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Article ; Online: Dantrolene sodium fails to reverse robust brain hyperthermia induced by MDMA and methamphetamine in rats.

Cameron-Burr, Keaton T / Bola, R Aaron / Kiyatkin, Eugene A

2023 Volume 240, Issue 4, Page(s) 785–795

Abstract: Rationale: Hyperthermia induced by psychomotor stimulants may cause leakage of the blood-brain barrier, vasogenic edema, and lethality in extreme cases. Current treatments such as whole-body cooling are only symptomatic and a clear need to develop ... ...

Abstract	Rationale: Hyperthermia induced by psychomotor stimulants may cause leakage of the blood-brain barrier, vasogenic edema, and lethality in extreme cases. Current treatments such as whole-body cooling are only symptomatic and a clear need to develop pharmacological interventions exists. Dantrolene sodium, a peripheral muscle relaxant used in the treatment of malignant hyperthermia, has been proposed as potentially effective to treat MDMA-hyperthermia in emergency rooms. However, debate around its efficacy for this indication persists. Objectives: To investigate dantrolene as a treatment for illicit hyperthermia induced by psychomotor stimulant drugs, we examined how Ryanodex®, a concentrated formulation of dantrolene sodium produced by Eagle Pharmaceuticals, influences 3,4-methylenedioxymethamphetamine (MDMA)- and methamphetamine (METH)-induced hyperthermia in awake freely moving rats. We injected rats with moderate doses of MDMA (9 mg/kg) and METH (9 mg/kg) and administered Ryanodex® intravenously (6 mg/kg) after the development of robust hyperthermia (>2.5 °C) mimicking clinical acute intoxication. We conducted simultaneous temperature recordings in the brain, temporal muscle, and skin to determine the basic mechanisms underlying temperature responses. To assess the efficacy of dantrolene in attenuating severe hyperthermia, we administered MDMA to rats maintained in a warm ambient environment (29 °C), conditions which produce robust brain and body hyperthermia (>40 °C) and lethality. Results: Dantrolene failed to attenuate MDMA- and METH-induced hyperthermia, though locomotor activity was significantly reduced. All animals maintained at warm ambient temperatures that received dantrolene during severe drug-induced hyperthermia died within or soon after the recording session. Conclusions: Our results suggest that dantrolene sodium formulations are not mechanistically suited to treat MDMA- and METH-induced hyperthermia.
MeSH term(s)	Rats ; Animals ; N-Methyl-3,4-methylenedioxyamphetamine ; Methamphetamine ; Dantrolene/pharmacology ; Body Temperature ; Brain ; Hyperthermia, Induced
Chemical Substances	N-Methyl-3,4-methylenedioxyamphetamine (KE1SEN21RM) ; Methamphetamine (44RAL3456C) ; Dantrolene (F64QU97QCR)
Language	English
Publishing date	2023-01-26
Publishing country	Germany
Document type	Journal Article
ZDB-ID	130601-7
ISSN	1432-2072 ; 0033-3158
ISSN (online)	1432-2072
ISSN	0033-3158
DOI	10.1007/s00213-023-06321-x
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Opioid Use and Driving Performance.

Cameron-Burr, Keaton T / Conicella, Albert / Neavyn, Mark J

Journal of medical toxicology : official journal of the American College of Medical Toxicology

2021 Volume 17, Issue 3, Page(s) 289–308

Abstract: Introduction: The USA is in an opioid epidemic, with an increased number of individuals taking psychoactive drugs while executing the tasks of everyday life, including operating a motor vehicle. The pharmacology of opioids has been widely studied, but ... ...

Abstract	Introduction: The USA is in an opioid epidemic, with an increased number of individuals taking psychoactive drugs while executing the tasks of everyday life, including operating a motor vehicle. The pharmacology of opioids has been widely studied, but the effects of opioids on psychomotor function, driving performance, and the risk of motor vehicle collision remain less clear. Clinicians are faced with the challenge of controlling patient pain while also reconciling conflicting messages from the literature about how safe it is for their patients taking opioids to engage in potentially dangerous routine tasks. Discussion: This review assesses the current literature regarding opioids as they relate to neurocognitive function, driving performance, and accident risk. Manuscripts are categorized by study context and subject matter: controlled experimental administration, illicit use, prescription use, retrospective forensic toxicology, and polydrug consumption. Conclusion: Illicit use, initiation of therapy, and opioid use in combination with other psychoactive medications are contexts most clearly associated with impairment of driving-related functions and/or operation of a motor vehicle. Clinicians should counsel patients on the risk of impairment when initiating therapy, when co-prescribing opioids and other psychoactive drugs, or when a patient is suspected of having an opioid use disorder.
MeSH term(s)	Accidents, Traffic/statistics & numerical data ; Adult ; Aged ; Aged, 80 and over ; Analgesics, Opioid/toxicity ; Female ; Humans ; Male ; Middle Aged ; Opioid-Related Disorders/epidemiology ; Psychomotor Disorders/chemically induced ; Retrospective Studies ; United States/epidemiology
Chemical Substances	Analgesics, Opioid
Language	English
Publishing date	2021-01-05
Publishing country	United States
Document type	Editorial ; Review
ZDB-ID	2435016-3
ISSN	1937-6995 ; 1556-9039
ISSN (online)	1937-6995
ISSN	1556-9039
DOI	10.1007/s13181-020-00819-y
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Article ; Online: Heroin Contaminated with Fentanyl Dramatically Enhances Brain Hypoxia and Induces Brain Hypothermia.

Solis, Ernesto / Cameron-Burr, Keaton T / Kiyatkin, Eugene A

eNeuro

2017 Volume 4, Issue 5

Abstract: While opioid abuse is an established medical and public health issue, the increased availability of highly potent synthetic opioids, such as fentanyl, has given rise to acute health complications, including a comatose state and death during drug overdose. ...

Abstract	While opioid abuse is an established medical and public health issue, the increased availability of highly potent synthetic opioids, such as fentanyl, has given rise to acute health complications, including a comatose state and death during drug overdose. Since respiratory depression that leads to acute hypoxia is the most dangerous complication of opioid drug use, we examined the effects of intravenous heroin and heroin contaminated with 10% fentanyl on oxygen levels in the nucleus accumbens (NAc) monitored using high-speed amperometry in freely moving rats. Additionally, we examined the effects of heroin, fentanyl, and their mixture on locomotion and temperatures in the NAc, temporal muscle, and skin. Both fentanyl and heroin at human-relevant doses (400 and 40 μg/kg, respectively) induced rapid, strong and transient decreases in NAc oxygen, indicative of brain hypoxia. When the heroin-fentanyl mixture was injected, the NAc hypoxic response was greatly potentiated in its duration, suggesting sustained hypoxia. In contrast to modest, monophasic brain temperature increases caused by heroin alone, the heroin-fentanyl mixture induced a biphasic temperature response, with a prominent postinjection decrease resulting from peripheral vasodilation. This hypothermic effect, albeit much smaller and more transient, was typical of fentanyl injected alone. Our findings indicate that accidental use of fentanyl instead of heroin, or even a relatively minor contamination of "street heroin" with fentanyl, poses great danger for acute health complications, including a comatose state and death.
MeSH term(s)	Animals ; Body Temperature/drug effects ; Drug Interactions ; Fentanyl/toxicity ; Heroin/toxicity ; Hypoxia, Brain/chemically induced ; Hypoxia, Brain/physiopathology ; Male ; Motor Activity/drug effects ; Muscle, Skeletal/drug effects ; Muscle, Skeletal/physiopathology ; Narcotics/toxicity ; Nucleus Accumbens/drug effects ; Nucleus Accumbens/metabolism ; Oxygen/metabolism ; Rats, Long-Evans ; Skin Physiological Phenomena/drug effects ; Street Drugs/toxicity ; Substance-Related Disorders/physiopathology ; Time Factors
Chemical Substances	Narcotics ; Street Drugs ; Heroin (70D95007SX) ; Oxygen (S88TT14065) ; Fentanyl (UF599785JZ)
Language	English
Publishing date	2017-10-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2800598-3
ISSN	2373-2822 ; 2373-2822
ISSN (online)	2373-2822
ISSN	2373-2822
DOI	10.1523/ENEURO.0323-17.2017
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Article: Rapid Physiological Fluctuations in Nucleus Accumbens Oxygen Levels Induced by Arousing Stimuli: Relationships with Changes in Brain Glucose and Metabolic Neural Activation.

Solis, Ernesto / Cameron-Burr, Keaton T / Kiyatkin, Eugene A

Frontiers in integrative neuroscience

2017 Volume 11, Page(s) 9

Abstract: Proper entry of oxygen from arterial blood into the brain is essential for maintaining brain metabolism under normal conditions and during functional neural activation. However, little is known about physiological fluctuations in brain oxygen and their ... ...

Abstract	Proper entry of oxygen from arterial blood into the brain is essential for maintaining brain metabolism under normal conditions and during functional neural activation. However, little is known about physiological fluctuations in brain oxygen and their underlying mechanisms. To address this issue, we employed high-speed amperometry with platinum oxygen sensors in freely moving male rats. Recordings were conducted in the nucleus accumbens (NAc), a critical structure for sensorimotor integration. Rats were exposed to arousing stimuli of different nature (brief auditory tone, a 1-min novel object presentation, a 3-min social interaction with a conspecific, and a 3-min tail-pinch). We found that all arousing stimuli increased NAc oxygen levels. Increases were rapid (4-10-s onset latencies), modest in magnitude (1-3 μM or 5%-15% over baseline) and duration (5-20 min), and generally correlated with the arousing potential of each stimulus. Two strategies were used to determine the mechanisms underlying the observed increases in NAc oxygen levels. First, we showed that NAc oxygen levels phasically increase following intra-NAc microinjections of glutamate (GLU) that excite accumbal neurons. Therefore, local neural activation with subsequent local vasodilation is involved in mediating physiological increases in NAc oxygen induced by arousing stimuli. Second, by employing oxygen monitoring in the subcutaneous space, a highly-vascularized area with no metabolic activity, we determined that physiological increases in NAc oxygen also depend on the rise in blood oxygen levels caused by respiratory activation. Due to the co-existence of different mechanisms governing oxygen entry into brain tissue, NAc oxygen responses differ from fluctuations in NAc glucose, which, within a normal behavioral continuum, are regulated exclusively by neuro-vascular coupling due to glucose's highly stable levels in the blood. Finally, we discuss the relationships between physiological fluctuations in NAc oxygen, glucose and metabolic brain activation assessed by intra-brain heat production.
Language	English
Publishing date	2017-04-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452962-X
ISSN	1662-5145
ISSN	1662-5145
DOI	10.3389/fnint.2017.00009
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Article ; Online: Intravenous Heroin Induces Rapid Brain Hypoxia and Hyperglycemia that Precede Brain Metabolic Response.

Solis, Ernesto / Cameron-Burr, Keaton T / Shaham, Yavin / Kiyatkin, Eugene A

eNeuro

2017 Volume 4, Issue 3

Abstract: Heroin use and overdose have increased in recent years as people transition from abusing prescription opiates to using the cheaper street drug. Despite a long history of research, many physiological effects of heroin and their underlying mechanisms ... ...

Abstract	Heroin use and overdose have increased in recent years as people transition from abusing prescription opiates to using the cheaper street drug. Despite a long history of research, many physiological effects of heroin and their underlying mechanisms remain unknown. Here, we used high-speed amperometry to examine the effects of intravenous heroin on oxygen and glucose levels in the nucleus accumbens (NAc) in freely-moving rats. Heroin within the dose range of human drug use and rat self-administration (100-200 μg/kg) induced a rapid, strong, but transient drop in NAc oxygen that was followed by a slower and more prolonged rise in glucose. Using oxygen recordings in the subcutaneous space, a densely-vascularized site with no metabolic activity, we confirmed that heroin-induced brain hypoxia results from decreased blood oxygen, presumably due to drug-induced respiratory depression. Respiratory depression and the associated rise in CO
Language	English
Publishing date	2017-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2800598-3
ISSN	2373-2822 ; 2373-2822
ISSN (online)	2373-2822
ISSN	2373-2822
DOI	10.1523/ENEURO.0151-17.2017
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Article ; Online: Fentanyl-Induced Brain Hypoxia Triggers Brain Hyperglycemia and Biphasic Changes in Brain Temperature.

Solis, Ernesto / Cameron-Burr, Keaton T / Shaham, Yavin / Kiyatkin, Eugene A

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

2017 Volume 43, Issue 4, Page(s) 810–819

Abstract: Fentanyl is a potent synthetic opioid used extensively in humans for general anesthesia and analgesia. Fentanyl has emerged as a recreational drug, often in combination with heroin, and can result in lethality during overdose. Fentanyl is well ... ...

Abstract	Fentanyl is a potent synthetic opioid used extensively in humans for general anesthesia and analgesia. Fentanyl has emerged as a recreational drug, often in combination with heroin, and can result in lethality during overdose. Fentanyl is well characterized as an anesthetic, but the basic physiological effects of fentanyl in the brain when taken as a drug of abuse are largely unknown. We used high-speed amperometry in freely moving rats to examine the effects of intravenous fentanyl at doses within the range of possible human intake (3-40 μg/kg) on oxygen and glucose levels in nucleus accumbens (NAc). Fentanyl induced a rapid, dose-dependent decrease in NAc oxygen followed by a more delayed and prolonged increase in NAc glucose. Fentanyl induced similar oxygen decreases in the basolateral amygdala, indicating that brain hypoxia could be a generalized phenomenon. We used oxygen recordings in the subcutaneous space to confirm that fentanyl-induced brain hypoxia results from decreases in blood oxygen levels caused by drug-induced respiratory depression. Temperature recordings in the NAc, muscle, and skin showed that fentanyl induces biphasic changes in brain temperature, with an initial decrease that results primarily from peripheral vasodilation, and a subsequent increase driven by metabolic brain activation. The initial vasodilation appears caused by respiratory depression-induced hypoxia and a subsequent rise in CO
MeSH term(s)	Analgesics, Opioid/toxicity ; Animals ; Body Temperature/drug effects ; Body Temperature/physiology ; Brain/drug effects ; Brain/metabolism ; Fentanyl/toxicity ; Glucose/metabolism ; Hyperglycemia/chemically induced ; Hyperglycemia/metabolism ; Hypoxia, Brain/chemically induced ; Hypoxia, Brain/metabolism ; Male ; Oxygen Consumption/drug effects ; Oxygen Consumption/physiology ; Rats ; Rats, Long-Evans
Chemical Substances	Analgesics, Opioid ; Glucose (IY9XDZ35W2) ; Fentanyl (UF599785JZ)
Language	English
Publishing date	2017-08-29
Publishing country	England
Document type	Journal Article
ZDB-ID	639471-1
ISSN	1740-634X ; 0893-133X
ISSN (online)	1740-634X
ISSN	0893-133X
DOI	10.1038/npp.2017.181
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Article: Sulfurization of Dissolved Organic Matter Increases HgâSulfideâDissolved Organic Matter Bioavailability to a Hg-Methylating Bacterium

Graham, Andrew M / Cameron-Burr Keaton T / Hajic Hayley A / Lee Connie / Msekela Deborah / Gilmour Cynthia C

Environmental Science & Technology. 2017 Aug. 15, v. 51, no. 16

2017

Abstract: Reactions of dissolved organic matter (DOM) with aqueous sulfide (termed sulfurization) in anoxic environments can substantially increase DOMâs reduced sulfur functional group content. Sulfurization may affect DOMâtrace metal interactions, including ... ...

Abstract	Reactions of dissolved organic matter (DOM) with aqueous sulfide (termed sulfurization) in anoxic environments can substantially increase DOMâs reduced sulfur functional group content. Sulfurization may affect DOMâtrace metal interactions, including complexation and metal-containing particle precipitation, aggregation, and dissolution. Using a diverse suite of DOM samples, we found that susceptibility to additional sulfur incorporation via reaction with aqueous sulfide increased with increasing DOM aromatic-, carbonyl-, and carboxyl-C content. The role of DOM sulfurization in enhancing Hg bioavailability for microbial methylation was evaluated under conditions typical of Hg methylation environments (Î¼M sulfide concentrations and low Hg-to-DOM molar ratios). Under the conditions of predicted metacinnabar supersaturation, microbial Hg methylation increased with increasing DOM sulfurization, likely reflecting either effective inhibition of metacinnabar growth and aggregation or the formation of Hg(II)âDOM thiol complexes with high bioavailability. Remarkably, Hg methylation efficiencies with the most sulfurized DOM samples were similar (>85% of total Hg methylated) to that observed in the presence of l-cysteine, a ligand facilitating rapid Hg(II) biouptake and methylation. This suggests that complexes of Hg(II) with DOM thiols have similar bioavailability to Hg(II) complexes with low-molecular-weight thiols. Overall, our results are a demonstration of the importance of DOM sulfurization to trace metal and metalloid (especially mercury) fate in the environment. DOM sulfurization likely represents another link between anthropogenic sulfate enrichment and MeHg production in the environment.
Keywords	bacteria ; bioavailability ; cysteine ; dissolved organic matter ; ligands ; mercury ; metalloids ; methylation ; methylmercury compounds ; sulfates ; sulfides ; sulfur ; thiols ; trace elements
Language	English
Dates of publication	2017-0815
Size	p. 9080-9088.
Publishing place	American Chemical Society
Document type	Article
ISSN	1520-5851
DOI	10.1021%2Facs.est.7b02781
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Article ; Online: Sulfurization of Dissolved Organic Matter Increases Hg-Sulfide-Dissolved Organic Matter Bioavailability to a Hg-Methylating Bacterium.

Graham, Andrew M / Cameron-Burr, Keaton T / Hajic, Hayley A / Lee, Connie / Msekela, Deborah / Gilmour, Cynthia C

Environmental science & technology

2017 Volume 51, Issue 16, Page(s) 9080–9088

Abstract: Reactions of dissolved organic matter (DOM) with aqueous sulfide (termed sulfurization) in anoxic environments can substantially increase DOM's reduced sulfur functional group content. Sulfurization may affect DOM-trace metal interactions, including ... ...

Abstract	Reactions of dissolved organic matter (DOM) with aqueous sulfide (termed sulfurization) in anoxic environments can substantially increase DOM's reduced sulfur functional group content. Sulfurization may affect DOM-trace metal interactions, including complexation and metal-containing particle precipitation, aggregation, and dissolution. Using a diverse suite of DOM samples, we found that susceptibility to additional sulfur incorporation via reaction with aqueous sulfide increased with increasing DOM aromatic-, carbonyl-, and carboxyl-C content. The role of DOM sulfurization in enhancing Hg bioavailability for microbial methylation was evaluated under conditions typical of Hg methylation environments (μM sulfide concentrations and low Hg-to-DOM molar ratios). Under the conditions of predicted metacinnabar supersaturation, microbial Hg methylation increased with increasing DOM sulfurization, likely reflecting either effective inhibition of metacinnabar growth and aggregation or the formation of Hg(II)-DOM thiol complexes with high bioavailability. Remarkably, Hg methylation efficiencies with the most sulfurized DOM samples were similar (>85% of total Hg methylated) to that observed in the presence of l-cysteine, a ligand facilitating rapid Hg(II) biouptake and methylation. This suggests that complexes of Hg(II) with DOM thiols have similar bioavailability to Hg(II) complexes with low-molecular-weight thiols. Overall, our results are a demonstration of the importance of DOM sulfurization to trace metal and metalloid (especially mercury) fate in the environment. DOM sulfurization likely represents another link between anthropogenic sulfate enrichment and MeHg production in the environment.
MeSH term(s)	Bacteria ; Biological Availability ; Cysteine ; Mercury ; Sulfides ; Water Pollutants, Chemical
Chemical Substances	Sulfides ; Water Pollutants, Chemical ; Mercury (FXS1BY2PGL) ; Cysteine (K848JZ4886)
Language	English
Publishing date	2017-08-15
Publishing country	United States
Document type	Journal Article
ISSN	1520-5851
ISSN (online)	1520-5851
DOI	10.1021/acs.est.7b02781
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