WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: There are currently no drugs clinically available to reverse general anesthesia. We previously reported that caffeine is able to accelerate ...emergence from anesthesia in rodents. This study was carried out to test the hypothesis that caffeine accelerates emergence from anesthesia in humans.
We conducted a single-center, randomized, double-blind crossover study with eight healthy males. Each subject was anesthetized twice with 1.2% isoflurane for 1 h. During the final 10 min of each session, participants received an IV infusion of either caffeine citrate (15 mg/kg, equivalent to 7.5 mg/kg of caffeine base) or saline placebo. The primary outcome was the average difference in time to emergence after isoflurane discontinuation between caffeine and saline sessions. Secondary outcomes included the end-tidal isoflurane concentration at emergence, vital signs, and Bispectral Index values measured throughout anesthesia and emergence. Additional endpoints related to data gathered from postanesthesia psychomotor testing.
All randomized participants were included in the analysis. The mean time to emergence with saline was 16.5 ± 3.9 (SD) min compared to 9.6 ± 5.1 (SD) min with caffeine (P = 0.002), a difference of 6.9 min (99% CI, 1.8 to 12), a 42% reduction. Participants emerged at a higher expired isoflurane concentration, manifested more rapid return to baseline Bispectral Index values, and were able to participate in psychomotor testing sooner when receiving caffeine. There were no statistically significant differences in vital signs with caffeine administration and caffeine-related adverse events.
Intravenous caffeine is able to accelerate emergence from isoflurane anesthesia in healthy males without any apparent adverse effects.
Rationale
Nonmedical use of prescription opioids is sometimes accompanied by the ingestion of ethanol. Whether ethanol increases the abuse liability-related effects of prescription opioids has not ...been determined.
Objective
The purpose of this study was to characterize the subjective, psychomotor, and physiological effects of oxycodone, a widely prescribed and abused opioid, and ethanol, alone and in combination.
Methods
Fourteen volunteers participated in a randomized, crossover trial in which they were exposed to placebo, oxycodone (10 mg), two doses of ethanol (0.3 and 0.6 g/kg), and oxycodone combined with the lower dose and the higher dose of ethanol on separate sessions.
Results
Several abuse liability-related subjective effects (drug liking, take again, pleasant bodily sensations) were not increased by the low dose of ethanol or oxycodone alone relative to placebo, but were when the two were combined. Self-reported liking of the higher dose of ethanol was higher than that of placebo, but oxycodone neither increased nor decreased this effect. Psychomotor and cognitive performance was not affected by any of the active drug conditions. Absorption of ethanol was decreased by oxycodone.
Conclusions
In this study, 10 mg of oral oxycodone combined with a low dose of ethanol generated abuse liability-related effects, but when tested separately, they did not. Further psychopharmacological investigations of this combination are warranted in light of these findings and the fact that nonmedical use of prescription opioids is sometimes accompanied by use of ethanol.
The Forkhead box M1 (FOXM1) is a transcription factor that has been implicated in normal cell growth and proliferation through control of cell cycle transition and mitotic spindle. It is implicated ...in carcinogenesis of various malignancies where it is activated by either amplification, increased stability, enhanced transcription, dysfunction of regulatory pathways, or activation of PI3K/AKT, epidermal growth factor receptor, Raf/MEK/MAPK, and Hedgehog pathways. This review describes the role of FOXM1 in breast cancer. This includes how FOXM1 impacts on different subtypes of breast cancer, that is, luminal/estrogen receptor positive (ER+), expressing human epidermal growth factor receptor 2 (HER2), basal-like breast cancer (BBC), and triple negative breast cancer (TNBC). The review also describes different tested preclinical therapeutic strategies targeting FOXM1. Developing clinically applicable therapies that specifically inhibit FOXM1 activity is a logical next step in biomarker-driven approaches against breast cancer but will not be without its challenges due to the unique properties of this transcription factor.
Abstract Background Non-medical use and abuse of prescription opioids is a significant problem in the United States. Little attention has been paid to assessing the relative psychopharmacological ...profile (including abuse liability-related effects) of specific prescription opioids. The purpose of this study was to directly compare the psychopharmacological profile of two widely prescribed and abused oral opioid combination products within the same subject. Methods Twenty non-drug-abusing volunteers participated in a crossover, randomized, double-blind study in which they received, all p.o.: placebo; 975 mg acetaminophen (ACET); 10 mg oxycodone (OXY)/487 mg ACET; 20 mg OXY/975 mg ACET; 15 mg hydrocodone (HYD)/487 mg ACET; and 30 mg HYD/975 mg ACET. OXY and HYD doses were chosen to equate the drugs on an objective measure of opiate effects: miosis. Dependent measures were subjective, psychomotor/cognitive, reinforcing, and physiological effects, and relative potency estimates. Results In general, the two opioid combination products at equi-miotic doses produced similar prototypic opiate-like effects and psychomotor impairment, and of similar magnitude. The higher dose of OXY/ACET produced slightly more abuse liability-related subjective effects than the higher dose of HYD/OXY, but also produced slightly more negative effects. Neither drug at either dose functioned as a reinforcer, as measured by the Multiple Choice Procedure. Relative potency ratios indicated that OXY/ACET was approximately 1.5 times more potent than HYD/ACET. Conclusions Consistent with a recent study published in this journal using identical doses of HYD and OXY (without ACET) in prescription opioid abusers (Walsh, S.L., Nuzzo, P.A., Lofwall, M.R., Holtman Jr., J.R., 2008. The relative abuse liability of oral oxycodone, hydrocodone and hydromorphone assessed in prescription drug abusers. Drug Alcohol Depend. 198, 191–202), we found little difference in the pharmacodynamic effects of HYD/ACET and OXY/ACET in non-drug-abusing volunteers.
Rationale
Methylnaltrexone bromide (MTNX) is a peripherally acting mu-opioid receptor antagonist, prescribed for the treatment of opioid-induced constipation in patients with advanced illness who are ...receiving palliative care. Studies have used this drug to determine if other opioid-induced effects besides constipation are altered by MTNX in humans and have suggested, based on their results, that these other effects are altered by peripheral opioid actions.
Objective
The primary objective of this report is to present results that provide indirect evidence that MTNX has centrally mediated effects, albeit slight, and secondarily to describe the effects of MTNX on psychopharmacological effects of morphine.
Methods
In a crossover, randomized, placebo-controlled, double-blind study, 29 healthy volunteers received 0.45 mg/kg MTNX or saline subcutaneously, followed by saline intravenously. In three other conditions, 0.143 mg/kg of morphine sulfate administered intravenously was preceded by subcutaneous administration of 0, 0.225, or 0.45 mg/kg MTNX. Before and after drug administration, subjective and physiological measures, including pupil diameter, were assessed.
Results
Two separate analyses confirmed that 0.45 mg/kg MTNX alone induced a slight degree of miosis, a centrally mediated opioid agonist effect. This dose had minimal subjective effects. MTNX at either or both the 0.225 and 0.45 mg/kg dose reduced some subjective effects of morphine without altering miosis.
Conclusions
We present indirect evidence that MTNX crosses the blood–brain barrier in humans. Therefore, whether the reductions in subjective effects of morphine by MTNX that were observed in past studies and in this study can be attributed to peripheral mechanisms is open to question.
Sensation-seeking is a personality trait that is linked to use and abuse of drugs. Laboratory studies have established that high sensation seekers, as measured by different instruments, are more ...likely to report abuse liability-related subjective effects from drugs such as nicotine, alcohol, and
d-amphetamine than low sensation seekers. One class of drugs that has not been studied to date in this fashion is opioids. Accordingly, a retrospective analysis encompassing five studies that examined oxycodone effects, including its abuse liability-related effects, was conducted in subjects categorized as high or low sensation seekers. In addition, because there appear to be sex differences in how males and females respond to opioids, this factor was taken into account in the analysis. Seventy one subjects who scored on the lower end (15 and 19 low sensation-seeking males and females, respectively) or the higher end (23 and 14 high sensation-seeking males and females) of the Disinhibition subscale of the Sensation-Seeking Scale-Form V were studied for their responses to 0, 10, and 20
mg of oral oxycodone. Ratings of “pleasant bodily sensations” were significantly higher after oxycodone administration than placebo only in male and female high sensation seekers. Ratings of “take again,” “drug liking,” “carefree,” and “elated (very happy)” also tended to differentiate high from low sensation seekers although Group
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Dose interactions were only marginally significant with the latter three ratings. Male and female low sensation seekers and female high sensation seekers reported dysphoric effects (e.g., ratings of nauseated) particularly after administration of the 20
mg oxycodone dose. The results of this analysis provide suggestive evidence that high sensation seekers are more likely to experience greater positive subjective effects from oxycodone than low sensation seekers, but likelihood of experiencing negative effects is more complex (involving both sensation-seeking status and sex).
Pazopanib is a multikinase angiogenesis inhibitor. Alisertib is a highly selective inhibitor of mitotic Aurora A kinase. There is preclinical evidence that mitosis-targeting agents exhibit ...antiangiogenic effects. Thus, the combination of these 2 agents may have a synergistic effect on tumor vasculature. The primary objective of this study is to determine the optimal tolerated dose (OTD) for alisertib and pazopanib.
This phase 1b study evaluated the OTD of alisertib twice a day, on days 1 to 7 with pazopanib, once a day, continuously in a 21-day cycle, both taken orally. Disease response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1 every 2 cycles. OTD cohort was expanded to assure safety and perform pharmacokinetics analysis.
A total of 27 patients received treatment. Seventy-seven percent of the patients had received at least 3 prior chemotherapy regimens. Dose-limiting toxicities occurred in dose level (DL) 2+ (grade 4 thrombocytopenia and grade 3 mucositis) and DL 3 (grade 3 liver transaminases elevation and grade 3 abdominal pain). The OTD was determined to be DL 2: alisertib 20 mg twice daily and pazopanib 600 mg daily. Pharmacokinetic analysis revealed that clearance of alisertib was reduced by ∼40% in the presence of pazopanib compared with clearance in the absence of pazopanib. Fourteen patients had stable disease and 2 patients had a partial response.
The combination of alisertib with pazopanib demonstrates manageable safety and early clinical evidence of antitumor activity in patients with advanced malignancies (NCT01639911).
Rationale
Nonmedical use and abuse of prescription opioids is a significant problem in the USA. Little attention has been paid to assessing the relative psychopharmacological profile (including abuse ...liability-related effects) of specific prescription opioids.
Objectives
The aim of this study is to directly compare the psychopharmacological profile of two oral opioids within the same subject.
Methods
A randomized, placebo-controlled, crossover study was done in which 20 non-drug-abusing volunteers ingested 10 and 20 mg of oxycodone, 30 and 60 mg of morphine, and placebo in separate sessions. Drug doses were equated on an objective measure of opiate effects: miosis. Subjective, psychomotor, reinforcing, and physiological effects of the opioids were assessed.
Results
In general, the two opioids at equimiotic doses produced similar prototypic opiate-like effects and psychomotor impairment of similar magnitude. However, several effects were found only with 20 mg oxycodone. Both drugs produced abuse liability-related subjective effects but also dysphoric effects, particularly with 60 mg morphine. Neither drug at either dose functioned as a reinforcer, as measured by the Multiple Choice Procedure. Relative potency ratios indicated an average oxycodone:morphine ratio of 3:1.
Conclusions
The psychopharmacological profile of oxycodone and morphine at equimiotic doses had many similarities; however, differences were found in producing abuse liability-related and dysphoric effects. In the medical community, it is commonly accepted that oral oxycodone is 1.5 to 2 times as potent as oral morphine in producing analgesia; using this ratio, although patients may experience similar degrees of pain relief, those receiving oxycodone may be experiencing stronger and potentially different psychopharmacological effects.
The subjective, psychomotor, and physiological effects of a widely prescribed and abused prescription opioid, oxycodone, have not been studied in a population of non-drug-abusing people.
To ...characterize the effects of oxycodone in non-drug-abusing volunteers.
Eighteen volunteers participated in a crossover, randomized, double-blind study in which they received, all p.o., placebo, 10 mg oxycodone, 20 mg oxycodone, 30 mg oxycodone, 40 mg morphine, and 2 mg lorazepam. Measures were assessed before and for 300 min after drug administration. End-of-session and 24-h post-session measures were taken to assess residual drug effects and overall subjects' assessments of the drug effects.
Subjective effects of oxycodone were dose related, with the majority of statistically significant effects limited to the two higher doses tested. Oxycodone produced a profile of subjective effects that included both pleasant and unpleasant effects. Morphine in general produced effects similar in magnitude to those of 10 mg and 20 mg oxycodone. Peak liking and drug-wanting ratings were increased by all doses of oxycodone and by morphine, and trough ratings of liking (dislike) were lower in the 20-mg and 30-mg oxycodone conditions, relative to the placebo condition. Post-session ratings of overall liking and drug wanting were not statistically significant, either at the end of the session or 24 h later. Cognitive and psychomotor impairment were obtained with the higher doses of oxycodone, but to a much lesser degree than that of lorazepam. Miosis and exophoria were increased in a dose-related manner by oxycodone.
Oxycodone produced effects similar to those of other mu opioid agonists. Although oxycodone produced abuse liability-related subjective effects, it also produced unpleasant effects, a phenomenon we have observed in other opioid studies in non-drug-abusing volunteers.
Pregabalin is an anticonvulsant drug indicated for neuropathic disorders and fibromyalgia. Some chronic pain patients suffering from these disorders take both this drug and an opioid for pain relief. ...Pregabalin is a scheduled drug under the Controlled Substances Act. The subjective effects of this drug have not been well-characterized, and the extent to which it alters the subjective effects of opioids has not been studied to the best of our knowledge. Using a double-blind, randomized, crossover design, 16 healthy volunteers were administered (in separate sessions) capsules containing placebo, 75mg pregabalin, 150mg pregabalin, 10mg oxycodone, and 75mg pregabalin combined with 10mg oxycodone. Subjective, psychomotor, and physiological measures were assessed during each of the five sessions. Pregabalin produced dose-related increases in some subjective effects and decreased respiration rate, but did not impact on psychomotor performance. Abuse liability-related subjective effects such as drug liking and desire to take the drug again were not increased by either pregabalin dose. Oxycodone produced increases in several subjective effects, including ratings of drug liking. When 75mg pregabalin was combined with oxycodone some subjective effects were altered relative to placebo, in contrast to when each drug was tested alone. Liking of oxycodone was not increased by 75mg pregabalin. However, recent studies have suggested that this drug is abused, and we would recommend that further psychopharmacological studies with pregabalin are warranted, including a study assessing its abuse liability across a range of doses in sedative abusers.
► Pregabalin had dose-related subjective effects. ► The subjective effects in general were not indicative of abuse liability. ► Pregabalin when combined with oxycodone did not increase liking of the opioid.
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