Endogenous opioid peptides serve as potent analgesics through the opioid receptor (OR) activation. However, they often suffer from poor metabolic stability, low lipophilicity, and low blood-brain barrier permeability. Researchers have developed many strategies to overcome the drawbacks of current pain medications and unwanted biological effects produced by the interaction with opioid receptors. Here, we tested multifunctional enkephalin analogs LYS739 (MOR/DOR agonist and KOR partial antagonist) and LYS744 (MOR/DOR agonist and KOR full antagonist) under in vivo conditions in comparison with MOR agonist, morphine. We applied 2D electrophoretic resolution to investigate differences in proteome profiles of crude membrane (CM) fractions isolated from the rat brain cortex and hippocampus exposed to the drugs (10 mg/kg, seven days). Our results have shown that treatment with analog LYS739 induced the most protein changes in cortical and hippocampal samples. The identified proteins were mainly associated with energy metabolism, cell shape and movement, apoptosis, protein folding, regulation of redox homeostasis, and signal transduction. Among these, the isoform of mitochondrial ATP synthase subunit beta (ATP5F1B) was the only protein upregulation in the hippocampus but not in the brain cortex. Contrarily, the administration of analog LYS744 caused a small number of protein alterations in both brain parts. Our results indicate that the KOR full antagonism, together with MOR/DOR agonism of multifunctional opioid ligands, can be beneficial in treating chronic pain states by reducing changes in protein expression levels but retaining analgesic efficacy.
- MeSH
- analgetika MeSH
- enkefaliny metabolismus MeSH
- hipokampus metabolismus MeSH
- krysa rodu rattus MeSH
- morfin * farmakologie MeSH
- mozek metabolismus MeSH
- opioidní analgetika farmakologie MeSH
- receptory opiátové mu * metabolismus MeSH
- receptory opiátové metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- bolest * farmakoterapie MeSH
- dítě MeSH
- fentanyl aplikace a dávkování škodlivé účinky MeSH
- lidé MeSH
- morfin aplikace a dávkování farmakologie škodlivé účinky MeSH
- opioidní analgetika * aplikace a dávkování klasifikace škodlivé účinky MeSH
- oxykodon aplikace a dávkování farmakologie MeSH
- tramadol aplikace a dávkování farmakologie škodlivé účinky MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- přehledy MeSH
Protracted opioid withdrawal is considered to be a traumatic event with many adverse effects. However, little attention is paid to its consequences on the protein expression in the rat brain. A better understanding of the changes at the molecular level is essential for designing future innovative drug therapies. Our previous proteomic data indicated that long-term morphine withdrawal is associated with altered proteins functionally involved in energy metabolism, cytoskeletal changes, oxidative stress, apoptosis, or signal transduction. In this study, we selected peroxiredoxin II (PRX II) as a marker of oxidative stress, 14-3-3 proteins as adaptors, and creatine kinase-B (CK-B) as a marker of energy metabolism to detect their amounts in the brain cortex and hippocampus isolated from rats after 3-month (3 MW) and 6-month morphine withdrawal (6 MW). Methodically, our work was based on immunoblotting accompanied by 2D resolution of PRX II and 14-3-3 proteins. Our results demonstrate significant upregulation of PRX II in the rat brain cortex (3-fold) and hippocampus (1.3-fold) after 3-month morphine abstinence, which returned to the baseline six months since the drug was withdrawn. Interestingly, the level of 14-3-3 proteins was downregulated in both brain areas in 3 MW samples and remained decreased only in the brain cortex of 6 MW. Our findings suggest that the rat brain cortex and hippocampus exhibit the oxidative stress-induced vulnerability represented by compensatory upregulation of PRX II after three months of morphine withdrawal.
- MeSH
- abstinenční syndrom * metabolismus MeSH
- hipokampus metabolismus MeSH
- krysa rodu rattus MeSH
- morfin metabolismus MeSH
- mozek metabolismus MeSH
- peroxiredoxiny metabolismus farmakologie MeSH
- proteiny 14-3-3 metabolismus MeSH
- proteomika MeSH
- upregulace MeSH
- závislost na morfiu * MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
x
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- MeSH
- buprenorfin * aplikace a dávkování farmakologie terapeutické užití MeSH
- chronická bolest etiologie farmakoterapie prevence a kontrola MeSH
- lidé MeSH
- management bolesti metody MeSH
- morfin terapeutické užití MeSH
- nádorová bolest farmakoterapie prevence a kontrola MeSH
- opioidní analgetika farmakologie klasifikace škodlivé účinky terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
BACKGROUND: Opioids and epidural analgesia are a mainstay of perioperative analgesia but their influence on cancer recurrence remains unclear. Based on retrospective data, we found that cancer recurrence following colorectal cancer surgery correlates with the number of circulating tumor cells (CTCs) in the early postoperative period. Also, morphine- but not piritramide-based postoperative analgesia increases the presence of CTCs and shortens cancer-specific survival. The influence of epidural analgesia on CTCs has not been studied yet. METHODS: We intend to enroll 120 patients in four centers in this prospective randomized controlled trial. The study protocol has been approved by Ethics Committees in all participating centers. Patients undergoing radical open colorectal cancer surgery are randomized into epidural, morphine, and piritramide groups for perioperative analgesia. The primary outcome is the difference in the number of CTCs in the peripheral blood before surgery, on the second postoperative day, and 2-4 weeks after surgery. The number of CTCs is measured using molecular biology methods. Perioperative care is standardized, and relevant data is recorded. A secondary outcome, if feasible, would be the expression and activity of various receptor subtypes in cancer tissue. We intend to perform a 5-year follow-up with regard to metastasis development. DISCUSSION: The mode of perioperative analgesia favorably affecting cancer recurrence would decrease morbidity/mortality. To identify such techniques, trials with long-term follow-up periods seem suboptimal. Given complex oncological therapeutic strategies, such trials likely disable the separation of perioperative analgesia effects from other factors. We believe that early postoperative CTCs presence/dynamics may serve as a sensitive marker of various perioperative interventions ́ influences on cancer recurrence. Importantly, it is unbiased to the influence of long-term factors and minimally invasive. Analysis of opioid/cannabinoid receptor subtypes in cancer tissue would improve understanding of underlying mechanisms and promote personalization of treatment. We are not aware of any similar ongoing studies. TRIAL REGISTRATION NUMBER: NCT03700411, registration date: October 3, 2018. STUDY STATUS: recruiting.
- MeSH
- epidurální analgezie * MeSH
- kolorektální nádory * chirurgie MeSH
- lidé MeSH
- lokální recidiva nádoru MeSH
- morfin MeSH
- multicentrické studie jako téma MeSH
- nádorové cirkulující buňky * MeSH
- opioidní analgetika terapeutické užití MeSH
- prospektivní studie MeSH
- randomizované kontrolované studie jako téma MeSH
- retrospektivní studie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- protokol klinické studie MeSH
BACKGROUND AND PURPOSE: Opioids and benzodiazepines are frequently combined in medical as well as in non-medical contexts. At high doses, such combinations often result in serious health complications attributed to pharmacodynamics interactions. Here, we investigate the contribution of the metabolic interactions between oxycodone, diazepam and diclazepam (a designer benzodiazepine) in abuse/overdose conditions through ex vivo, in vivo and in silico approaches. EXPERIMENTAL APPROACH: A preparation of pooled human liver microsomes was used to study oxycodone metabolism in the presence or absence of diazepam or diclazepam. In mice, diazepam or diclazepam was concomitantly administered with oxycodone to mimic acute intoxication. Diclazepam was introduced on Day 10 in mice continuously infused with oxycodone for 15 days to mimic chronic intoxication. In silico modelling was used to study the molecular interactions of the three drugs with CYP3A4 and 2D6. KEY RESULTS: In mice, in acute conditions, both diazepam and diclazepam inhibited the metabolism of oxycodone. In chronic conditions and at pharmacologically equivalent doses, diclazepam drastically enhanced the production of oxymorphone. In silico, the affinity of benzodiazepines was higher than oxycodone for CYP3A4, inhibiting oxycodone metabolism through CYP3A4. Oxycodone metabolism is likely to be diverted towards CYP2D6. CONCLUSION AND IMPLICATIONS: Acute doses of diazepam or diclazepam result in the accumulation of oxycodone, whereas chronic administration induces the accumulation of oxymorphone, the toxic metabolite. This suggests that overdoses of opioids in the presence of benzodiazepines are partly due to metabolic interactions, which in turn explain the patterns of toxicity dependent on usage. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.
- MeSH
- benzodiazepiny toxicita MeSH
- cytochrom P-450 CYP3A MeSH
- diazepam farmakologie MeSH
- lidé MeSH
- modely u zvířat MeSH
- myši MeSH
- opioidní analgetika toxicita MeSH
- oxykodon * MeSH
- oxymorfon MeSH
- předávkování léky * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE OF THE STUDY Many physicians believe that loco-regional anaesthesia and analgesia improve the postoperative course of patients indicated for total hip arthroplasty compared to general anaesthesia. However, there are many patients who refuse subarachnoid or epidural anaesthesia, or have contraindications or conditions making the use of such techniques impossible. An alternative option is the combination of general anaesthesia and a peripheral nerve blockade. The aim of this prospective randomized open-label clinical trial was to compare the efficacy and quality of postoperative analgesia between fascia iliaca block combined with general anaesthesia (GA) and subarachnoid anaesthesia with morphine and bupivacaine (SAB). MATERIAL AND METHODS After having obtained the ethics committee approval and the patients consent, a prospective, open-label, randomized trial was conducted in patients referred for total hip arthroplasty (THR). The GA group was administered ultrasound-guided fascia iliaca block with 40 ml of 0.25% bupivacaine solution after the induction of general anaesthesia. In the SAB group, subarachnoid blockade was performed with a mixture of 3 ml of 0.5% bupivacaine with 0.150 mg morphine prepared in the hospital pharmacy. Right after surgery the patients were taken to the ICU for 24 hours, after which they were transferred to a general ward. In addition to vital signs monitoring, pain intensity using a 0-10 numeric rating scale (NRS), first morphine administration at NRS >4, total morphine consumption and potential adverse effects were observed over the period of 72 hours. RESULTS There was no statistical difference between the GA (14 persons) and the SAB (14 persons) group in demographic parameters, time to first morphine administration (10 hrs vs. 19 hrs, p=0.10), number of persons with no need for morphine after surgery (5 vs. 7), tingling sensation (1 vs. 0) or numbness of the limb (0 vs. 1). There was no difference in cardiorespiratory parameters or side effects of therapy. In neither case was there respiratory depression or delayed rehabilitation. No patient developed delirium after surgery, and no patient reported dissatisfaction with pain management. DISCUSSION The fascia iliaca block and subarachnoid anaesthesia using local anaesthetic with opioid addition have been repeatedly published for patients after total hip arthroplasty, but this study is unique by comparing the two methods. The study added a new piece of knowledge to the findings of several recent meta-analyses on the comparable outcomes of general and subarachnoid anaesthesia for hip replacement in the perioperative period. CONCLUSIONS If subarachnoid anaesthesia cannot be used in hip arthroplasty, general anaesthesia with fascia iliaca block provides comparable analgesia and quality of postoperative course. Key words: total hip arthroplasty, general anaesthesia, fascia iliaca block, subarachnoid anaesthesia, postoperative analgesia, postoperative course.
- MeSH
- bupivakain terapeutické užití MeSH
- celková anestezie MeSH
- fascie MeSH
- lidé MeSH
- morfin terapeutické užití MeSH
- náhrada kyčelního kloubu * škodlivé účinky MeSH
- nervová blokáda * metody MeSH
- pooperační bolest farmakoterapie etiologie prevence a kontrola MeSH
- prospektivní studie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
- MeSH
- bolest farmakoterapie MeSH
- delirium farmakoterapie MeSH
- dyspnoe farmakoterapie MeSH
- hydratace organismu MeSH
- lidé MeSH
- midazolam aplikace a dávkování terapeutické užití MeSH
- morfin farmakologie terapeutické užití MeSH
- nádory * komplikace MeSH
- paliativní péče metody psychologie MeSH
- péče o umírající * metody psychologie MeSH
- umírající psychologie MeSH
- úzkost farmakoterapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
This review summarizes our work in the field of syn-thesis of natural products and their derivatives. Applica-tion of modern synthetic method is discussed in the con-text of the syntheses of both enantiomers of hydromor-phone, (–)-tetrodotoxin (a marine toxin), and selaginpul-vilins C and D (natural fluorene derivatives). Further, syn-thesis of notoincisol A, selagibenzophenones A and B is described to clarify the structural aspects of the com-pounds. Last but not least, synthesis and pharmaceutical profilation of derivatives of magnolol and honokiol is dis-cussed as well.Fulltext of this article is available on the website of this Journal.
- MeSH
- alkyny chemická syntéza chemie MeSH
- biologické přípravky MeSH
- hydromorfon chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- lignany chemická syntéza chemie MeSH
- polyacetyleny chemická syntéza chemie MeSH
- polycyklické sloučeniny chemická syntéza chemie MeSH
- Selaginellaceae chemie MeSH
- techniky syntetické chemie * metody MeSH
- tetrodotoxin chemická syntéza chemie farmakologie MeSH
- vyvíjení léků MeSH
- Check Tag
- lidé MeSH
