damage due to infections such as post herpetic neuralgia (shingles) or cancer. Current therapeutic options fall short of what is ideal. Many pains are either resistant to drug based therapies so that the drugs used in treatments have to be administered at doses that cause side effects. Approximately one third of patients with chronic pain have pain due to nerve damage. This is called neuropathic pain and it is particularly resistant to therapy with opioids (morphine like drugs). A process in the nervous system called sensitisation causes this resistance to opioids so that therapeutic effect has to be balanced against side effects that increase with dose. Dose-related side effects such as sedation and confusion impact adversely on quality of life. More therapeutic agents are needed in this area, particularly compounds that are effective in sensitisation states. Many spinal cord mechanisms involved with pain neurotransmission and modulation have been identified. These involve receptors and ion channels that each contribute to the onward transmission of incoming pain signal information. They are often arranged in parallel such that a drug blocking or interacting with one specific element causes none or minimal effect on the overall system function and the resulting nociception or pain experience. It would be better to use two drugs that interact at different points in the system rather than to use one compound targeting one specific point at a high dose in an attempt to increase the antinociceptive effect. The question addressed in this thesis is whether such multi-drug combinations can lead to greater antinociception than can be achieved with the drugs when given alone and furthermore, to achieve that with no dose related side effects. This philosophy was used to design several series’ of experiments, each in three parts. In the first part of each drug’s investigation was established whether lower doses of the compound produced sedation and cardiovascular effects. Only doses of the compounds that caused no such effects were then investigated for antinociceptive activity. In the second part, dose response curves for the reversal of hyperalgesia in a variety of rat pain models were constructed: paw inflammation, diabetic neuropathy, cancer or chemotherapy. These experiments were performed for administration of four compounds given alone and in the third part of the study, when administered in combinations with non-sedating doses of other analgesics that target a different part of the pain pathways. Thus it was possible using this approach to identify doses of all four drugs given alone and in drug combinations that caused analgesic or antinociceptive properties at doses below those which cause side-effects and further to determine if these combinations achieved the goal: increased antinociceptive effect greater than could be achieved with either compound alone and without causing unwanted side effects.