PubMed · 14221113
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S M FREE, J W WILSON. 1964. A MATHEMATICAL CONTRIBUTION TO STRUCTURE-ACTIVITY STUDIES.. https://doi.org/10.1021/jm00334a001
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Intramuscular injections are still part of routine care in the treatment of children. Vaccines, premedications and analgesics are administered by this route. The pain associated with an intramuscular injection is severe, the risk of complications is increased, and pharmacodynamics and pharmacokinetics are unpredictable. In many cases, equivalent alternatives of rectal, oral or intranasal routes of administering pharmacologic agents exist. Intramuscular injection of analgesics and premedications to children are-except in case of emergencies-obsolete. This demand corresponds to the guidelines of the World Health Organization (WHO) and the International Association for the Study of Pain (IASP).
We are reporting on the case of an 11-year old girl with a malignant tumour. The extreme pain throughout the body could not be treated by conventional methods. By intravenous application of a morphine and s-ketamine mixture we were able to achieve a very effective analgesic result. Apart from the opiate effect of the morphine the decisive factor was the NMDA-antagonism of the s-ketamine. The latter suppresses central sensitisation and chronic pain and reduces or even prevents the development of opioid tolerance. It was possible to use smaller opiate doses more effectively, thus reducing the side effects of the pain therapy. Under associated whole-body thermochemotherapy the girl experienced general pain relief and we were able to return to conventional therapy with a fentanyl plaster.
A series of 2'-fluoro-3'-(substituted phenyl)deschloroepibatidine analogues (5a-k) showed high affinity for alpha4beta2 binding with no affinity at alpha7 nAChRs. The most potent compound was 2'-fluoro-3'-(4-nitrophenyl)deschloroepibatidine (5g) which possessed a Ki value of 0.009 nM. Surprisingly, none of the compounds showed agonist effects in pain tests and body temperature changes in mice even when tested at 10-15 mg/kg with the exception of 5b, which showed only very weak agonist effects. In contrast, all the compounds were potent functional antagonists of nicotine-induced antinociception. Interestingly, the 3'-substituted phenyl analogues 5b-k were 10-870-fold more effective as antagonists in the tail-flick test versus the hot-plate procedure. They failed to antagonize nicotine-induced hypothermia. The 4-chlorophenyl analogue (5e) (AD50 = 0.0003 in the tail-flick test) was the most potent and selective analogue. These results suggest that these compounds will be highly useful for identifying which specific receptor subtypes are involved in each of nicotine's pharmacological effects. These compounds also deserve consideration as potential pharmacotherapies for treatment of smoking cessation.