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Introduction: Dronabinol is approved in the USA for chemotherapy-induced nausea as well as vomiting and HIV-induced anorexia, while cannabidiol is primarily approved for childhood epileptic disorders Lennox-Gastaut and Dravet syndrome. The use pattern for these prescription cannabinoids in the USA is unknown. This study examined Medicaid claims for two FDA-approved prescription cannabinoids, dronabinol and cannabidiol, approved in 1985 and 2018, respectively, from 2016-2020 to better understand the pharmacoepidemiologic trends and distribution of these drugs in US Medicaid amidst the increasing use of non-pharmaceutical formulations of cannabis. Methods: The longitudinal study analyzed Medicaid prescription claims that were calculated by extracting the prescriptions on a state level from 2016 to 2020 for two cannabinoids, dronabinol and cannabidiol, where outcomes over each year were calculated. Outcomes were (1) the number of prescriptions for each state corrected for the number of Medicaid enrollees and (2) dronabinol and cannabidiol spending. Spending refers to the amount reimbursed by the state Medicaid program. Results: Dronabinol prescriptions per state decreased by 25.3% from 2016 to 2020, while cannabidiol prescriptions increased by 16,272.99% from 2018 to 2020. The spending on these drugs parallels that of their prescription trend with a 66.3% decrease in reimbursement for dronabinol ($5.7 million in 2020), whereas cannabidiol increased by +26,582.0% ($233.3 million in 2020). Dronabinol prescriptions, when corrected for the number of enrollees, in Connecticut were 136.4 times larger than in New Mexico, and seventeen states had zero prescriptions. Idaho's prescriptions of cannabidiol (27.8/10,000 enrollees) were significantly elevated relative to the national average and were 15.4-fold higher than Washington, DC (1.8/10K enrollees). Conclusions: The prescriptions of pharmaceutical-grade tetrahydrocannabinol decreased while those of cannabidiol increased. This study also identified pronounced state-level variation in cannabinoid prescribing to Medicaid patients. State formularies and prescription drug list variation may contribute to the drug reimbursements in Medicaid, though further research is needed to identify the health policy or pharmacoeconomic origins of these disparities. Keywords: Cannabidiol, Dronabinol, Medical marijuana, Prescription, Author(s): Edward Y. Liu [a]; Kenneth L. McCall [b,c]; Brian J. Piper [a,d] Introduction Dronabinol is synthetic tetrahydrocannabinol (THC) that has been US Food and Drug Administration (FDA) approved since [...]

Glucocorticoid therapy has been associated with adverse cardiometabolic effects during pregnancy. Inflammation-mediated cardiac dysfunction, an independent risk factor for morbidity and mortality, has been linked to defective glucose-6phosphate dehydrogenase (G6PD) dependent antioxidant defenses and increased endoglin expression. We therefore sought to investigate the effects of dexamethasone (DEX) on cardiac endoglin and G6PD-dependent antioxidant defense. Twenty-four rats were randomly assigned to nonpregnant (PRE(-)), DEX-exposed nonpregnant (PRE(-) + DEX), pregnant (PRE(+)), and DEX-exposed pregnant (PRE(+) + DEX) rats, respectively (n = 6 per group). PRE(-) and PRE(+) rats received vehicle (per oral (po)), while PRE(-) + DEX and PRE(+) + DEX groups were administered DEX (0.2 mg/kg po) between gestational days 14 and 19, respectively. Results showed that DEX caused increased cardiac pro-inflammatory markers (adenosine deaminase (ADA) activity, endoglin, vascular cell adhesion molecule-1 (VCAM-1), tissue injury markers (LDH, GGT, AST, ALT, and ALP), metabolic disturbances (elevated fasting plasma glucose, free fatty acid (FFA), lactate, cardiac FFA, and lactate) and depressed G6PD-dependent antioxidant defenses (G6PD activity, reduced glutathione/oxidized glutathione ratio, and nitric oxide) in pregnant and nonpregnant rats. The present study demonstrates that DEX led to increased cardiac endoglin and VCAM-1 that is accompanied by defective G6PD-dependent antioxidant defenses but not cardiac lipid accumulation in both pregnant and nonpregnant rats. Key words: reactive oxygen species, ADA, endoglin, G6PD, VCAM-1. On a associe le traitement par les glucocorticoides a des effets indesirables cardiometaboliques pendant la grossesse. On a lie le dysfonctionnement cardiaque medie par l'inflammation, un facteur de risque independant pour la morbidite et la mortalite, a des modes de defense antioxydants dependants de la glucose-6-phosphate deshydrogenase (G6PD) defectueux, ainsi qu'a une augmentation de l'expression de l'endogline. Par consequent, nous nous sommes employes a etudier les effets de la dexamethasone (DEX) sur l'endogline cardiaque et des modes de defense antioxydants dependants de la G6PD. Nous avons reparti aleatoirement 24 rates dans des groupes de rates non gravides (GR(-)), non gravides exposees a la DEX (GR(-) + DEX), gravides (GR(+)) et gravides exposees a la DEX (GR(+) + DEX) (n = 6 par groupe). Les rates GR(-) et GR(+) ont recu le vehicule (par oral (po)) tandis que les groupes GR(-) + DEX et GR(+) + DEX ont recu de la DEX (0,2 mg/kg po) entre les journees gestationnelles 14 et 19. Les resultats ont montre que la DEX entrainait une hausse des marqueurs cardiaques pro-inflammatoires (activite de l'adenosine desaminase (ADA), taux d'endogline et de VCAM-1 (pour << vascular cell adhesion molecule-1 >>)), ainsi que des marqueurs de lesions tissulaires (LDH, GGT, AST, ALT et ALP) et de perturbations metaboliques (augmentation de la glycemie a jeun, des taux d'acides gras libres (AGL), de lactate, ainsi que des taux d'AGL et de lactate cardiaques) avec une deterioration des modes de defense antioxydants dependants de la G6PD (activite de la G6PD, ratio glutathion reduit/glutathion oxyde, et taux d'oxyde nitrique) chez les rates gravides et non gravides. La presente etude a montre que la DEX menait a une hausse de l'endogline et de la VCAM-1 cardiaques, accompagnee de modes de defense dependants de la G6PD defectueux, mais sans accumulation de lipides cardiaques chez les rates gravides comme non gravides. [Traduit par la Redaction] Mots-cles: derives reactifs de l'oxygene, adenosine desaminase, endogline, G6PD, VCAM-1., Introduction Maternal physiology is extremely influenced by placental hormones particularly in the last trimester of the pregnancy. The variations in hormonal levels usually alter glucose and lipid metabolism and such [...]

Purpose To compare pain incidence and changes in pain scores with fentanyl versus placebo as pre-emptive treatment during turning and 30 min post-turning in mechanically ventilated critically ill patients. Methods We performed a randomized, double-blind, parallel-group, placebo-controlled clinical trial in the intensive care unit of a university hospital. Seventy-five mechanically ventilated patients were randomized to an intervention group (fentanyl) or a control group (placebo). Patients in the intervention group received 1 [micro]g/kg (medical patients) or 1.5 [micro]g/kg (surgical patients) of fentanyl 10 min before turning. Pain indicators were assessed using the behavioral pain scale. Safety was assessed by determining the frequency and severity of pre-defined adverse events. Pain was evaluated at rest (T0), at turn start and end (T1 and T2) and at 5, 15 and 30 min post-turning (T3, T4 and T5). Results The two groups had similar baseline characteristics. The area under the curve for BPS values was significantly smaller in the fentanyl group than in the control group [median and interquartile range (IQR): 132 (108-150) vs. 147 (125-180); p = 0.016, respectively]. Nineteen non-serious adverse events were recorded in 14 patients, with no significant between-group differences (23 % fentanyl group vs. 14 % control group; p = 0.381). Conclusions These results suggest an intravenous bolus of fentanyl of 1 [micro]g/kg for medical patients or 1.5 [micro]g/kg for surgical patients reduces the incidence of turning-associated pain in critically ill patients on mechanical ventilation. ClinicalTrials.gov: NCT 01950000., Author(s): Gemma Robleda [sup.1], Ferran Roche-Campo [sup.2] [sup.3], Maria-Àngels Sendra [sup.2], Marta Navarro [sup.2], Ana Castillo [sup.2], Ainhoa Rodríguez-Arias [sup.4], Elena Juanes-Borrego [sup.4], Ignasi Gich [sup.5] [sup.6] [sup.7], Gerard Urrutia [...]

Genetic manipulation of the [[alpha].sub.2A]-adrenergic receptor ([[alpha].sub.2A]-AR) in mice has revealed the role of this subtype in numerous responses, including agonist-induced hypotension and sedation. Unexpectedly, [[alpha].sub.2]-agonist treatment of mice heterozygous for the [[alpha].sub.2A]-AR ([[alpha].sub.2A]-A[R.sup.+/-]) lowers blood pressure without sedation, indicating that more than 50% of [[alpha].sub.2A]-AR must be activated to evoke sedation. We postulated that partial activation of [[alpha].sub.2A]-AR in wild-type [[alpha].sub.2A]-A[R.sup.+/+] animals could be achieved with partial agonists, agents with variable ability to couple receptor occupancy to effector activation, and might elicit one versus another pharmacological response. In vitro assays reveal that moxonidine is a partial agonist at [[alpha].sub.2A]-AR. Although moxonidine was developed to preferentially interact with imidazoline binding sites, it requires the [[alpha].sub.2A]-AR to lower blood pressure because we observe no hypotensive response to moxonidine in [[alpha].sub.2A]-AR-null ([[alpha].sub.2A]-A[R.sup.-/-]) mice. Moreover, we observe that moxonidine lowers blood pressure without sedation in wild-type mice, consistent with the above hypothesis regarding partial agonists. Our findings suggest that weak partial agonists can evoke response-selective pathways and might be exploited successfully to achieve [[alpha].sub.2A]-AR pharmacotherapy where concomitant sedation is undesirable, i.e., in treatment of depression or attention deficit hyperactivity disorder, in suppression of epileptogenesis, or enhancement of cognition. Furthermore, rigorous physiological and behavioral assessment of mice heterozygous for particular receptors provides a general strategy for elucidation of pathways that might be selectively activated by partial agonists, thus achieving response-specific therapy.

The development of small-molecule antagonists of the substance P (SP)-preferring tachykinin NK(sub 1) receptor during the past decade represents an important opportunity to exploit these molecules as novel therapeutic agents. On the basis of its anatomical localization and function, SP has been implicated in diverse pathophysiologies; of these, diseases of the CNS have been examined in the greatest detail. Although SP is best known as a pain neurotransmitter, it also controls vomiting and various behavioural, neurochemical and cardiovascular responses to stress. Recent clinical trials have confirmed the efficacy of NK(sub 1) receptor antagonists to alleviate depression and emesis but, surprisingly, not pain. Thus, multiple clinical trials, targeted to appropriate patient populations, are necessary to define the therapeutic potential of novel neurotransmitter ligands.

Drug discrimination experiments with pigeons has shown reinforcement schedules play a significant role in shaping dose-effect curves. Training regimens to distinguish saline from phenobarbital and other substances are described.

Cortistatin is a neuropeptide that depresses neuronal electrical activity and induces low-frequency waves in the cerebral cortex. The peptide is structurally similar to somatostatin but is produced by a different gene. Cortistatin controls the hippocampal neuron activity and sleep physiology in a manner different from that of somatostatin. An uncharacterized receptor in the peptide may be responsible for the effects.

The synthesis of 10,11-dimethoxydibenz(b,f)oxepin provides the material for a study of A1 adenosine receptor ligands. The process involves condensation of bis(2-formylphenyl) ether with potassium cyanide in dimethyl sulfoxide, followed by reductive methylation of the benzoin with sodium hydride and dimethyl sulfate in tetrahydrofuran. The overall yield is 19% from the ether. Dibenz(b,f)oxepins exhibit depressant, anticonvulsant, analgesic, antiinflammatory, sedative, psychotropic and antiestrogenic properties.

The ability of morphine to alleviate pain is mediated through a heterotrimeric guanine nucleotide binding protein (G protein)-coupled heptahelical receptor (GPCR), the µ opioid receptor (µOR). The efficiency of GPCR signaling is tightly regulated and ultimately limited by the coordinated phosphorylation of the receptors by specific GPCR kinases and the subsequent interaction of the phosphorylated receptors with Β-arrestin 1 and Β-arrestin 2. Functional deletion of the Β-arrestin 2 gene in mice resulted in remarkable potentiation and prolongation of the analgesic effect of morphine, suggesting that µOR desensitization was impaired. These results provide evidence in vivo for the physiological importance of Β-arrestin 2 in regulating the function of a specific GPCR, the µOR. Moreover, they suggest that inhibition of Β-arrestin 2 function might lead to enhanced analgesic effectiveness of morphine and provide potential new avenues for the study and treatment of pain, narcotic tolerance, and dependence., GPCRs have important roles in mediating fundamental physiological processes such as vision, olfaction, cardiovascular function, and pain perception. Cellular communication through GPCRs requires the coordination of processes governing receptor activation, [...]