Pharmacokinetics and analgesic potency of [Delta]9-tetrahydrocannabinol (THC)

It is known from the folk medicine that Cannabis may reduce pain. The aim of the pain study was to compare analgesic effects of oral delta-9-tetrahydrocannabinol (THC, dronabinol, Marinol‚, main psychoactive component of the Cannabis plant) and a THC-morphine combination to morphine and placebo. This pain study was performed with 12 healthy volunteers in four different experimental models of acute pain. Additionally, side effects and vital functions were monitored and blood samples collected for the pharmacokinetic profiling of oral THC. In none of the pain models THC showed a significant analgesic effect. The THC-morphine combination showed a slight tendency to an additive effect compared to morphine alone, but this was not statistically significant. The side effects observed with THC were mainly sleepiness and mild to intermediate psychotropic side effects. The plasma concentrations of THC, analysed with gas chromatography mass-spectrometry, were very low, showed a plasma peak time of 60 to 120 min with high inter-individual variation. In addition, an extensive liver first pass metabolism could be observed leading to high metabolite-THC ratios. In the second part of the present work the aim was to develop an application form as alternative to the Marinol‚ capsules. The very lipophilic THC was solubilised with Cremophor‚ RH 40 leading to a water-soluble THC formulation, which could be used as inhalation solution for the pulmonal administration of THC. This formulation underwent an in vitro quality assurance focussing on stability and physiological tolerability. Additionally, the particle size of the droplets in the aerosol and the output rate of the evaluated nebuliser system for the clinical application were determined. In the third part of this work, the developed application form (inhalation solution) was used for a second clinical study with eight healthy volunteers. The pharmacokinetic properties of pulmonal THC were compared to intravenous THC and the analgesic effects were determined comparing with pulmonal placebo. With the pulmonal application form the very low bioavailability of oral THC could be increased up to 6-fold. Comparing the elimination half-lives, a 5-fold decrease of the half-life after pulmonal and intravenous THC compared to oral THC was observed, indicating that absorption is the time-determining step in the pharmacokinetic behaviour of orally administered THC. This was also reflected by the peak plasma concentration time, which occurred right at the end of the inhalation procedure of about 20 min (3 to 6-times earlier than with oral THC). Peak plasma concentrations were much higher after pulmonal than oral administration causing much less side effects, indicating that not only THC itself is responsible for the psychotropic side effects but also the known strongly psychoactive 11-hydroxy-THC. Metabolite-THC ratios were found to be much lower after pulmonal and intravenous THC than after oral THC. The most prominent side effect of pulmonal THC was the irritation of the throat and coughing during the inhalation, which were reversible within short time after finishing the inhalation procedure. Despite the increased bioavailability of pulmonal THC no analgesic effect resulted, suggesting that the bioavailability does not affect the efficacy in the pain reducing properties of THC. We assume that the used experimental pain models, which were all models of acute pain, were not appropriate to study the analgesic properties of THC. Further experiments are needed to evaluate the appropriate pain tests for THC and healthy subjects. In addition, it would be very interesting to investigate the analgesic effect of the pulmonal THC in patients suffering from chronic and neuropathic pain

An investigation of pain mechanisms in a model of osteoarthritis : modulation by the endocannabinoid receptor system

Osteoarthritis (OA) is expected to become the fourth leading cause of disability worldwide by 2020. There is no cure, and joint replacement surgery becomes a final resort. Chronic pain associated with OA is poorly controlled by current treatments, and often involve chronic use of non-steroidal anti-inflammatory drugs (NSAIDs), which is associated with serious side-effects. OA is associated with alterations in endocannabinoid (EC), an attractive target for the control of pain. ECs are rapidly degraded by a number of enzymes, including cyclooxygenase-2 (COX- 2), the major target of NSAIDs. However, the role of COX-2 in EC-mediated effects on nociceptive transmission is not fully understood. The aims of this thesis were to investigate peripheral and spinal pain responses in a model of OA pain, understand the role of COX-2 inhibition on neuronal responses and the potential role of ECs in mediating these effects, and to establish the functional effects of the EC system in a model of OA pain. Effects of spinal and peripheral administration of the COX-2 inhibitor nimesulide (1-1 OOlJgin 501JL)on mechanically evoked responses of dorsal horn neurones in the naive, anaesthetised rat were measured, and the contribution of the CB1 receptor was determined with the antagonist AM251 (11Jgin 50IJL). Effects of nimesulide on spinal levels of ECs and related compounds were quantified using liquid chromatography-tandem mass spectrometry. Spinal, but not peripheral, injection of nimesulide significantly reduced mechanically evoked responses of dorsal horn neurones. Inhibitory effects of spinal nimesulide were blocked by the CB1 receptor antagonist AM251, but spinal EC levels were not elevated. Indeed, both anandamide and N-oleoylethanolamide were significantly decreased by nimesulide, highlighting a putative role for other oxidative enzymes of ECs in the generation of CB1-active metabolites. The monosodium-iodoacetate (MIA) model of OA pain has recently received much interest, but is not yet fully defined. Work in this thesis sought to further characterise this model. Cytokine levels in synovial fluid, spinal cord and hindpaw skin at early time-points post- intra-articular injection (1mg MIA in 50IJL, P.O. 3-24hr) were measured, and the later (P.O. day 28-31) effects on neuronal responses and pain behaviour were determined. Intra-articular injection of 1mg MIA produced stable and robust changes in two measures of pain relevant to clinical OA, and evidence for the presence of central sensitisation was demonstrated. It was also demonstrated that early-stage painful responses in this model are not associated with changes in cytokines in the joint. Effects of spinal and systemic administration of nimesulide (3-100IJg in 501JL)on mechanically evoked and post-stimulus responses of dorsal horn neurones in MIA-treated rats were also measured, as were the effects of spinal cannabinoid receptor antagonism with AM251 (0.1- 10IJg in 501JL)and the CB2 receptor antagonist SR144528 (0.001-0.1IJg in 50IJL). Spinal and systemic COX-2 inhibition in the MIA model attenuated spinal neuronal responses to both noxious and innocuous stimuli, demonstrating the importance of both spinal and peripheral COX-2 products in mediating neuronal responses in this model. Antagonism of the spinal cannabinoid receptors resulted in elevated spinal neuronal responses in MIA-treated rats, demonstrating a functional role for spinal EC-mediated modulation of nociceptive transmission in the MIA model, expanding on work in this lab which showed elevated spinal ECs in the MIA model of OA pain. This work therefore demonstrates that the central EC system may be an important target for the treatment of OA pain

The attitude of students towards their secondary school subjects

Thesis (Ed.M.)--Boston University, 1948. This item was digitized by the Internet Archive

An investigation of pain mechanisms in a model of osteoarthritis : modulation by the endocannabinoid receptor system

Osteoarthritis (OA) is expected to become the fourth leading cause of disability worldwide by 2020. There is no cure, and joint replacement surgery becomes a final resort. Chronic pain associated with OA is poorly controlled by current treatments, and often involve chronic use of non-steroidal anti-inflammatory drugs (NSAIDs), which is associated with serious side-effects. OA is associated with alterations in endocannabinoid (EC), an attractive target for the control of pain. ECs are rapidly degraded by a number of enzymes, including cyclooxygenase-2 (COX- 2), the major target of NSAIDs. However, the role of COX-2 in EC-mediated effects on nociceptive transmission is not fully understood. The aims of this thesis were to investigate peripheral and spinal pain responses in a model of OA pain, understand the role of COX-2 inhibition on neuronal responses and the potential role of ECs in mediating these effects, and to establish the functional effects of the EC system in a model of OA pain. Effects of spinal and peripheral administration of the COX-2 inhibitor nimesulide (1-1 OOlJgin 501JL)on mechanically evoked responses of dorsal horn neurones in the naive, anaesthetised rat were measured, and the contribution of the CB1 receptor was determined with the antagonist AM251 (11Jgin 50IJL). Effects of nimesulide on spinal levels of ECs and related compounds were quantified using liquid chromatography-tandem mass spectrometry. Spinal, but not peripheral, injection of nimesulide significantly reduced mechanically evoked responses of dorsal horn neurones. Inhibitory effects of spinal nimesulide were blocked by the CB1 receptor antagonist AM251, but spinal EC levels were not elevated. Indeed, both anandamide and N-oleoylethanolamide were significantly decreased by nimesulide, highlighting a putative role for other oxidative enzymes of ECs in the generation of CB1-active metabolites. The monosodium-iodoacetate (MIA) model of OA pain has recently received much interest, but is not yet fully defined. Work in this thesis sought to further characterise this model. Cytokine levels in synovial fluid, spinal cord and hindpaw skin at early time-points post- intra-articular injection (1mg MIA in 50IJL, P.O. 3-24hr) were measured, and the later (P.O. day 28-31) effects on neuronal responses and pain behaviour were determined. Intra-articular injection of 1mg MIA produced stable and robust changes in two measures of pain relevant to clinical OA, and evidence for the presence of central sensitisation was demonstrated. It was also demonstrated that early-stage painful responses in this model are not associated with changes in cytokines in the joint. Effects of spinal and systemic administration of nimesulide (3-100IJg in 501JL)on mechanically evoked and post-stimulus responses of dorsal horn neurones in MIA-treated rats were also measured, as were the effects of spinal cannabinoid receptor antagonism with AM251 (0.1- 10IJg in 501JL)and the CB2 receptor antagonist SR144528 (0.001-0.1IJg in 50IJL). Spinal and systemic COX-2 inhibition in the MIA model attenuated spinal neuronal responses to both noxious and innocuous stimuli, demonstrating the importance of both spinal and peripheral COX-2 products in mediating neuronal responses in this model. Antagonism of the spinal cannabinoid receptors resulted in elevated spinal neuronal responses in MIA-treated rats, demonstrating a functional role for spinal EC-mediated modulation of nociceptive transmission in the MIA model, expanding on work in this lab which showed elevated spinal ECs in the MIA model of OA pain. This work therefore demonstrates that the central EC system may be an important target for the treatment of OA pain

1955-04-14 Rowan County News

Rowan County News published on April 14, 1955

Development of novel small-size peptides as putative therapeutic drugs

This thesis focuses on the development of small peptide molecules with either antifungal properties or with the ability to control protein deposits that cause the characteristic brain damage in Alzheimer's disease (AD). Thus, our ultimate aim is to design putative therapeutic agents supported by computational techniques. Apropos of AD, this is a very complex disease where brain damage is associated with the degradation of the human mind and memory. Currently, researchers consent that a key role is played by a peptide called beta-amyloid. This peptide is not toxic by itself, however it becomes toxic to nerve-cells when several of its molecules clump together forming aggregates. This is the beginning of a slow but unstoppable brain deterioration, which ultimately leads to dementia. The currently available AD drugs delay, at best, the loss of memory, but do not stop the neural degradation. Its severity and the increasing number of AD patients, are the worldwide driving force to acquire more effective drugs. In our own research we focused on the development of new peptides that prevent or slow down the formation of the aggregated beta-amyloid. Computational techniques allowed us to explore the self-bound beta-amyloid molecules, as well as their interaction with new potential drugs. With this fascinating information we designed small peptides aimed at disrupting the aggregated beta-amyloid. Then, its anti-amyloid activity of was tested in vitro and in vivo. Both tests have produced not only positive but also striking and promising results indicating the potential therapeutic application of these new anti-amyloid peptides.