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SUMMARY
Introduction
The thesis is focused on the research of efficacy and side effects of non-traditional, i.e. nasal administration of oxytocin and nasal and intramuscular administration of remifentanil. Nasal administration has the advantage of being non-invasive and useful in situations with difficult vein access (young children, extensive burns, terrorist attacks and battlefields). The dissertation has two parts that are closely related: nasal, intramuscular and conjunctival administration of remifentanil, nasal and intramuscular administration of oxytocin. Remifentanil is an ultra-short- acting opioid that is registered for intravenous administration only. Its main advantage over other opioids is its rapid metabolism after intravenous administration and absent accumulation even after prolonged infusion. Remifentanil is the only opioid for which, with the exception of two papers, intranasal administration has not been described yet; data on intramuscular and conjunctival administration are completely lacking. Oxytocin is a hormone that is used therapeutically primarily for its peripheral effects in the uterus and breast during pregnancy.
However, other central effects have also been observed, i.e. anxiolytic effect, reduction of social stress levels and increase in empathy. It can be useful in premedication of patients, psychological relaxation of integrated rescue system crews after intervention and generally for induction of sedation and anxiolysis non-invasively. However, data on efficacy after nasal administration in experimental settings other than monitoring of sexual activity are scarce.
The aims
The aim of the study was to evaluate the efficacy and safety of intramuscular, nasal and conjunctival administration of remifentanil in experimental animals (rabbits) and nasal and intramuscular administration of oxytocin (in rhesus macaque monkeys and rabbits) before further human trials.
Methods
For non-traditional administration of remifentanil, rabbits (n=10 in each group) were randomized into six groups: remifentanil 1 μg/kg and 3 μg/kg i.m., 5.0 μg/kg and 10.0 μg/kg conjunctival, and 10 μg/kg and 25.0 μg/kg intranasal. Sedative effects were assessed by loss of righting reflex. In all rabbits, mean arterial blood pressure was monitored by non-invasive means, arterial blood oxygen saturation by pulse oximetry, and heart rate. Ocular irritation was measured using the original standard EN ISO 10993-10 (855220). Plasma remifentanil
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concentration was measured in some rabbits after onset of remifentanil effect and after a further 10 min by gas chromatography. Oxytocin was tested in 20 rabbits and 20 monkeys nasally and intramuscularly. The dose was 5 IU (8.5 μg) in all cases, i.e. 2.5 μg/kg (1.5 IU/kg) in rabbits and 2.1 μg/kg (1.2 IU/kg) in monkeys. Sedative effects in the rabbit were measured by loss of righting reflex, in monkeys by a 3-point scale: 0 - agitated, aggressive, 1 - lightly sedated, tolerates touch but observes surroundings, 2 - heavily sedated, eyes closed. Measurements of cardiorespiratory parameters were identical to the first study.
Statistical analysis was performed in a department of biostatistics. Results with normal distribution were statistically processed by two-way ANOVA test for repeated measures with post-hoc Tukey's t-test. For data, which after transformation (logarithm, square root) did not have a normal distribution, non-parametric methods, i.e. the Friedman analysis and Kruskal- Wallis analysis, were used. Bonferroni correction were used for multiple comparisons. All tests were two-sided, and a P<0.05 was assumed to be statistically significant.
Conclusion
Remifentanil administered by all non-traditional routes has demonstrated high efficacy and safety, opening the way for further trials in humans, especially after intramuscular and nasal routes of administration. The results of the oxytocin experiment demonstrated previously unpublished differences between different groups of experimental animals. The results in primates deserve further experiments for future use in human medicine.
Keywords: remifentanil, oxytocin, animal experiment, nasal administration, intramuscular administration, conjunctival administration
