4 CFR 25.8 - Alcoholic beverages and narcotics.

Code of Federal Regulations, 2014 CFR

2014-01-01

... alcoholic beverages, narcotic drugs, hallucinogens, marijuana, barbiturates, or amphetamines is prohibited..., marijuana, barbiturate, or amphetamine. This prohibition shall not apply in cases where the drug is being...

4 CFR 25.8 - Alcoholic beverages and narcotics.

Code of Federal Regulations, 2011 CFR

2011-01-01

... alcoholic beverages, narcotic drugs, hallucinogens, marijuana, barbiturates, or amphetamines is prohibited..., marijuana, barbiturate, or amphetamine. This prohibition shall not apply in cases where the drug is being...

4 CFR 25.8 - Alcoholic beverages and narcotics.

Code of Federal Regulations, 2012 CFR

2012-01-01

... alcoholic beverages, narcotic drugs, hallucinogens, marijuana, barbiturates, or amphetamines is prohibited..., marijuana, barbiturate, or amphetamine. This prohibition shall not apply in cases where the drug is being...

4 CFR 25.8 - Alcoholic beverages and narcotics.

Code of Federal Regulations, 2010 CFR

2010-01-01

... alcoholic beverages, narcotic drugs, hallucinogens, marijuana, barbiturates, or amphetamines is prohibited..., marijuana, barbiturate, or amphetamine. This prohibition shall not apply in cases where the drug is being...

4 CFR 25.8 - Alcoholic beverages and narcotics.

Code of Federal Regulations, 2013 CFR

2013-01-01

... alcoholic beverages, narcotic drugs, hallucinogens, marijuana, barbiturates, or amphetamines is prohibited..., marijuana, barbiturate, or amphetamine. This prohibition shall not apply in cases where the drug is being...

32 CFR 228.9 - Prohibition on narcotics and illegal substances.

Code of Federal Regulations, 2014 CFR

2014-07-01

... narcotic drug, hallucinogen, marijuana, barbiturate or amphetamine is prohibited. Operation of a motor..., hallucinogens, marijuana, barbiturates or amphetamines is also prohibited. These prohibitions shall not apply in...

32 CFR 228.9 - Prohibition on narcotics and illegal substances.

Code of Federal Regulations, 2011 CFR

2011-07-01

... narcotic drug, hallucinogen, marijuana, barbiturate or amphetamine is prohibited. Operation of a motor..., hallucinogens, marijuana, barbiturates or amphetamines is also prohibited. These prohibitions shall not apply in...

32 CFR 228.9 - Prohibition on narcotics and illegal substances.

Code of Federal Regulations, 2013 CFR

2013-07-01

... narcotic drug, hallucinogen, marijuana, barbiturate or amphetamine is prohibited. Operation of a motor..., hallucinogens, marijuana, barbiturates or amphetamines is also prohibited. These prohibitions shall not apply in...

32 CFR 228.9 - Prohibition on narcotics and illegal substances.

Code of Federal Regulations, 2012 CFR

2012-07-01

... narcotic drug, hallucinogen, marijuana, barbiturate or amphetamine is prohibited. Operation of a motor..., hallucinogens, marijuana, barbiturates or amphetamines is also prohibited. These prohibitions shall not apply in...

32 CFR 228.9 - Prohibition on narcotics and illegal substances.

Code of Federal Regulations, 2010 CFR

2010-07-01

... narcotic drug, hallucinogen, marijuana, barbiturate or amphetamine is prohibited. Operation of a motor..., hallucinogens, marijuana, barbiturates or amphetamines is also prohibited. These prohibitions shall not apply in...

Synthesis of Barbiturate-Based Methionine Aminopeptidase-1 Inhibitors

PubMed Central

Haldar, Manas K.; Scott, Michael D.; Sule, Nitesh; Srivastava, D. K.; Mallik, Sanku

2008-01-01

The syntheses of a new class of barbiturate-based inhibitors for human and E. Coli Methionine Aminopeptidase -1 (MetAP-1) are described. Some of the synthesized inhibitors show selective inhibition of the human enzyme with high potency. PMID:18343108

Comparative Actions of Barbiturates Studied by Pollen Grain Germination.

ERIC Educational Resources Information Center

Kordan, Herbert A.; Mumford, Pauline M.

1979-01-01

Describes a simple experimental system whereby the comparative actions of long, medium, and short-acting barbiturates can be demonstrated in a relatively short period of time under optical microscopy using pollen grains as the biological test or assay system. (Author/HM)

38 CFR 1.218 - Security and law enforcement at VA facilities.

Code of Federal Regulations, 2012 CFR

2012-07-01

... the influence of alcoholic beverages, narcotic drugs, hallucinogens, marijuana, barbiturates, or amphetamines is prohibited. Entering property under the influence of any narcotic drug, hallucinogen, marijuana... property of any narcotic drug, hallucinogen, marijuana, barbiturate, or amphetamine (unless prescribed by a...

38 CFR 1.218 - Security and law enforcement at VA facilities.

Code of Federal Regulations, 2010 CFR

2010-07-01

... the influence of alcoholic beverages, narcotic drugs, hallucinogens, marijuana, barbiturates, or amphetamines is prohibited. Entering property under the influence of any narcotic drug, hallucinogen, marijuana... property of any narcotic drug, hallucinogen, marijuana, barbiturate, or amphetamine (unless prescribed by a...

38 CFR 1.218 - Security and law enforcement at VA facilities.

Code of Federal Regulations, 2013 CFR

2013-07-01

... the influence of alcoholic beverages, narcotic drugs, hallucinogens, marijuana, barbiturates, or amphetamines is prohibited. Entering property under the influence of any narcotic drug, hallucinogen, marijuana... property of any narcotic drug, hallucinogen, marijuana, barbiturate, or amphetamine (unless prescribed by a...

38 CFR 1.218 - Security and law enforcement at VA facilities.

Code of Federal Regulations, 2014 CFR

2014-07-01

... the influence of alcoholic beverages, narcotic drugs, hallucinogens, marijuana, barbiturates, or amphetamines is prohibited. Entering property under the influence of any narcotic drug, hallucinogen, marijuana... property of any narcotic drug, hallucinogen, marijuana, barbiturate, or amphetamine (unless prescribed by a...

38 CFR 1.218 - Security and law enforcement at VA facilities.

Code of Federal Regulations, 2011 CFR

2011-07-01

... the influence of alcoholic beverages, narcotic drugs, hallucinogens, marijuana, barbiturates, or amphetamines is prohibited. Entering property under the influence of any narcotic drug, hallucinogen, marijuana... property of any narcotic drug, hallucinogen, marijuana, barbiturate, or amphetamine (unless prescribed by a...

21 CFR 862.3150 - Barbiturate test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Barbiturate test system. 862.3150 Section 862.3150 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...

21 CFR 862.3150 - Barbiturate test system.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Barbiturate test system. 862.3150 Section 862.3150 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...

21 CFR 862.3150 - Barbiturate test system.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Barbiturate test system. 862.3150 Section 862.3150 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...

21 CFR 862.3150 - Barbiturate test system.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Barbiturate test system. 862.3150 Section 862.3150 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Toxicology Test Systems § 862...

[Cerebral protection].

PubMed

Cattaneo, A D

1993-09-01

Cerebral protection means prevention of cerebral neuronal damage. Severe brain damage extinguishes the very "human" functions such as speech, consciousness, intellectual capacity, and emotional integrity. Many pathologic conditions may inflict injuries to the brain, therefore the protection and salvage of cerebral neuronal function must be the top priorities in the care of critically ill patients. Brain tissue has unusually high energy requirements, its stores of energy metabolites are small and, as a result, the brain is totally dependent on a continuous supply of substrates and oxygen, via the circulation. In complete global ischemia (cardiac arrest) reperfusion is characterized by an immediate reactive hyperemia followed within 20-30 min by a delayed hypoperfusion state. It has been postulated that the latter contributes to the ultimate neurologic outcome. In focal ischemia (stroke) the primary focus of necrosis is encircled by an area (ischemic penumbra) that is underperfused and contains neurotoxic substances such as free radicals, prostaglandins, calcium, and excitatory neurotransmitters. The variety of therapeutic effort that have addressed the question of protecting the brain reflects their limited success. 1) Barbiturates. After an initial enthusiastic endorsement by many clinicians and years of vigorous controversy, it can now be unequivocally stated that there is no place for barbiturate therapy following resuscitation from cardiac arrest. One presumed explanation for this negative statement is that cerebral metabolic suppression by barbiturates (and other anesthetics) is impossible in the absence of an active EEG. Conversely, in the event of incomplete ischemia EEG activity in usually present (albeit altered) and metabolic suppression and hence possibly protection can be induced with barbiturates. Indeed, most of the animal studies led to a number of recommendations for barbiturate therapy in man for incomplete ischemia. 2) Isoflurane. From a cerebral metabolic standpoint, exposure to isoflurane at concentration of 2 MAC is credited with providing the same potential for protection as high dose barbiturate (isoelectric EEG). A possible major difference between barbiturates and isoflurane is the modest cerebral vasodilation induced by the latter while barbiturates are associated with decreased CBF. This suggests that in focal ischemia isoflurane may elicit an intracerebral steal. 3) Calcium entry blockers. Some calcium entry blockers with the distinctive feature of acting preferably on cerebral as opposed to systemic vascular smooth muscles may exert beneficial effects during or after brain ischemia. Two such drugs which have shown promise are nimodipine and lidoflazine. In animal and human studies nimodipine has been reported to improve the neurologic outcome of both the cerebral vasospasm and the postischemic hypoperfusion state.(ABSTRACT TRUNCATED AT 400 WORDS)

Direct Synthesis of 5-Aryl Barbituric Acids by Rhodium(II)-Catalyzed Reactions of Arenes with Diazo Compounds.

PubMed

Best, Daniel; Burns, David J; Lam, Hon Wai

2015-06-15

A commercially available rhodium(II) complex catalyzes the direct arylation of 5-diazobarbituric acids with arenes, allowing straightforward access to 5-aryl barbituric acids. Free N-H groups are tolerated on the barbituric acid, with no complications arising from N-H insertion processes. This method was applied to the concise synthesis of a potent matrix metalloproteinase (MMP) inhibitor. © 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Barbiturates Block Sodium and Potassium Conductance Increases in Voltage-Clamped Lobster Axons

PubMed Central

Blaustein, M. P.

1968-01-01

Sodium pentobarbital and sodium thiopental decrease both the peak initial (Na) and late steady-state (K) currents and reduce the maximum sodium and potassium conductance increases in voltage-clamped lobster giant axons. These barbiturates also slow the rate at which the sodium conductance turns on, and shift the normalized sodium conductance vs. voltage curves in the direction of depolarization along the voltage axis. Since pentobarbital (pKa = 8.0) blocks the action potential more effectively at pH 8.5 than at pH 6.7, the anionic form of the drug appears to be active. The data suggest that these drugs affect the axon membrane directly, rather than secondarily through effects on intermediary metabolism. It is suggested that penetration of the lipid layer of the membrane by the nonpolar portion of the barbiturate molecules may cause the decrease in membrane conductances, while electrostatic interactions involving the anionic group on the barbiturate, divalent cations, and "fixed charges" in the membrane could account for the slowing of the rate of sodium conductance turn-on and the shift of the normalized conductance curves along the voltage axis. PMID:5648829

Barbiturate ingestion in three adult captive tigers (Panthera tigris) and concomitant fatal botulism of one.

PubMed

Williams, J H; Bester, L; Venter, L; Pretorius, D; Greyling, F

2011-12-01

Zoo animals, including tigers, have been reported to suffer from barbiturate intoxication, with pentabarbitone being most commonly recorded. Clinical signs range from mild ataxia to general anaesthesia with recovery over hours to days with several factors affecting hepatic barbiturate metabolism and tissue partitioning. Botulism is an often fatal intoxication in man, animals, birds and certain fish. The occurrence in carnivores is uncommon to rare, with only 2 reports found of botulism in felids. This report relates to 3 adult captive cohabiting tigers that simultaneously developed signs of abdominal discomfort, progressive ataxia, recumbency and comatose sleep resembling stage 2 anaesthesia, alternating with periods of distracted wakefulness and ataxic movements. These signs occurred 4 days after being fed the carcass of a horse that had ostensibly died of colic and not been euthanased. The male tiger that was the dominant animal in the feeding hierarchy was worst affected and had to be given intravenous fluids. The female that was lowest in hierarchy was unaffected. After 48-72 hours of treatment at the Onderstepoort Veterinary Academic Hospital the females could eat and made an uneventful recovery. The male tiger showed partial recovery but died during the night a few hours after drinking water on his return to the owner. Necropsy revealed severe oesophageal dilation and impaction with decaying grass; some of this material and water were present in the pharynx and trachea, and had been aspirated causing acute widespread bronchopneumonia. Colon content tested negative for common pesticides but, together with liver, tested positive for barbiturate. Serum taken on the day of admission had tested negative for barbiturate and the residual serum from the 3 animals later tested negative for botulinum toxin. Colon and oesophageal content from the male at necropsy were positive for Clostridium botulinum toxin type C by the mouse bioassay neutralisation test, confirming that this male had had concomitant barbiturate toxicity and botulism, and had succumbed to aspiration bronchopneumonia secondary to pharyngeal, laryngeal and oesophageal paralysis and oesophageal

High-Resolution X-Ray Structures of Two Functionally Distinct Members of the Cyclic Amide Hydrolase Family of Toblerone Fold Enzymes

PubMed Central

Peat, Thomas S.; Balotra, Sahil; Wilding, Matthew; Hartley, Carol J.; Newman, Janet

2017-01-01

ABSTRACT The Toblerone fold was discovered recently when the first structure of the cyclic amide hydrolase, AtzD (a cyanuric acid hydrolase), was elucidated. We surveyed the cyclic amide hydrolase family, finding a strong correlation between phylogenetic distribution and specificity for either cyanuric acid or barbituric acid. One of six classes (IV) could not be tested due to a lack of expression of the proteins from it, and another class (V) had neither cyanuric acid nor barbituric acid hydrolase activity. High-resolution X-ray structures were obtained for a class VI barbituric acid hydrolase (1.7 Å) from a Rhodococcus species and a class V cyclic amide hydrolase (2.4 Å) from a Frankia species for which we were unable to identify a substrate. Both structures were homologous with the tetrameric Toblerone fold enzyme AtzD, demonstrating a high degree of structural conservation within the cyclic amide hydrolase family. The barbituric acid hydrolase structure did not contain zinc, in contrast with early reports of zinc-dependent activity for this enzyme. Instead, each barbituric acid hydrolase monomer contained either Na+ or Mg2+, analogous to the structural metal found in cyanuric acid hydrolase. The Frankia cyclic amide hydrolase contained no metal but instead formed unusual, reversible, intermolecular vicinal disulfide bonds that contributed to the thermal stability of the protein. The active sites were largely conserved between the three enzymes, differing at six positions, which likely determine substrate specificity. IMPORTANCE The Toblerone fold enzymes catalyze an unusual ring-opening hydrolysis with cyclic amide substrates. A survey of these enzymes shows that there is a good correlation between physiological function and phylogenetic distribution within this family of enzymes and provide insights into the evolutionary relationships between the cyanuric acid and barbituric acid hydrolases. This family of enzymes is structurally and mechanistically distinct from other enzyme families; however, to date the structure of just two, physiologically identical, enzymes from this family has been described. We present two new structures: a barbituric acid hydrolase and an enzyme of unknown function. These structures confirm that members of the CyAH family have the unusual Toblerone fold, albeit with some significant differences. PMID:28235873

One barbiturate and two solvated thiobarbiturates containing the triply hydrogen-bonded ADA/DAD synthon, plus one ansolvate and three solvates of their coformer 2,4-diaminopyrimidine.

PubMed

Hützler, Wilhelm Maximilian; Egert, Ernst; Bolte, Michael

2016-09-01

A path to new synthons for application in crystal engineering is the replacement of a strong hydrogen-bond acceptor, like a C=O group, with a weaker acceptor, like a C=S group, in doubly or triply hydrogen-bonded synthons. For instance, if the C=O group at the 2-position of barbituric acid is changed into a C=S group, 2-thiobarbituric acid is obtained. Each of the compounds comprises two ADA hydrogen-bonding sites (D = donor and A = acceptor). We report the results of cocrystallization experiments of barbituric acid and 2-thiobarbituric acid, respectively, with 2,4-diaminopyrimidine, which contains a complementary DAD hydrogen-bonding site and is therefore capable of forming an ADA/DAD synthon with barbituric acid and 2-thiobarbituric acid. In addition, pure 2,4-diaminopyrimidine was crystallized in order to study its preferred hydrogen-bonding motifs. The experiments yielded one ansolvate of 2,4-diaminopyrimidine (pyrimidine-2,4-diamine, DAPY), C4H6N4, (I), three solvates of DAPY, namely 2,4-diaminopyrimidine-1,4-dioxane (2/1), 2C4H6N4·C4H8O2, (II), 2,4-diaminopyrimidine-N,N-dimethylacetamide (1/1), C4H6N4·C4H9NO, (III), and 2,4-diaminopyrimidine-1-methylpyrrolidin-2-one (1/1), C4H6N4·C5H9NO, (IV), one salt of barbituric acid, viz. 2,4-diaminopyrimidinium barbiturate (barbiturate is 2,4,6-trioxopyrimidin-5-ide), C4H7N4(+)·C4H3N2O3(-), (V), and two solvated salts of 2-thiobarbituric acid, viz. 2,4-diaminopyrimidinium 2-thiobarbiturate-N,N-dimethylformamide (1/2) (2-thiobarbiturate is 4,6-dioxo-2-sulfanylidenepyrimidin-5-ide), C4H7N4(+)·C4H3N2O2S(-)·2C3H7NO, (VI), and 2,4-diaminopyrimidinium 2-thiobarbiturate-N,N-dimethylacetamide (1/2), C4H7N4(+)·C4H3N2O2S(-)·2C4H9NO, (VII). The ADA/DAD synthon was succesfully formed in the salt of barbituric acid, i.e. (V), as well as in the salts of 2-thiobarbituric acid, i.e. (VI) and (VII). In the crystal structures of 2,4-diaminopyrimidine, i.e. (I)-(IV), R2(2)(8) N-H...N hydrogen-bond motifs are preferred and, in two structures, additional R3(2)(8) patterns were observed.

New one-pot synthesis of spiro[furo[2,3-d]pyrimidine-6,5'-pyrimidine]pentaones and their sulfur analogues.

PubMed

Jalilzadeh, Mohammad; Noroozi Pesyan, Nader; Rezaee, Fereshteh; Rastgar, Saeed; Hosseini, Yaser; Sahin, Ertan

2011-08-01

Reaction of barbituric acid (BA), 1,3-dimethyl barbituric acid (DMBA) and 2-thiobarbituric acid (TBA) with cyanogen bromide and various aldehydes in presence of triethylamine afforded a new class of heterocyclic stable 5-alkyl and/or 5-aryl-1H, 1'H-spiro[furo[2,3-d]pyrimidine-6,5'-pyrimidine]2,2',4,4',6'(3H,3'H,5H)-pentaones which are dimeric forms of barbiturate (uracil and thiouracil derivatives) at 0 °C to ambient temperatures. Structure elucidation is proved by X-ray crystallography, (1)H NMR, (13)C NMR, FT-IR, CHN and mass analyses techniques. Mechanisms of the formations are discussed.

Allyl m-Trifluoromethyldiazirine Mephobarbital: An Unusually Potent Enantioselective and Photoreactive Barbiturate General Anesthetic

DOE Office of Scientific and Technical Information (OSTI.GOV)

Savechenkov, Pavel Y.; Zhang, Xi; Chiara, David C.

2012-12-10

We synthesized 5-allyl-1-methyl-5-(m-trifluoromethyl-diazirynylphenyl)barbituric acid (14), a trifluoromethyldiazirine-containing derivative of general anesthetic mephobarbital, separated the racemic mixture into enantiomers by chiral chromatography, and determined the configuration of the (+)-enantiomer as S by X-ray crystallography. Additionally, we obtained the {sup 3}H-labeled ligand with high specific radioactivity. R-(-)-14 is an order of magnitude more potent than the most potent clinically used barbiturate, thiopental, and its general anesthetic EC{sub 50} approaches those for propofol and etomidate, whereas S-(+)-14 is 10-fold less potent. Furthermore, at concentrations close to its anesthetic potency, R-(-)-14 both potentiated GABA-induced currents and increased the affinity for the agonist muscimol inmore » human {alpha}1{beta}2/3{gamma}2L GABA{sub A} receptors. Finally, R-(-)-14 was found to be an exceptionally efficient photolabeling reagent, incorporating into both {alpha}1 and {beta}3 subunits of human {alpha}1{beta}3 GABAA receptors. These results indicate R-(-)-14 is a functional general anesthetic that is well-suited for identifying barbiturate binding sites on Cys-loop receptors.« less

Economic evaluation of decompressive craniectomy versus barbiturate coma for refractory intracranial hypertension following traumatic brain injury.

PubMed

Alali, Aziz S; Naimark, David M J; Wilson, Jefferson R; Fowler, Robert A; Scales, Damon C; Golan, Eyal; Mainprize, Todd G; Ray, Joel G; Nathens, Avery B

2014-10-01

Decompressive craniectomy and barbiturate coma are often used as second-tier strategies when intracranial hypertension following severe traumatic brain injury is refractory to first-line treatments. Uncertainty surrounds the decision to choose either treatment option. We investigated which strategy is more economically attractive in this context. We performed a cost-utility analysis. A Markov Monte Carlo microsimulation model with a life-long time horizon was created to compare quality-adjusted survival and cost of the two treatment strategies, from the perspective of healthcare payer. Model parameters were estimated from the literature. Two-dimensional simulation was used to incorporate parameter uncertainty into the model. Value of information analysis was conducted to identify major drivers of decision uncertainty and focus future research. Trauma centers in the United States. Base case was a population of patients (mean age = 25 yr) who developed refractory intracranial hypertension following traumatic brain injury. We compared two treatment strategies: decompressive craniectomy and barbiturate coma. Decompressive craniectomy was associated with an average gain of 1.5 quality-adjusted life years relative to barbiturate coma, with an incremental cost-effectiveness ratio of $9,565/quality-adjusted life year gained. Decompressive craniectomy resulted in a greater quality-adjusted life expectancy 86% of the time and was more cost-effective than barbiturate coma in 78% of cases if our willingness-to-pay threshold is $50,000/quality-adjusted life year and 82% of cases at a threshold of $100,000/quality-adjusted life year. At older age, decompressive craniectomy continued to increase survival but at higher cost (incremental cost-effectiveness ratio = $197,906/quality-adjusted life year at mean age = 85 yr). Based on available evidence, decompressive craniectomy for the treatment of refractory intracranial hypertension following traumatic brain injury provides better value in terms of costs and health gains than barbiturate coma. However, decompressive craniectomy might be less economically attractive for older patients. Further research, particularly on natural history of severe traumatic brain injury patients, is needed to make more informed treatment decisions.

Changing pattern of drugs used for self-poisoning.

PubMed Central

Proudfoot, A T; Park, J

1978-01-01

In 1967-76 the annual number of admissions to a poisoning treatment centre rose from 964 to 2134. The proportion of admissions caused by taking barbiturate hypnotics and methaqualone fell considerably while that caused by taking benzodiazepines and tricyclic antidepressants increased. As a result the proportion of patients admitted unconscious fell from 23% to 15%. The declining contributions of barbiturates and methaqualone and increased importance of tricyclic antidepressants were significant in all grades of coma. The change in drugs taken, however, has not yet reduced the percentage of unconscious patients needing endotracheal intubation or assisted ventilation, and hypothermia remains as common. Only hypotension has become less frequent as antidepressants replace barbiturates as the main cause of drug-induced coma. The use of salicylates for self-poisoning is declining slowly, and paracetamol poisoning is now as common. PMID:620215

Psychiatry in the U.S. Army: Lessons for Community Psychiatry

DTIC Science & Technology

2005-01-01

narcosynthesis and hypnosis may still be useful techniques in treating acute reactions in which amnesia is present and in treating some refractory PTSD...residency under Army auspices) also required instruction in combat psychiatry and was introduced to the techniques of hypnosis and barbiturate interviews. As...manifestations and prevalence of gain in illness, brief directive methods of psychotherapy, and the use of hypnosis and barbiturate interviews as

Barbiturate euthanasia solution-induced tissue artifact in nonhuman primates.

PubMed

Grieves, J L; Dick, E J; Schlabritz-Loutsevich, N E; Butler, S D; Leland, M M; Price, S E; Schmidt, C R; Nathanielsz, P W; Hubbard, G B

2008-06-01

Barbiturate euthanasia solutions are a humane and approved means of euthanasia. Overdosing causes significant tissue damage in a variety of laboratory animals. One hundred seventeen non-human primates (NHP) representing 7 species including 12 fetuses euthanized for humane and research reasons by various vascular routes with Euthasol, Sodium Pentobarbital, Fatal Plus, Beuthanasia D, or Euthanasia 5 were evaluated for euthanasia-induced tissue damage. Lungs and livers were histologically graded for hemolysis, vascular damage, edema, and necrosis. Severity of tissue damage was analyzed for differences on the basis of agent, age, sex, dose, and injection route. Severity of tissue damage was directly related to dose and the intracardiac injection route, but did not differ by species, sex, and agent used. When the recommended dose of agent was used, tissue damage was generally reduced, minimal, or undetectable. Barbiturate-induced artifacts in NHPs are essentially the same as in other laboratory species.

Trisubstituted barbiturates and thiobarbiturates: Synthesis and biological evaluation as xanthine oxidase inhibitors, antioxidants, antibacterial and anti-proliferative agents.

PubMed

Figueiredo, Joana; Serrano, João L; Cavalheiro, Eunice; Keurulainen, Leena; Yli-Kauhaluoma, Jari; Moreira, Vânia M; Ferreira, Susana; Domingues, Fernanda C; Silvestre, Samuel; Almeida, Paulo

2018-01-01

Barbituric and thiobarbituric acid derivatives have become progressively attractive to medicinal chemists due to their wide range of biological activities. Herein, different series of 1,3,5-trisubstituted barbiturates and thiobarbiturates were prepared in moderate to excellent yields and their activity as xanthine oxidase inhibitors, antioxidants, antibacterial agents and as anti-proliferative compounds was evaluated in vitro. Interesting bioactive barbiturates were found namely, 1,3-dimethyl-5-[1-(2-phenylhydrazinyl)ethylidene]pyrimidine-2,4,6(1H,3H,5H)-trione (6c) and 1,3-dimethyl-5-[1-[2-(4-nitrophenyl)hydrazinyl]ethylidene]pyrimidine-2,4,6(1H,3H,5H)-trione (6e), which showed concomitant xanthine oxidase inhibitory effect (IC 50 values of 24.3 and 27.9 μM, respectively), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity (IC 50 values of 18.8 and 23.8 μM, respectively). In addition, 5-[1-(2-phenylhydrazinyl)ethylidene]pyrimidine-2,4,6(1H,3H,5H)-trione (6d) also revealed DPPH radical scavenger effect, with an IC 50 value of 20.4 μM. Moreover, relevant cytotoxicity against MCF-7 cells (IC 50  = 13.3 μM) was observed with 5-[[(2-chloro-4-nitrophenyl)amino]methylene]-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (7d). Finally, different 5-hydrazinylethylidenepyrimidines revealed antibacterial activity against Acinetobacter baumannii (MIC values between 12.5 and 25.0 μM) which paves the way for developing new treatments for infections caused by this Gram-negative coccobacillus bacterium, known to be an opportunistic pathogen in humans with high relevance in multidrug-resistant nosocomial infections. The most promising bioactive barbiturates were studied in silico with emphasis on compliance with the Lipinski's rule of five as well as several pharmacokinetics and toxicity parameters. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Pharmacological Protection of the Retina against Damaging Laser Exposures: A Feasibility Study

DTIC Science & Technology

1988-09-01

subsequently administered through this route. Because rabbits can easily be lethally overdosed with barbiturates, surgical plane anesthesia was achieved by...adequately anesthetized. After removal of the second eye, the rabbit was euthanatized by barbiturate overdose . The eye was excised from the rabbit as quickly...Component mq/L uM L-glutamine 73 500 taurine 0.75 6 choline Cl 0.6 4.3 myo-inositol 27 150 Na pyruvate 22 200 ascorbate 18 100 glucose 1800 10,000

Barbiturates

USGS Publications Warehouse

Thomas, N.J.

1999-01-01

Barbiturate products are commonly used to euthanize domestic animals. The primary active component in euthanasia solutions is sodium pentobarbital, but some products also contain other minor ingredients (Fig. 48.1).Euthanasia solutions are generally injected intravenously in domestic animals; therefore, after death, the solutions will be most concentrated in the blood and the highly vascularized organs, such as the liver or spleen, of the euthanized animal.Euthanized carcasses that are available as carrion pose a hazard to scavenging birds and mammals. Large domestic animal carcasses, such as horses, that are not used for food or rendering but that are sufficiently valuable (monetarily or psychologically) to warrant veterinary services and euthanasia drugs are the most common sources of barbiturate poisoning in scavengers. In one instance in British Columbia, a single cow carcass was responsible for poisoning 29 bald eagles.Circumstances that interfere with burial, such as frozen winter soil or bulky carcasses, result in euthanized carcasses being available for scavenger species. This problem could increase in the future if more stringent air-quality standards restrict carcass incineration.

Intermediates of Krebs cycle correct the depression of the whole body oxygen consumption and lethal cooling in barbiturate poisoning in rat.

PubMed

Ivnitsky, Jury Ju; Schäfer, Timur V; Malakhovsky, Vladimir N; Rejniuk, Vladimir L

2004-10-01

Rats poisoned with one LD50 of thiopental or amytal are shown to increase oxygen consumption when intraperitoneally given sucinate, malate, citrate, alpha-ketoglutarate, dimethylsuccinate or glutamate (the Krebs cycle intermediates or their precursors) but not when given glucose, pyruvate, acetate, benzoate or nicotinate (energy substrates of other metabolic stages etc). Survival was increased with succinate or malate from control groups, which ranged from 30-83% to 87-100%. These effects were unrelated to respiratory depression or hypoxia as judged by little or no effect of succinate on ventilation indices and by the lack of effect of oxygen administration. Body cooling of comatose rats at ambient temperature approximately 19 degrees C became slower with succinate, the rate of cooling correlated well with oxygen consumption decrease. Succinate had no potency to modify oxygen consumption and body temperature in intact rats. A condition for antidote effect of the Krebs intermediate was sufficiently high dosage (5 mmol/kg), further dose increase made no odds. Repeated dosing of succinate had more marked protective effect, than a single one, to oxygen consumption and tended to promote the attenuation of lethal effect of barbiturates. These data suggest that suppression of whole body oxygen consumption with barbiturate overdose could be an important contributor to both body cooling and mortality. Intermediates of Krebs cycle, not only succinate, may have a pronounced therapeutic effect under the proper treatment regimen. Availability of Krebs cycle intermediates may be a limiting factor for the whole body oxygen consumption in barbiturate coma, its role in brain needs further elucidation.

Targeted deletion of the GABRA2 gene encoding alpha2-subunits of GABA(A) receptors facilitates performance of a conditioned emotional response, and abolishes anxiolytic effects of benzodiazepines and barbiturates.

PubMed

Dixon, C I; Rosahl, T W; Stephens, D N

2008-07-01

Mice with point-mutated alpha2 GABA(A) receptor subunits (rendering them diazepam insensitive) are resistant to the anxiolytic-like effects of benzodiazepines (BZs) in the conditioned emotional response (CER) test, but show normal anxiolytic effects of a barbiturate. We investigated the consequence of deleting the alpha2-subunit on acquisition of the CER with increasing intensity of footshock, and on the anxiolytic efficacy of a benzodiazepine, diazepam, and a barbiturate, pentobarbital. alpha2 knockout (KO) and wildtype (WT) mice were trained in a conditioned emotional response (CER) task, in which lever pressing for food on a variable interval (VI) schedule was suppressed during the presentation of a compound light/tone conditioned stimulus (CS+) that predicted footshock. The ability of diazepam and of pentobarbital to reduce suppression during the CS+ was interpreted as an anxiolytic response. There were no differences between the genotypes in shock sensitivity, as assessed by their flinch responses to increasing levels of shock. However, alpha2 KO mice showed a greater suppression of lever pressing than WT littermates in the presence of a compound cue signalling footshock. Diazepam (0, 0.5, 1 and 2 mg/kg) induced a dose-dependent anxiolytic-like effect in WT mice but no such effect was seen in KO mice. Similarly, although pentobarbital (20 mg/kg) reduced the ability of the CS+ to reduce lever pressing rates in WT mice, this effect was not seen in the KO. These findings suggest that alpha2-containing GABA(A) receptors mediate the anxiolytic effects of barbiturates, as well as benzodiazepines, and that they may be involved in neuronal circuits underlying conditioned anxiety.

Associations of Adverse Clinical Course and Ingested Substances among Patients with Deliberate Drug Poisoning: A Cohort Study from an Intensive Care Unit in Japan.

PubMed

Ichikura, Kanako; Okumura, Yasuyuki; Takeuchi, Takashi

2016-01-01

Some patients with deliberate drug poisoning subsequently have an adverse clinical course. The present study aimed to examine whether the type of drugs ingested and psychiatric diagnoses were related to an adverse clinical course. We conducted a cohort study of patients with deliberate drug poisoning admitted to the intensive care unit of a university hospital located in Tokyo, Japan, between September 2006 and June 2013. Intensive care unit (ICU) stay of ≥4 days was used as a primary outcome measure, while the incidence of aspiration pneumonitis was used as a secondary outcome measure. Ingested substances and psychiatric diagnoses were used as explanatory variables. Of the 676 patients with deliberate drug poisoning, 88% had a history of psychiatric treatment and 82% had ingested psychotropic drugs. Chlorpromazine-promethazine-phenobarbital combination drug (Vegetamin®) ranked fifth among the most frequently ingested substances in cases of deliberate drug poisoning and had the highest incidence of prolonged ICU stay (20%) and aspiration pneumonitis (29%). The top three major classes consisted of benzodiazepines (79%), new-generation antidepressants (25%), and barbiturates/non-barbiturates (23%). Barbiturate overdose was independently associated with increased odds of both prolonged ICU stay (8% vs. 17%; odds ratio [OR], 2.97; 95% confidence interval [CI], 1.60-5.55) and aspiration pneumonitis (8% vs. 24%; OR, 3.83; 95% CI, 2.18-6.79) relative to those associated with overdose of only other sedative-hypnotics (i.e., benzodiazepines). These results suggest that judicious prescribing of barbiturates by psychiatrists could reduce the risk of an adverse clinical course when a patient attempts an overdose.

Multi-Component synthesis and computational studies of three novel thio-barbituric acid carbohydrate derivatives

NASA Astrophysics Data System (ADS)

Gupta, Stuti; Khare, Naveen K.

2017-01-01

The thio-barbituric acid is convenient starting compound for the preparation of fused heterocycles and its 5-substituted derivatives which are pharmacologically one of the most important classes of compounds. The fused compounds of thio-barbituric acid, 4-(1R,2S,3S,4S)-1,2,3,4,5-tetrahydroxy pentyl-10-phenyl-1,3,6,8,9,10 hexahydro-2,7-dithiooxopyrido [2,3-d; 6,5'] dipyrimidine-4,5 diones (1), 4-(1S,2S,3S,4S)-1,2,3,4,5-tetrahydroxy pentyl-10-phenyl-1,3,6,8,9,10 hexahydro-2,7-dithiooxopyrido [2,3-d; 6,5'] dipyrimidine-4,5 diones (2), 3-(1R,2S,3S)-1,2,3,4-tetrahydroxy butyl-10-phenyl-1,3,6,8,9,10 hexahydro-2,7-dithiooxopyrido [2,3-d; 6,5'] dipyrimidine-4,5 diones (3) have been synthesized in single step by the condensation of thio-barbituric acid with sugars (L-rhamnose, L-fucose and L-arabinose) & aniline using para-toluene sulfonic acid (p-TSA) as an effective acid catalyst under refluxing conditions. The molecular structure and detailed spectroscopic analysis of all three novel synthesized thiones derivatives have been performed using experimental techniques like 1H, 13C NMR, 2D (COSY, HSQC, DEPT-135 and DEPT-90) as well as theoretical calculations by density functional theory (DFT) using B3LYP and 6-311G + (d, p) basis set. The strength and nature of weak intramolecular interactions have been studied by atom in molecule (AIM) approach. Global reactivity descriptors have been computed to predict reactivity and reactive sites in the molecule.

Binding of urea and thiourea with a barbiturate derivative: experimental and theoretical approach.

PubMed

Dixit, Namrata; Shukla, P K; Mishra, P C; Mishra, Lallan; Roesky, Herbert W

2010-01-14

A barbiturate derivative [1,5-dihydro-5-[5-pyrimidine-2,4(1H,3H)-dionyl]-2H-chromeno[2,3-d] pyrimidine-2,4(3H)-dione)] (L1) possesses functionalities complementary to amide and thioamide. Hence its binding with urea and thiourea, is monitored using UV-vis and fluorescence titrations as well as isothermal titration calorimetry (ITC) study. Theoretical studies on hydrogen-bonded complexes of L1-urea and L1-thiourea in the gas phase, aqueous, and DMSO medium are carried out using density functional theory (DFT) at the B3LYP/6-31G** level. The theoretical calculations support the experimental results.

Structure-energy relationship in barbituric acid: a calorimetric, computational, and crystallographic study.

PubMed

Roux, María Victoria; Temprado, Manuel; Notario, Rafael; Foces-Foces, Concepción; Emel'yanenko, Vladimir N; Verevkin, Sergey P

2008-08-14

This paper reports the value of the standard (p(o) = 0.1 MPa) molar enthalpy of formation in the gas phase at T = 298.15 K for barbituric acid. The enthalpies of combustion and sublimation were measured by static bomb combustion calorimetry and transference (transpiration) method in a saturated N2 stream and a gas-phase enthalpy of formation value of -(534.3 +/- 1.7) kJ x mol(-1) was determined at T = 298.15 K. G3-calculated enthalpies of formation are in very good agreement with the experimental value. The behavior of the sample as a function of the temperature was studied by differential scanning calorimetry, and a new polymorph of barbituric acid at high temperature was found. In the solid state, two anhydrous forms are known displaying two out of the six hydrogen-bonding patterns observed in the alkyl/alkenyl derivatives retrieved from the Cambridge Crystallographic Database. The stability of these motifs has been analyzed by theoretical calculations. X-ray powder diffraction technique was used to establish to which polymorphic form corresponds to the commercial sample used in this study and to characterize the new form at high temperature.

Monoalkylated barbiturate derivatives: X-ray crystal structure, theoretical studies, and biological activities

NASA Astrophysics Data System (ADS)

Barakat, Assem; Al-Majid, Abdullah Mohammed; Soliman, Saied M.; Islam, Mohammad Shahidul; Ghawas, Hussain Mansur; Yousuf, Sammer; Choudhary, M. Iqbal; Wadood, Abdul

2017-08-01

Barbiturate derivatives are privileged structures with a broad range of pharmaceutical applications. We prepared a series of 5-monoalkylated barbiturate derivatives (3a-l) and evaluated, in vitro, their antioxidant (DPPH assay), and α-glucosidase inhibitory activities. Compounds 3a-l were synthesized via Michael addition. The structure of compound 3k was determined using X-ray single-crystal diffraction, and geometric parameters were calculated using density functional theory at the B3LYP/6-311G(d,p) level of theory. Further, the structural analysis of 3k were also investigated. Biological studies revealed that compounds 3b (IC50 = 133.1 ± 3.2 μM), 3d (IC50 = 305 ± 7.7 μM), and 3e (IC50 = 184 ± 2.3 μM) have potent α-glucosidase enzyme inhibitors and showed greater activity than the standard drug acarbose (IC50 = 841 ± 1.73 μM). Compounds 3a-3i were found to show weak antioxidant activity against 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radicals (IC50 = 91 ± 0.75 to 122 ± 1.0 μM) when tested against a standard antioxidant, gallic acid (IC50 = 23 ± 0.43 μM).

Positive and Negative Allosteric Modulation of an α1β3γ2 γ-Aminobutyric Acid Type A (GABAA) Receptor by Binding to a Site in the Transmembrane Domain at the γ+-β− Interface*

PubMed Central

Jayakar, Selwyn S.; Zhou, Xiaojuan; Savechenkov, Pavel Y.; Chiara, David C.; Desai, Rooma; Bruzik, Karol S.; Miller, Keith W.; Cohen, Jonathan B.

2015-01-01

In the process of developing safer general anesthetics, isomers of anesthetic ethers and barbiturates have been discovered that act as convulsants and inhibitors of γ-aminobutyric acid type A receptors (GABAARs) rather than potentiators. It is unknown whether these convulsants act as negative allosteric modulators by binding to the intersubunit anesthetic-binding sites in the GABAAR transmembrane domain (Chiara, D. C., Jayakar, S. S., Zhou, X., Zhang, X., Savechenkov, P. Y., Bruzik, K. S., Miller, K. W., and Cohen, J. B. (2013) J. Biol. Chem. 288, 19343–19357) or to known convulsant sites in the ion channel or extracellular domains. Here, we show that S-1-methyl-5-propyl-5-(m-trifluoromethyl-diazirynylphenyl) barbituric acid (S-mTFD-MPPB), a photoreactive analog of the convulsant barbiturate S-MPPB, inhibits α1β3γ2 but potentiates α1β3 GABAAR responses. In the α1β3γ2 GABAAR, S-mTFD-MPPB binds in the transmembrane domain with high affinity to the γ+-β− subunit interface site with negative energetic coupling to GABA binding in the extracellular domain at the β+-α− subunit interfaces. GABA inhibits S-[3H]mTFD-MPPB photolabeling of γ2Ser-280 (γM2–15′) in this site. In contrast, within the same site GABA enhances photolabeling of β3Met-227 in βM1 by an anesthetic barbiturate, R-[3H]methyl-5-allyl-5-(m-trifluoromethyl-diazirynylphenyl)barbituric acid (mTFD-MPAB), which differs from S-mTFD-MPPB in structure only by chirality and two hydrogens (propyl versus allyl). S-mTFD-MPPB and R-mTFD-MPAB are predicted to bind in different orientations at the γ+-β− site, based upon the distance in GABAAR homology models between γ2Ser-280 and β3Met-227. These results provide an explanation for S-mTFD-MPPB inhibition of α1β3γ2 GABAAR function and provide a first demonstration that an intersubunit-binding site in the GABAAR transmembrane domain binds negative and positive allosteric modulators. PMID:26229099

Withdrawal strategies for outpatients

PubMed Central

Mezciems, Edgar

1996-01-01

This article discusses outpatient withdrawal strategies for patients addicted to alcohol, benzodiazepines, barbiturates, and opiates and describes some practical ways to support recovery. PMID:8828877

Daily isoflurane exposure increases barbiturate insensitivity in medullary respiratory and cortical neurons via expression of ε-subunit containing GABA ARs.

PubMed

Hengen, Keith B; Nelson, Nathan R; Stang, Kyle M; Johnson, Stephen M; Smith, Stephanie M; Watters, Jyoti J; Mitchell, Gordon S; Behan, Mary

2015-01-01

The parameters governing GABAA receptor subtype expression patterns are not well understood, although significant shifts in subunit expression may support key physiological events. For example, the respiratory control network in pregnant rats becomes relatively insensitive to barbiturates due to increased expression of ε-subunit-containing GABAARs in the ventral respiratory column. We hypothesized that this plasticity may be a compensatory response to a chronic increase in inhibitory tone caused by increased central neurosteroid levels. Thus, we tested whether increased inhibitory tone was sufficient to induce ε-subunit upregulation on respiratory and cortical neurons in adult rats. Chronic intermittent increases in inhibitory tone in male and female rats was induced via daily 5-min exposures to 3% isoflurane. After 7d of treatment, phrenic burst frequency was less sensitive to barbiturate in isoflurane-treated male and female rats in vivo. Neurons in the ventral respiratory group and cortex were less sensitive to pentobarbital in vitro following 7d and 30d of intermittent isoflurane-exposure in both male and female rats. The pentobarbital insensitivity in 7d isoflurane-treated rats was reversible after another 7d. We hypothesize that increased inhibitory tone in the respiratory control network and cortex causes a compensatory increase in ε-subunit-containing GABAARs.

Thiobarbiturate and barbiturate salts of pefloxacin drug: Growth, structure, thermal stability and IR-spectra

NASA Astrophysics Data System (ADS)

Golovnev, Nicolay N.; Molokeev, Maxim S.; Lesnikov, Maxim K.; Sterkhova, Irina V.; Atuchin, Victor V.

2017-12-01

Three new salts of pefloxacin (PefH) with thiobarbituric (H2tba) and barbituric (H2ba) acids, pefloxacinium 2-thiobarbiturate trihydrate, PefH2(Htba)·3H2O (1), pefloxacinium 2-thiobarbiturate, PefH2(Htba) (2) and bis(pefloxacinium barbiturate) hydrate, (PefH2)2(Hba)2·2.56H2O (3) are synthesized and structurally characterized by the X-ray single-crystal diffraction. The structures of 1-3 contain intramolecular hydrogen bonds Csbnd H⋯F, Osbnd H⋯O. Intermolecular hydrogen bonds Nsbnd H⋯O and Osbnd H⋯O form a 2D plane network in 1. In 2 and 3, intermolecular hydrogen bonds Nsbnd H⋯O form the infinite chains. In 1-3, the Htba- and Hba- ions are connected with PefH2+ only by one intermolecular hydrogen bond Nsbnd H⋯O. In 2 and 3, two Htba- and Hba- ions are connected by two hydrogen bonds Nsbnd H⋯O. These pairs form infinite chains. All three structures are stabilized by the π-π interactions of the head-to-tail type between PefH2+ ions. Compounds 2 and 3 are characterized by powder XRD, TG-DSC and FT-IR.

Synergism of isothermal regimen and sodium succinate in experimental therapy of barbiturate coma.

PubMed

Reinyuk, V L; Shefer, T V; Ivnitskii, Yu Yu

2006-07-01

In rats with experimental thiopental coma rectal temperature decreased by 9.4 degrees C, oxygen consumption 5-fold, and arteriovenous Po(2)gradient decreased 2-fold within 3 h; CO(2)accumulated in the blood and mixed type acidosis developed. Administration of sodium succinate under these conditions increased arteriovenous Po(2)gradient and reduced manifestations of metabolic acidosis. Maintenance of normal body temperature (warming) corrected primarily manifestations of respiratory acidosis. Each therapeutic agent reduced inhibition of O(2)consumption by 1/4; animal survival tended to increase from 42 to 50%. Combined use of these treatments potentiated the antiacidotic effect and increased survival to 92%. The authors conclude that hypothermia inhibits the therapeutic effect of succinate in barbiturate coma.

An unusual case of relay pentobarbital toxicosis in a dog.

PubMed

Bischoff, Karyn; Jaeger, Robin; Ebel, Joseph G

2011-09-01

Sodium pentobarbital and phenytoin are common constituents of veterinary euthanasia solutions in the United States. Relay, or secondary, barbiturate toxicosis has been reported in carnivorous animals that have fed from the carcasses of euthanized livestock. This case report presents barbiturate toxicosis in a dog. A 2-year-old female spayed Australian shepherd presented comatose 2 h after ingesting an unknown substance on the beach. The material was retrieved from the stomach by gastric lavage and visually identified as fish or other animal tissue. The dog recovered with symptomatic and supportive therapy and was released on the third day of hospitalization. Tissue found on the beach near where the dog walked and a urine sample from the dog were analyzed by gas chromatography/mass spectrometry. Both samples were positive for pentobarbital and phenytoin. The tissue was consistent with mammalian blubber based on gross and histological examination. Three weeks previously, a juvenile humpback whale had stranded on the beach where the dog had ingested the unknown substance. The whale had been euthanized with a barbiturate solution, necropsied, and removed from the beach. It was not definitively determined that the pentobarbital-containing blubber ingested by the dog was from the euthanized whale, but that was the most likely source. Although attempts were made to remove the whale's remains from the beach, practical considerations made complete removal challenging, if not impossible.

3D-QSAR Studies on Barbituric Acid Derivatives as Urease Inhibitors and the Effect of Charges on the Quality of a Model.

PubMed

Ul-Haq, Zaheer; Ashraf, Sajda; Al-Majid, Abdullah Mohammed; Barakat, Assem

2016-04-30

Urease enzyme (EC 3.5.1.5) has been determined as a virulence factor in pathogenic microorganisms that are accountable for the development of different diseases in humans and animals. In continuance of our earlier study on the helicobacter pylori urease inhibition by barbituric acid derivatives, 3D-QSAR (three dimensional quantitative structural activity relationship) advance studies were performed by Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) methods. Different partial charges were calculated to examine their consequences on the predictive ability of the developed models. The finest developed model for CoMFA and CoMSIA were achieved by using MMFF94 charges. The developed CoMFA model gives significant results with cross-validation (q²) value of 0.597 and correlation coefficients (r²) of 0.897. Moreover, five different fields i.e., steric, electrostatic, and hydrophobic, H-bond acceptor and H-bond donors were used to produce a CoMSIA model, with q² and r² of 0.602 and 0.98, respectively. The generated models were further validated by using an external test set. Both models display good predictive power with r²pred ≥ 0.8. The analysis of obtained CoMFA and CoMSIA contour maps provided detailed insight for the promising modification of the barbituric acid derivatives with an enhanced biological activity.

The role of regional nerve block anesthesia for carotid endarterectomy: an experimental comparison with previous series with the use of general anesthesia and barbiturates for cerebral protection.

PubMed

Agrifoglio, G; Agus, G B; Bonalumi, F; Costantini, A; Carlesi, R

1987-01-01

A retrospective analysis was performed on a consecutive series of 60 cases divided into two groups given carotid endarterectomy (C.E.) for atherosclerotic disease. In the first group general anesthesia and barbiturate cerebral protection were employed; in group two, loco-regional anesthesia. Indications and risk factors were similar in the two groups; the surgical procedure was identical. The differences in the results are reported and factors contributing to cerebral protection or reduction in the risk of stroke are analyzed. The analysis indicates that loco-regional anesthesia for C.E. is a reliable method for detecting cerebral ischemia and guaranteeing cerebral protection by means of a temporary shunt when strictly necessary.

Identifying Drugs

MedlinePlus

... Phencyclidine) Peyote and Mescaline Psilocybin Rohypnol Salvia Divinorum Spice/ K2, Synthetic Marijuana Steroids U-47700 Amphetamines Barbiturates ... Phencyclidine) Peyote and Mescaline Psilocybin Rohypnol Salvia Divinorum Spice/ K2, Synthetic Marijuana Steroids U-47700 Aerosol cans ...

Bibliography [On Drugs].

ERIC Educational Resources Information Center

National Association of Student Personnel Administrators, Detroit, MI.

A bibliography of materials on drugs is presented. The book and paper back entries are annotated. Selected technical references are listed under these major findings: (1) dependency, (2) barbiturates, (3) amphetamines, and (4) general pharmacology. (PS)

41 CFR Appendix to Part 102 - 74-Rules and Regulations Governing Conduct on Federal Property

Code of Federal Regulations, 2012 CFR

2012-01-01

... from— (a) Being under the influence, using or possessing any narcotic drugs, hallucinogens, marijuana... alcoholic beverages, narcotic drugs, hallucinogens, marijuana, barbiturates, or amphetamines. Alcoholic...

41 CFR Appendix to Part 102 - 74-Rules and Regulations Governing Conduct on Federal Property

Code of Federal Regulations, 2010 CFR

2010-07-01

... from— (a) Being under the influence, using or possessing any narcotic drugs, hallucinogens, marijuana... alcoholic beverages, narcotic drugs, hallucinogens, marijuana, barbiturates, or amphetamines. Alcoholic...

41 CFR Appendix to Part 102 - 74-Rules and Regulations Governing Conduct on Federal Property

Code of Federal Regulations, 2014 CFR

2014-01-01

... from— (a) Being under the influence, using or possessing any narcotic drugs, hallucinogens, marijuana... alcoholic beverages, narcotic drugs, hallucinogens, marijuana, barbiturates, or amphetamines. Alcoholic...

41 CFR Appendix to Part 102 - 74-Rules and Regulations Governing Conduct on Federal Property

Code of Federal Regulations, 2013 CFR

2013-07-01

... from— (a) Being under the influence, using or possessing any narcotic drugs, hallucinogens, marijuana... alcoholic beverages, narcotic drugs, hallucinogens, marijuana, barbiturates, or amphetamines. Alcoholic...

41 CFR Appendix to Part 102 - 74-Rules and Regulations Governing Conduct on Federal Property

Code of Federal Regulations, 2011 CFR

2011-01-01

... from— (a) Being under the influence, using or possessing any narcotic drugs, hallucinogens, marijuana... alcoholic beverages, narcotic drugs, hallucinogens, marijuana, barbiturates, or amphetamines. Alcoholic...

Influence of chronic barbiturate administration on sleep apnea after hypersomnia presentation: case study.

PubMed Central

Takhar, J; Bishop, J

2000-01-01

When sleepiness is excessive, undesirable, inappropriate or unexplained, it often indicates a clinical disorder that is generically termed hypersomnia. One of the leading causes of hypersomnia is sleep apnea. We present the case of a 44-year-old woman with a history of bipolar spectrum disorder and epilepsy who initially showed evidence of hypersomnia. The hypersomnia settled with changes to her medication, but the patient was subsequently found to have severe obstructive sleep apnea. The relation between the patient's medication and sleep apnea is discussed, and the possible respiratory-suppressant effects of chronic barbiturate treatment are considered. The role of other evoking factors within the context of this case and the mechanisms by which drug interactions and psychotropic treatment may worsen, obscure or perpetuate sleep apnea are also examined. PMID:11022396

EFFECTS OF X-IRRADIATION ON THE HEXOBARBITAL METABOLIZING ENZYME SYSTEM OF RAT LIVER MICROSOMES.

DTIC Science & Technology

RADIATION EFFECTS , *ENZYME INHIBITORS, *HYPNOTICS AND SEDATIVES, ENZYMES, BIOSYNTHESIS, METABOLISM, DETOXIFICATION, BARBITURATES, OXIDATION...MICROSOMES, LIVER, REGENERATION(ENGINEERING), EXCISION, SUBLETHAL DOSAGE, TOXICITY , HYPNOSIS, SLEEP, HEAD(ANATOMY), MALES, FEMALES, RATS.

METHOD OF SUPPRESSING GASTROINTESTINAL UREASE ACTIVITY

DOEpatents

Visek, W.J.

1963-04-23

This patent shows a method of increasing the growth rate of chicks. Certain diacyl substituted ureas such as alloxan, murexide, and barbituric acid are added to their feed, thereby suppressing gastrointestinal urease activity and thus promoting growth. (AEC)

PERTURBATION OF VOLTAGE-SENSITIVE CALCIUM FUNCTION IN PHEOCHROMOCYTOMA CELLS BY VOLATILE ORGANIC SOLVENTS.

EPA Science Inventory

Volatile organic solvents such as toluene (TOL) and trichloroethylene perturb nervous system function and share characteristic effects with other central nervous system depressants such as anesthetic gasses, ethanol, benzodiazepines and barbiturates. Recently, mechanistic studies...

Neurotoxic effects of carambola in rats: the role of oxalate.

PubMed

Chen, Chien-Liang; Chou, Kang-Ju; Wang, Jyh-Seng; Yeh, Jeng-Hsien; Fang, Hua-Chang; Chung, Hsiao-Min

2002-05-01

Carambola (star fruit) has been reported to contain neurotoxins that cause convulsions, hiccups, or death in uremic patients, and prolong barbiturate-induced sleeping time in rats. The constituent responsible for these effects remains uncertain. Carambola contains a large quantity of oxalate, which can induce depression of cerebral function and seizures. This study was conducted to investigate the role of oxalate in carambola toxicity in rats. The effects on barbiturate-induced sleeping time and death caused by intraperitoneal administration of carambola juice were observed in Sprague-Dawley rats. To obtain a dose-dependent response curve and evaluate the lethal dose, rats were treated with serial amounts of pure carambola juice diluted with normal saline in a volume of 1:1. To test the role of oxalate in the neurotoxic effect of carambola, either 5.33 g/kg carambola after oxalate removal or 5.33 g/kg of pure carambola juice diluted with normal saline were administered intraperitoneally, while the control group was given normal saline before pentobarbital injection. The effects of carambola and oxalate-removed carambola on barbiturate-induced sleeping time were compared with those of saline. To assess the lethal effect of oxalate in carambola, we gave rats chemical oxalate at comparable concentrations to the oxalate content of carambola. Carambola juice administration prolonged barbiturate-induced sleeping time in a dose-dependent manner. The sleeping time of rats that received normal saline and 1.33 g/kg, 2.67 g/kg, 5.33 g/kg, and 10.67 g/kg of carambola juice were 66 +/- 16.6, 93.7 +/- 13.4, 113.3 +/- 11.4, 117.5 +/- 29.0, and 172.5 +/- 38.8 minutes, respectively. The three higher-dose groups had longer sleeping times than controls (p < 0.05 or 0.005). This effect was eliminated after the removal of oxalate from carambola juice. Four of eight rats in the 10.67-g/kg group and all rats in the 21.33 g/kg and chemical oxalate groups died after seizure. Lethal doses of carambola juice were rendered harmless by the oxalate removal procedure. Oxalate is a main constituent of carambola neurotoxicity. This finding suggests that patients with carambola intoxication should be treated for oxalate toxicosis.

Medical Readings on Drug Abuse.

ERIC Educational Resources Information Center

Byrd, Oliver E.

Summaries are presented of over 150 articles in the recent medical and psychiatric literature. Topics covered are: effects of drugs, tobacco, alcohol, drugs used in medicine, vapor sniffing, marijuana, barbiturates, tranquilizers, amphetamines, methamphetamine, lysergic acid diethylamide, other hallucinogens, heroin and the opiates, psychiatric…

44 CFR 15.9 - Alcoholic beverages and narcotics.

Code of Federal Regulations, 2012 CFR

2012-10-01

... beverages, narcotic drugs, hallucinogens, marijuana, barbiturates or amphetamines as defined in Title 21 of... property being under the influence of or using or possessing any narcotic drug, marijuana, hallucinogen... influence of alcoholic beverages; (d) Bringing alcoholic beverages, narcotic drugs, hallucinogens, marijuana...

44 CFR 15.9 - Alcoholic beverages and narcotics.

Code of Federal Regulations, 2014 CFR

2014-10-01

... beverages, narcotic drugs, hallucinogens, marijuana, barbiturates or amphetamines as defined in Title 21 of... property being under the influence of or using or possessing any narcotic drug, marijuana, hallucinogen... influence of alcoholic beverages; (d) Bringing alcoholic beverages, narcotic drugs, hallucinogens, marijuana...

44 CFR 15.9 - Alcoholic beverages and narcotics.

Code of Federal Regulations, 2013 CFR

2013-10-01

... beverages, narcotic drugs, hallucinogens, marijuana, barbiturates or amphetamines as defined in Title 21 of... property being under the influence of or using or possessing any narcotic drug, marijuana, hallucinogen... influence of alcoholic beverages; (d) Bringing alcoholic beverages, narcotic drugs, hallucinogens, marijuana...

44 CFR 15.9 - Alcoholic beverages and narcotics.

Code of Federal Regulations, 2011 CFR

2011-10-01

... beverages, narcotic drugs, hallucinogens, marijuana, barbiturates or amphetamines as defined in Title 21 of... property being under the influence of or using or possessing any narcotic drug, marijuana, hallucinogen... influence of alcoholic beverages; (d) Bringing alcoholic beverages, narcotic drugs, hallucinogens, marijuana...

44 CFR 15.9 - Alcoholic beverages and narcotics.

Code of Federal Regulations, 2010 CFR

2010-10-01

... beverages, narcotic drugs, hallucinogens, marijuana, barbiturates or amphetamines as defined in Title 21 of... property being under the influence of or using or possessing any narcotic drug, marijuana, hallucinogen... influence of alcoholic beverages; (d) Bringing alcoholic beverages, narcotic drugs, hallucinogens, marijuana...

Studies of Circulatory and Metabolic Changes during Ketamine Narcosis,

DTIC Science & Technology

1985-03-13

Braun, U., Hensel, I., Kettler, D., Lohr, B.: The effects of methoxyflurane , halothane, dipiritramide, barbiturate and ketamine on the total oxygen...narcosis caus- ed by ether, halothane, methoxyflurane , ketamine and piritranide, as well as neuroleptanalgesia. Lecture at the XIIth. General Con

Postoperative Cerebral Infarction Risk Factors and Postoperative Management of Pediatric Patients with Moyamoya Disease.

PubMed

Muraoka, Shinsuke; Araki, Yoshio; Kondo, Goro; Kurimoto, Michihiro; Shiba, Yoshiki; Uda, Kenji; Ota, Shinji; Okamoto, Sho; Wakabayashi, Toshihiko

2018-05-01

Although revascularization surgery for patients with moyamoya disease can effectively prevent ischemic events and thus improve the long-term clinical outcome, the incidence of postoperative ischemic complications affects patients' quality of life. This study aimed to clarify the risk factors associated with postoperative ischemic complications and to discuss the appropriate perioperative management. Fifty-eight revascularization operations were performed in 37 children with moyamoya disease. Patients with moyamoya syndrome were excluded from this study. Magnetic resonance imaging was performed within 7 days after surgery. Postoperative cerebral infarction was defined as a diffusion-weighted imaging high-intensity lesion with or without symptoms. We usually use fentanyl and dexmedetomidine as postoperative analgesic and sedative drugs for patients with moyamoya disease. We used barbiturate coma therapy for pediatric patients with moyamoya disease who have all postoperative cerebral infarction risk factors. Postoperative ischemic complications were observed in 10.3% of the children with moyamoya disease (6 of 58). Preoperative cerebral infarctions (P = 0.0005), younger age (P = 0.038), higher Suzuki grade (P = 0.003), and posterior cerebral artery stenosis/occlusion (P = 0.003) were related to postoperative ischemic complications. Postoperative cerebral infarction occurred all pediatric patients using barbiturate coma therapy. The risk factors associated with postoperative ischemic complications for children with moyamoya disease are preoperative infarction, younger age, higher Suzuki grade, and posterior cerebral artery stenosis/occlusion. Barbiturate coma therapy for pediatric patients with moyamoya disease who have the previous risk factors is insufficient for prevention of postoperative cerebral infarction. More studies are needed to identify the appropriate perioperative management. Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical Aspects of General Anesthesia: Part II. Current Practices

ERIC Educational Resources Information Center

Brunsvold, Robert; Ostercamp, Daryl L.

2006-01-01

The basics of balanced general anesthesia developed since 1956 and the update on existing practices of intravenous induction anesthetics and inhalational anesthetics are discussed. Some of the progressive anesthetics discussed are propofol instead of barbiturate such as thiopental or methohexital, inhalational anesthetic halothane,…

Synthesis of pyrimidine-2,4,6-trione derivatives: Anti-oxidant, anti-cancer, α-glucosidase, β-glucuronidase inhibition and their molecular docking studies.

PubMed

Barakat, Assem; Islam, Mohammad Shahidul; Al-Majid, Abdullah Mohammed; Ghabbour, Hazem A; Yousuf, Sammer; Ashraf, Mahwish; Shaikh, Nimra Naveed; Iqbal Choudhary, M; Khalil, Ruqaiya; Ul-Haq, Zaheer

2016-10-01

This paper describes a facile protocol, efficient, and environmentally benign for the synthesis a series of barbiturate acid substituted at C5 position 3a-o. The desired compounds subjected in vitro for different set of bioassays including against anti-oxidant (DPPH and super oxide scavenger assays), anti-cancer, α-glucosidase and β-glucuronidase inhibitions. Compound 3m (IC50=22.9±0.5μM) found to be potent α-glucosidase enzyme inhibitors and showed more activity than standard acarbose (IC50=841±1.73μM). Compound 3f (IC50=86.9±4.33μM) found to be moderate β-Glucuronidase enzyme inhibitors and showed activity comparatively less than the standard d-saccharic acid 1,4-lactone (IC50=45.75±2.16μM). Furthermore, in sillico investigation was carried out to investigate bonding mode of barbiturate acid derivatives. Copyright © 2016 Elsevier Inc. All rights reserved.

Knoevenagel Reaction of Unprotected Sugars

NASA Astrophysics Data System (ADS)

Scherrmann, Marie-Christine

The Knoevenagel reaction of unprotected sugars was investigated in the 1950s using zinc chloride as promoter. The so-called Garcia Gonzalez reaction had been almost forgotten for 50 years, until the emergence of new water tolerant catalysts having Lewis acid behavior. The reaction was thus reinvestigated and optimal conditions have been found to prepare trihydroxylated furan derivatives from pentose or β-tetrahydrofuranylfuran from hexoses with non-cyclic β-keto ester or β-diketones. Other valuable compounds such as β-linked tetrahydrobenzofuranyl glycosides or hydroxyalkyl-3,3,6,6,-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione can be obtained using cyclic β-dicarbonylic derivatives. Apart from one report in the 1950s, the Knoevenagel reaction of unprotected carbohydrate in basic condition has been studied only in the mid-1980s to prepare C-glycosyl barbiturates from barbituric acids and, later on, from non-cyclic β-diketones, β-C-glycosidic ketones. The efficient method exploited to prepare such compounds has found an industrial development in cosmetics.

[Biperiden abuse as a partial factor in polytoxicomania].

PubMed

Schulte, R M

1988-03-01

We found 16 patients (15%) taking the anticholinergic biperiden because of its psychotropic action, occasionally, rather frequently or regularly, among a subgroup of 120 drug-dependent patients (drugs of the barbiturate and amphetamin types) out of a studied total of 194 imprisoned male addicts. These biperiden abusers suffered without exception from polytoxicomania associated with drug dependence and alcoholism. Most prominent was drug dependence on drugs of the morphine type. We could not prove a case of an isolated "primary" abuse of biperiden. Direct medical prescription was a rather secondary factor in procuring this preparation, in contrast to analgesics, tranquilisers, barbiturates and clomethiazol. Increase of biperiden abuse is due, on the one hand, to a generally noticeable tendency to polytoxicomania, and on the other hand to a change in Federal German drug prescription rules effective 1 August 1986 according to which fenetylline hydrochloride, a sympathomimetic, is now subject to medical prescription. Other centrally acting anticholinergics were unknown among this group of patients and were not abused. The results are discussed on the basis of available literature.

[Selected Readings for the Professional Working with Drug Related Problems.

ERIC Educational Resources Information Center

Wisconsin Univ., Madison.

A bibliography of selected readings compiled at the University of Wisconsin for the National Drug Education Training Program. These selected readings include information on narcotics, amphetamines, mescaline, psilogybin, hallucinogens, LSD, barbiturates, alcohol, and other stimulants. The intended user of this bibliography is the professional…

The Effectiveness of the Human Patient Simulator in Teaching Anesthesia Pharmacology to First Year Nurse Anesthesia Students

DTIC Science & Technology

2002-12-01

month period. Simulator scenarios included overdose of inhalation anesthetic, oxygen source failure, cardiac arrest, malignant hypothermia, tension...may most effectively attenuate emergence delirium? a. Propofol b. Versed*** c. Fentanyl d. Droperidol 6. Barbituric acid is formed by the

29 CFR Appendix A to Subpart T to... - Examples of Conditions Which May Restrict or Limit Exposure to Hyperbaric Conditions

Code of Federal Regulations, 2012 CFR

2012-07-01

... duration of isolation. History of seizure disorder other than early febrile convulsions. Malignancies... or drug use. Conditions requiring continuous medication for control (e.g., antihistamines, steroids, barbiturates, moodaltering drugs, or insulin). Meniere's disease. Hemoglobinopathies. Obstructive or...

29 CFR Appendix A to Subpart T of... - Examples of Conditions Which May Restrict or Limit Exposure to Hyperbaric Conditions

Code of Federal Regulations, 2013 CFR

2013-07-01

... duration of isolation. History of seizure disorder other than early febrile convulsions. Malignancies... or drug use. Conditions requiring continuous medication for control (e.g., antihistamines, steroids, barbiturates, moodaltering drugs, or insulin). Meniere's disease. Hemoglobinopathies. Obstructive or...

29 CFR Appendix A to Subpart T to... - Examples of Conditions Which May Restrict or Limit Exposure to Hyperbaric Conditions

Code of Federal Regulations, 2011 CFR

2011-07-01

... duration of isolation. History of seizure disorder other than early febrile convulsions. Malignancies... or drug use. Conditions requiring continuous medication for control (e.g., antihistamines, steroids, barbiturates, moodaltering drugs, or insulin). Meniere's disease. Hemoglobinopathies. Obstructive or...

29 CFR Appendix A to Subpart T of... - Examples of Conditions Which May Restrict or Limit Exposure to Hyperbaric Conditions

Code of Federal Regulations, 2014 CFR

2014-07-01

... duration of isolation. History of seizure disorder other than early febrile convulsions. Malignancies... or drug use. Conditions requiring continuous medication for control (e.g., antihistamines, steroids, barbiturates, moodaltering drugs, or insulin). Meniere's disease. Hemoglobinopathies. Obstructive or...

Utah Drop-Out Drug Use Questionnaire.

ERIC Educational Resources Information Center

Governor's Citizen Advisory Committee on Drugs, Salt Lake City, UT.

This questionnaire assesses drug use practices in high school drop-outs. The 79 items (multiple choice or apply/not apply) are concerned with demographic data and use, use history, reasons for use/nonuse, attitudes toward drugs, availability of drugs, and drug information with respect to narcotics, amphetamines, LSD, Marijuana, and barbiturates.…

21 CFR 1301.90 - Employee screening procedures.

Code of Federal Regulations, 2010 CFR

2010-04-01

..., assumed that the following questions will become a part of an employer's comprehensive employee screening program: Question. Within the past five years, have you been convicted of a felony, or within the past two.... Question. In the past three years, have you ever knowingly used any narcotics, amphetamines or barbiturates...

29 CFR Appendix A to Subpart T to... - Examples of Conditions Which May Restrict or Limit Exposure to Hyperbaric Conditions

Code of Federal Regulations, 2010 CFR

2010-07-01

... duration of isolation. History of seizure disorder other than early febrile convulsions. Malignancies... or drug use. Conditions requiring continuous medication for control (e.g., antihistamines, steroids, barbiturates, moodaltering drugs, or insulin). Meniere's disease. Hemoglobinopathies. Obstructive or...

Corrigendum to ;Monoalkylated barbiturate derivatives: X-ray crystal structure, theoretical studies, and biological activities; [J. Mol. Struct. 1141 (2017) 624-633

NASA Astrophysics Data System (ADS)

Barakat, Assem; Al-Majid, Abdullah Mohammed; Soliman, Saied M.; Islam, Mohammad Shahidul; Ghawas, Hussain Mansur; Yousuf, Sammer; Choudhary, M. Iqbal; Wadood, Abdul

2017-09-01

;The correct CCDC reference for the compound 3k is 1546475 instead of 1024287 as mentioned in the text on page 625. The authors regret this error and would like to apologize for any inconvenience caused to anyone.;

21 CFR 522.775 - Doxapram.

Code of Federal Regulations, 2011 CFR

2011-04-01

... anesthesia, 0.5 mg/lb in inhalation anesthesia; for intravenous use in horses at 0.25 mg/lb body weight in barbiturate anesthesia, 0.2 mg/lb in inhalation anesthesia, 0.25 mg/lb with chloral hydrate with or without... horses to stimulate respiration during and after general anesthesia; or to speed awakening and return of...

Restrictions in Means for Suicide: An Effective Tool in Preventing Suicide: The Danish Experience

ERIC Educational Resources Information Center

Nordentoft, Merete; Qin, Ping; Helweg-Larsen, Karin

2007-01-01

Restriction of means for suicide is an important part of suicide preventive strategies in different countries. The effect on method-specific suicide rate and overall suicide rate of restrictions on availability of carbon monoxide, barbiturates, and dextropropoxyphene was examined. From 1970 to 2000, overall suicide mortality and method-specific…

Patterns of Psychiatric Need and Intervention among U. S. Army Troops of the Vietnam Conflict

DTIC Science & Technology

1982-10-01

symptomatic, command referred and forensic cases, plus attendant work) _______ ________ __________ b. Direct treatment of patients...barbiturate to facilitate recall, abreaction, and reintegration) C 1 2 3 4 5 U C 1 2 3 4 5 U C 1 2 3 4 5 U Hypnosis : (similar but without

Desorption electrospray ionization (DESI) with atmospheric pressure ion mobility spectrometry for drug detection.

PubMed

Roscioli, Kristyn M; Tufariello, Jessica A; Zhang, Xing; Li, Shelly X; Goetz, Gilles H; Cheng, Guilong; Siems, William F; Hill, Herbert H

2014-04-07

Desorption electrospray ionization (DESI) was coupled to an ambient pressure drift tube ion mobility time-of-flight mass spectrometer (IM-TOFMS) for the direct analysis of active ingredients in pharmaceutical samples. The DESI source was also coupled with a standalone IMS demonstrating potential of portable and inexpensive drug-quality testing platforms. The DESI-IMS required no sample pretreatment as ions were generated directly from tablets and cream formulations. The analysis of a range of over-the-counter and prescription tablet formations was demonstrated for amphetamine (methylphenidate), antidepressant (venlafaxine), barbiturate (Barbituric acid), depressant (alprazolam), narcotic (3-methylmorphine) and sympatholytic (propranolol) drugs. Active ingredients from soft and liquid formulations, such as Icy Hot cream (methyl salicylate) and Nyquil cold medicine (acetaminophen, dextromethorphan, doxylamine) were also detected. Increased sensitivity for selective drug responses was demonstrated through the formation of sodiated adduct ions by introducing small quantities of NaCl into the DESI solvent. Of the drugs and pharmaceuticals tested in this study, 68% (22 total samples) provided a clear ion mobility response at characteristic mobilities either as (M + H)(+), (M - H)(-), or (M + Na)(+) ions.

Determination of sedative hypnotics in sewage sludge by pressurized liquid extraction with high-performance liquid chromatography and tandem mass spectrometry.

PubMed

Arbeláez, Paula; Granados, Judith; Borrull, Francesc; Marcé, Rosa Maria; Pocurull, Eva

2014-12-01

This paper describes a method for the determination of eight sedative hypnotics (benzodiazepines and barbiturates) in sewage sludge using pressurized liquid extraction and liquid chromatography with tandem mass spectrometry. Pressurized liquid extraction operating conditions were optimized and maximum recoveries were reached using methanol under the following operational conditions: 100ºC, 1500 psi, extraction time of 5 min, one extraction cycle, flush volume of 60% and purge time of 120 s. Pressurized liquid extraction recoveries were higher than 88% for all the compounds except for carbamazepine (55%). The repeatability and reproducibility between days, expressed as relative standard deviation (n = 5), were lower than 6 and 10%, respectively. The detection limits for all compounds were lower than 12.5 μg/kg of dry weight. The method was applied to determine benzodiazepines and barbiturates in sewage sludge from urban sewage treatment plants, and carbamazepine showed the highest concentration (7.9-18.9 μg/kg dry weight). © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Impact of helical organization on the photovoltaic properties of oligothiophene supramolecular polymers† †Electronic supplementary information (ESI) available: Synthesis and characterization of 3 and 4, UV-vis spectra, solar cell device properties and AFM images. See DOI: 10.1039/c7sc05093c

PubMed Central

Ouchi, Hayato; Kizaki, Takahiro; Yamato, Masaki; Lin, Xu; Hoshi, Nagahiro; Silly, Fabien; Kajitani, Takashi; Fukushima, Takanori

2018-01-01

Helical self-assembly of functional π-conjugated molecules offers unique photochemical and electronic properties in the spectroscopic level, but there are only a few examples that demonstrate their positive impact on the optoelectronic device level. Here, we demonstrate that hydrogen-bonded tapelike supramolecular polymers of a barbiturated oligo(alkylthiophene) show notable improvement in their photovoltaic properties upon organizing into helical nanofibers. A tapelike hydrogen-bonded supramolecular array of barbiturated oligo(butylthiophene) molecules was directly visualized by STM at a liquid–solid interface. TEM, AFM and XRD revealed that the tapelike supramolecular polymers further organize into helical nanofibers in solution and bulk states. Bulk heterojunction solar cells of the helical nanofibers and soluble fullerene showed a power conversion efficiency of 4.5%, which is markedly high compared to that of the regioisomer of butyl chains organizing into 3D lamellar agglomerates. PMID:29780493

Remote Photoregulated Ring Gliding in a [2]Rotaxane via a Molecular Effector.

PubMed

Tron, Arnaud; Pianet, Isabelle; Martinez-Cuezva, Alberto; Tucker, James H R; Pisciottani, Luca; Alajarin, Mateo; Berna, Jose; McClenaghan, Nathan D

2017-01-06

A molecular barbiturate messenger, which is reversibly released/captured by a photoswitchable artificial molecular receptor, is shown to act as an effector to control ring gliding on a distant hydrogen-bonding [2]rotaxane. Thus, light-driven chemical communication governing the operation of a remote molecular machine is demonstrated using an information-rich neutral molecule.

21 CFR 522.775 - Doxapram.

Code of Federal Regulations, 2013 CFR

2013-04-01

... No. 000010 in § 510.600(c) of this chapter. (c) Conditions of use—(1) Amount. For intravenous use in dogs and cats at a dose of 21/2 to 5 mg per pound (/lb) body weight in barbiturate anesthesia, 0.5 mg... repeated in 15 to 20 minutes if necessary. (2) Indications for use. Administer to dogs, cats, and horses to...

21 CFR 522.775 - Doxapram.

Code of Federal Regulations, 2014 CFR

2014-04-01

... No. 000010 in § 510.600(c) of this chapter. (c) Conditions of use—(1) Amount. For intravenous use in dogs and cats at a dose of 21/2 to 5 mg per pound (/lb) body weight in barbiturate anesthesia, 0.5 mg... repeated in 15 to 20 minutes if necessary. (2) Indications for use. Administer to dogs, cats, and horses to...

21 CFR 522.1642 - Oxymorphone hydrochloride injection.

Code of Federal Regulations, 2012 CFR

2012-04-01

... chloride. (b) Sponsor. See No. 060951 in § 510.600(c) of this chapter. (c) Conditions of use. (1) The drug... intramuscular, subcutaneous or intravenous administration to cats and dogs as follows: Animal Body weight....0 Cats Small 0.4-0.75 Large 0.75-1.5 (2) Do not mix with a barbiturate in the same syringe to...

21 CFR 522.775 - Doxapram.

Code of Federal Regulations, 2012 CFR

2012-04-01

... Nos. 000010 and 015914 in § 510.600(c) of this chapter. (c) Conditions of use—(1) Amount. For intravenous use in dogs and cats at a dose of 21/2 to 5 mg per pound (/lb) body weight in barbiturate... be repeated in 15 to 20 minutes if necessary. (2) Indications for use. Administer to dogs, cats, and...

Amphetamines, Barbiturates and Hallucinogens; An Analysis of Use, Distribution, and Control. Final Report.

ERIC Educational Resources Information Center

McGlothlin, William H.

This report is the third of three monographs to provide perspectives on the use, distribution, and control of illicit drugs. The first, conducted in 1971, described the prevalence, use patterns, sources, distribution, and economics of the marihuana market. The second (1972) estimated the cost, benefits, and potential of approaches to narcotic…

Substance Use by Fourth-Year Students at 13 U.S. Medical Schools.

ERIC Educational Resources Information Center

Conard, Scott; And Others

1988-01-01

A study investigated drug use by fourth-year medical students in 13 schools and compared drug use patterns with those of an age- and sex-matched cohort. Medical students reported less use of marijuana, cocaine, cigarettes, LSD, barbiturates, and amphetamines, similar use of opiates, and slightly more use of tranquilizers and alcohol. (MSE)

Antiemetics With Concomitant Sedative Use in Civil Aviation Pilot Fatalities: From 2000 to 2006

DTIC Science & Technology

2007-10-01

Unclassified Unclassified 13 Form DOT F 1700.7 (8-72) Reproduction of completed page authorized iii CONTENTS INTRODUCTION...sedative hypnotics , and ethanol. Antiemetics and drugs with antiemetic properties such as metoclopramide, diphenhydramine (a sedating...antihistamines, ethanol, barbiturates, serotonin modulators, and/or sedative- hypnotics . Antihistamines such as diphenhydramine are commonly used. The

Journal of Special Operations Medicine, Volume 2, Edition 3

DTIC Science & Technology

2002-01-01

propranolol, methyldopa, guanethidine Thyroid hormones--thyroxine Hallucinogens--LSD Salicylates, barbiturates General anesthetics --halothane...Alcohol LSD, lysergic acid diethylamide. Volume 2, Edition 3 / Summer 02 21 must be available and palatable , and water intake must be monitored. Water... palatability are controversial. High sugar solutions may impede water absorption. Salt losses should be made up (during the first 2 weeks in a hot

DIETARY EXPOSURE OF PHENOBARBITAL TO MALE AND FEMALE CD1 MICE FOR 2 OR 7 DAYS: EXAMINATION OF IN-LIFE, HEPATOCELLULAR ENZYME, PROLIFERATION, AND GENE EXPRESSION RESPONSES.

EPA Science Inventory

Phenobarbital (PB) is a barbiturate used to relieve anxiety and control epilepsy. PB is also an archetypical inducer of the constitutive androstane receptor (CAR), resulting in liver hypertrophy in humans and both liver hypertrophy and hyperplasia in rodents. In this study, male ...

A Review of Palliative Sedation.

PubMed

Bobb, Barton

2016-09-01

Palliative sedation has become a standard practice to treat refractory symptoms at end-of-life. Dyspnea and delirium are the two most commonly treated symptoms. The medications used in palliative sedation are usually benzodiazepines, barbiturates, antipsychotics, and/or anesthetics. Some ethical considerations remain, especially surrounding the use of palliative sedation in psychological distress and existential suffering. Copyright © 2016 Elsevier Inc. All rights reserved.

Reversible photocapture of a [2]rotaxane harnessing a barbiturate template.

PubMed

Tron, Arnaud; Thornton, Peter J; Lincheneau, Christophe; Desvergne, Jean-Pierre; Spencer, Neil; Tucker, James H R; McClenaghan, Nathan D

2015-01-16

Photoirradiation of a hydrogen-bonded molecular complex comprising acyclic components, namely, a stoppered thread (1) with a central barbiturate motif and an optimized doubly anthracene-terminated acyclic Hamilton-like receptor (2b), leads to an interlocked architecture, which was isolated and fully characterized. The sole isolated interlocked photoproduct (Φ = 0.06) is a [2]rotaxane, with the dimerized anthracenes assuming a head-to-tail geometry, as evidenced by NMR spectroscopy and consistent with molecular modeling (PM6). A different behavior was observed on irradiating homologous molecular complexes 1⊂2a, 1⊂2b, and 1⊂2c, where the spacers of 2a, 2b, and 2c incorporated 3, 6, and 9 methylene units, respectively. While no evidence of interlocked structure formation was observed following irradiation of 1⊂2a, a kinetically labile rotaxane was obtained on irradiating the complex 1⊂2c, and ring slippage was revealed. A more stable [2]rotaxane was formed on irradiating 1⊂2b, whose capture is found to be fully reversible upon heating, thereby resetting the system, with some fatigue (38%) after four irradiation–thermal reversion cycles.

[Effects of acupuncture stimulation of different acupoint groups on sleeping latency, serum and hippocampal TNF-α and IL-25 contents in rats with gastric mucosal injury].

PubMed

Huang, Ying-Hua; Li, Qian; Yang, Ping; Yan, Ya-Nan; Ma, Hui-Fang

2015-04-01

To observe the effect of acupuncture intervention on gastric ulcer (GU) and sleeping quality from the viewpoint of brain-gut axis which plays an important role in the regulation of many vital functions in the body. Forty male Wistar rats were randomized into normal control, GU model, acupuncture of "Zhongwan"(CV 12)-"Zusanli"(ST 36, gastric function regulating acupoints), acupuncture of "Shenmai" (BL 62)-"Zhaohai" (KI 6, sleep-promotion acupoints), and acupuncture of CV 12-ST 36+ BL 62-KI 6 (combined treatment) groups, with 8 rats in each group. GU model was established by intragastric perfusion of dehydrated alcohol (1 mL/rat), and sleep model established by intraperitoneal injection of pentobarbital sodium (40 mg/kg) after the last treatment. The abovementioned acupoints were punctured with filiform needles and stimulated by manipulating the needle for about 30 s, once every 5 min during 20 min of needle retention. The treatment was conducted once daily for five days. The contents of tumor necrosis factor-alpha (TNF-α) and interleukin-25(IL-25) in the serum and hippocampal tissues were detected by ELISA. Compared with the normal control group, the gastric ulcer index score, barbiturate-induced sleeping time, and TNF-α and IL-25 contents in both serum and hippocampus were significantly increased in the model group (P < 0.01). Following acupuncture treatment, in comparison with the model group, the gastric ulcer index score, barbiturate-induced sleeping time, and TNF-α and IL-25 contents in both serum and hippocampus were significantly down-regulated in the CV 12-ST 36, BL 62-KI 6 and combined treatment groups (P < 0.01, P < 0.05). The effects of the CV 12-ST 36 and combined treatment groups were remarkably superior to those of the BL 62-KI 6 group in down-regulating ulcer index score, serum IL-25, and hippocampal TNF-α and IL-25 contents (P < 0.01, P < 0.05). In addition, the effects of the BL 62-KI 6 and combined treatment groups was considerably better than that of the CV 12-ST 36 group in shortening barbiturate-induced sleeping time (P < 0.01, P < 0.05). The effect of the combined treatment group was markedly better than that of the CV 12-ST 36 and BL 62-KI 6 groups in lowering serum TNF-α content (P < 0.05). Acupuncture stimulation of CV 12, ST 36, KI 6 and BL 62 can relieve the gastric mucosal lesion, and shorten barbiturate-induced sleeping time in gastric ulcer rats, which may be related to its effects in reducing TNF-α and IL-25 contents in the serum and hippocampus tissues, suggesting a correlation between the gastrointestinal disorder and sleeping.

Synthesis of novel heterocycles through reaction of indolin-2-one derivatives with active methylene and amino reagents.

PubMed

Abdel-Latif, F F; Ahmed, E K; Mekheimer, R; Mashaly, M M

1997-10-01

Several new spiro compounds were synthesized via one-pot ternary condensation of isatin, malononitrile and each of thiobarbituric acid, barbituric acid, 3-methyl-pyrazolin-5-one, 1-phenyl-3-methyl-pyrazolin-5-one, acetylacetone, benzoylacetone, ethyl acetoacetate, phenacyl cyanide or ethyl-cyanoacetate dimer. Structures and reaction mechanism were reported and supported via a second synthetic route.

Thiopental inhibits nitric oxide production in rat aorta.

PubMed

Castillo, C; Asbun, J; Escalante, B; Villalón, C M; López, P; Castillo, E F

1999-12-01

We studied whether thiopental affects endothelial nitric oxide dependent vasodilator responses and nitrite production (an indicator of nitric oxide production) elicited by acetylcholine, histamine, and A23187 in rat aorta (artery in which nitric oxide is the main endothelial relaxant factor). In addition, we evaluated the barbiturate effect on nitric oxide synthase (NOS) activity in both rat aorta and kidney homogenates. Thiopental (10-100 microg/mL) reversibly inhibited the endothelium-dependent relaxation elicited by acetylcholine, histamine, and A23187. On the contrary, this anesthetic did not modify the endothelium-independent but cGMP-dependent relaxation elicited by sodium nitroprusside (1 nM - 1 microM) and nitroglycerin (1 nM - 1 microM), thus excluding an effect of thiopental on guanylate cyclase of vascular smooth muscle. Thiopental (100 microg/mL) inhibited both basal (87.8+/-14.3%) and acetylcholine- or A23187-stimulated (78.6+/-3.9 and 39.7+/-5.6%, respectively) production of nitrites in aortic rings. In addition the barbiturate inhibited (100 microg/mL) the NOS (45+/-4 and 42.8+/-9%) in aortic and kidney homogenates, respectively (measured as 14C-labeled citrulline production). In conclusion, thiopental inhibition of endothelium-dependent relaxation and nitrite production in aortic rings strongly suggests an inhibitory effect on NOS. Thiopental inhibition of the NOS provides further support to this contention.

Acid-base equilibrium in aqueous solutions of 1,3-dimethylbarbituric acid as studied by 13C NMR spectroscopy

NASA Astrophysics Data System (ADS)

Gryff-Keller, A.; Kraska-Dziadecka, A.

2011-12-01

13C NMR spectra of 1,3-dimethylbarbituric acid in aqueous solutions of various acidities and for various solute concentrations have been recorded and interpreted. The spectra recorded at pH = 2 and below contain the signals of the neutral solute molecule exclusively, while the ones recorded at pH = 7 and above only the signals of the appropriate anion, which has been confirmed by theoretical GIAO-DFT calculations. The signals in the spectra recorded for solutions of pH < 7 show dynamic broadenings. The lineshape analysis of these signals has provided information on the kinetics of the processes running in the dynamic acid-base equilibrium. The kinetic data determined this way have been used to clarify the mechanisms of these processes. The numerical analysis has shown that under the investigated conditions deprotonation of the neutral solute molecules undergoes not only via a simple transfer of the C-H proton to water molecules but also through a process with participation of the barbiturate anions. Moreover, the importance of tautomerism, or association, or both these phenomena for the kinetics of the acid-base transformations in the investigated system has been shown. Qualitatively similar changes of 13C NMR spectra with the solution pH variation have been observed for the parent barbituric acid.

What predicts the change from episodic to chronic migraine?

PubMed

Bigal, Marcelo E; Lipton, Richard B

2009-06-01

Because migraine worsens in a sizeable subgroup of sufferers, but not in most, identifying factors that predict the change from episodic into chronic migraine is of extreme interest and should be seen as a priority in headache research. Potentially remediable risk factors include frequency of migraine attacks, obesity, excessive use of medications containing opioids and barbiturates, caffeine overuse, stressful life events, depression, sleep disorders and cutaneous allodynia. While we wait for evidence regarding the benefits of risk factor modifications in the prevention of chronic migraine, several interventions are justifiable based on their other established benefits. For example, decreasing headache frequency with behavioral and pharmacological interventions will decrease current disability even if it does not modify clinical course. Monitoring the body mass index and encouraging maintenance of normal body weight is good practice in patients with and without migraine. Avoiding overuse of caffeine is desirable apart from its potential benefit in preventing progression. Sleep problems should be investigated and treated. Psychiatric comorbidities should be identified and addressed. Medications containing opioids and barbiturates should be reserved for a few selected cases of migraine, and their use should be monitored. For these interventions, the possibility of preventing progression may motivate clinicians to offer good care and patients to engage in the treatment plan.

Chemical models and their mechanistic implications for the transformation of 6-cyanouridine 5'-monophosphate catalyzed by orotidine 5'-monophosphate decarboxylase.

PubMed

Chien, Tun-Cheng; Jen, Cheng-Hung; Wu, Yuen-Jen; Liao, Chen-Chieh

2008-01-01

Orotidine 5'-monophosphate decarboxylase (ODCase) catalyzes an unprecedented transformation of 6- cyanouridine 5'-monophosphate (6-CN-UMP) into barbiturate nucleoside 5'-monophosphate (6-hydroxyuridine 5'-monophosphate, BMP). The reactions of 6- cyano-1,3-dimethyluracil toward various nucleophilic conditions have been studied as chemical models in order to understand the possible mechanism for the ODCase-catalyzed transformation of 6-CN-UMP.

Department of Clinical Investigation Annual Research Progress Report, Fiscal Year 1989

DTIC Science & Technology

1989-09-30

and DES. Patients with a history of deep vein thrombosis, cerebral embolus, stroke , congestive heart failure, or ischemic heart disease will not be...Adolescent Health Care 9(6): 498-500, 1988 Weir MR Intravascular Injuries from Intramuscular Penicillin. Clinical Pediatrics 27(2): 85-90, 1988 Weir...Military Medicine 154(9): 455-57, 1989 Piatt JH, Goodkin R Barbiturates in Severe Head Injury . J Neurosurgery 70(3): 501-02, 1989 * Piatt JH

Highlights from the Worldwide Survey of Nonmedical Drug Use and Alcohol Use Among Military Personnel: 1980.

DTIC Science & Technology

1980-11-14

Prepared with assistance of: Yukiko Gamnes and Edward Farley W9 KEY WORDS (Continue on revere.r side it necessary and identify by block number) Drug use... side if neresestry aund idennty by block ntimber) his survey report provides a comprehensive, detailed and accurate estimallte or the preval ence of drug...34 Other Uppers ............. Preludin, Ritalin , Sandrex Tranquilizers ............ Valium, Librium, Miltown Barbiturates ............. Seconal (reds

Antagonism Between Luminal and Caffeine, Studied by the Use of Radioisotopes; RECHERCHES SUR LES BARBITURIQUES RADIOACTIFS: LA DISTRIBUTION DU LUMINAL DANS L'ORGANISME ANIMAL EN PRESENCE DE CAFEINE

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aliprandi, B.; Masironi, R.

1959-10-31

The normal pattern of distribution of luminal in the animal organism was determined in mice using a tracer technique. The effect of an antagonistic drug, e.g., caffeine, on this normal distribution pattern was studied. The results confirmed the hypothesis of the in vivo breaking of the barbituric ring. (J.S.R.)

21 CFR 522.1642 - Oxymorphone hydrochloride injection.

Code of Federal Regulations, 2011 CFR

2011-04-01

... (pounds) Dosage (milligram) Dogs 2 to 5 0.75 5 to 15 0.75-1.5 15 to 30 1.5-2.5 30 to 60 2.5-4.0 Over 60 4.0 Cats Small 0.4-0.75 Large 0.75-1.5 (2) Do not mix with a barbiturate in the same syringe to... Section 522.1642 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES...

21 CFR 522.1642 - Oxymorphone hydrochloride injection.

Code of Federal Regulations, 2010 CFR

2010-04-01

... (pounds) Dosage (milligram) Dogs 2 to 5 0.75 5 to 15 0.75-1.5 15 to 30 1.5-2.5 30 to 60 2.5-4.0 Over 60 4.0 Cats Small 0.4-0.75 Large 0.75-1.5 (2) Do not mix with a barbiturate in the same syringe to... Section 522.1642 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES...

Thiopentone anaesthesia at Pearl Harbor.

PubMed

Bennetts, F E

1995-09-01

A wartime embargo on casualty figures and an imprecise contemporary editorial contributed to the persisting belief that a grossly excessive mortality rate from barbiturate anaesthesia for surgery of the injured occurred after the Japanese attack on the American bases in Hawaii in December 1941. From accounts by surgical staff and official hospital records which have become available through US Freedom of Information legislation, it is clear that the rumoured death rate from this cause has been greatly exaggerated.

Chemical models and their mechanistic implications for the transformation of 6-cyanouridine 5'-monophosphate catalyzed by orotidine 5'-monophosphate decarboxylase.

PubMed

Wu, Yuen-Jen; Liao, Chen-Chieh; Jen, Cheng-Hung; Shih, Yu-Chiao; Chien, Tun-Cheng

2010-07-14

The reactions of 6-cyano-1,3-dimethyluracil have been studied as chemical models to illustrate the mechanism for the transformation of 6-cyanouridine 5'-monophosphate (6-CN-UMP) to barbiturate ribonucleoside 5'-monophosphate (BMP) catalyzed by orotidine 5'-monophosphate decarboxylase (ODCase). The results suggest that the Asp residue in the ODCase active site plays the role of a general base in the transformation.

Evaluation of plasma levels of melatonin after midazolam or sodium thiopental anesthesia in children.

PubMed

Muñoz-Hoyos, Antonio; Heredia, Francisco; Moreno, Francisco; García, Joaquín José; Molina-Carballo, Antonio; Escames, Germaine; Acuña-Castroviejo, Darío

2002-05-01

Midazolam and sodium thiopental are two commonly used drugs in anesthesia for minor surgical procedures in children. A relationship exists between benzodiazepines (BNZ), barbiturates and melatonin. Whereas these drugs increase pineal melatonin production, the indoleamine amplifies the effects of both BNZ and barbiturates on the central nervous system (CNS). Our purpose was thus to analyze the plasma levels of melatonin before and during midazolam or sodium thiopental anesthesia in children subjected to ambulatory surgical procedures. Midazolam (0.4 mg/kg) or sodium thiopental (5 mg/kg) were administered i.v. to 33 and 32 children (aged between 2 and 14 yr), respectively, and blood samples were taken before and 5, 10 and 20 min after the drugs were administered. Melatonin was measured in plasma by a commercial radioimmunoassay kit previously standardized in our laboratory. The results showed that neither midazolam nor sodium thiopental anesthesia significantly affected the levels of melatonin studied at anytime. Significant correlations were found comparing the levels of melatonin between the different times studied. These results suggest that midazolam or sodium thiopental did not affect melatonin production by the pineal gland, thus avoiding a possible potentiating effect of the indoleamine on the central effects of these drugs during anesthesia. However, the possibility that changes in melatonin had been masked by the antioxidant role of the neurohormone are discussed.

Structural Characterization of the Molecular Events during a Slow Substrate-Product Transition in Orotidine 5'-Monophosphate Decarboxylase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fujihashi, Masahiro; Wei, Lianhu; Kotra, Lakshmi P

2009-04-06

Crystal structures of substrate-product complexes of Methanobacterium thermoautotrophicum orotidine 5'-monophosphate decarboxylase, obtained at various steps in its catalysis of the unusual transformation of 6-cyano-uridine 5'-monophosphate (UMP) into barbituric acid ribosyl monophosphate, show that the cyano substituent of the substrate, when bound to the active site, is first bent significantly from the plane of the pyrimidine ring and then replaced by an oxygen atom. Although the K72A and D70A/K72A mutants are either catalytically impaired or even completely inactive, they still display bending of the C6 substituent. Interestingly, high-resolution structures of the D70A and D75N mutants revealed a covalent bond between C6more » of UMP and the Lys72 side chain after the -CN moiety's release. The same covalent bond was observed when the native enzyme was incubated with 6-azido-UMP and 6-iodo-UMP; in contrast, the K72A mutant transformed 6-iodo-UMP to barbituric acid ribosyl 5'-monophosphate. These results demonstrate that, given a suitable environment, native orotidine 5'-monophosphate decarboxylase and several of its mutants are not restricted to the physiologically relevant decarboxylation; they are able to catalyze even nucleophilic substitution reactions but consistently maintain distortion on the C6 substituent as an important feature of catalysis.« less

Structural characterization of the molecular events during a slow substrate-product transition in orotidine 5'-monophosphate decarboxylase.

PubMed

Fujihashi, Masahiro; Wei, Lianhu; Kotra, Lakshmi P; Pai, Emil F

2009-04-17

Crystal structures of substrate-product complexes of Methanobacterium thermoautotrophicum orotidine 5'-monophosphate decarboxylase, obtained at various steps in its catalysis of the unusual transformation of 6-cyano-uridine 5'-monophosphate (UMP) into barbituric acid ribosyl monophosphate, show that the cyano substituent of the substrate, when bound to the active site, is first bent significantly from the plane of the pyrimidine ring and then replaced by an oxygen atom. Although the K72A and D70A/K72A mutants are either catalytically impaired or even completely inactive, they still display bending of the C6 substituent. Interestingly, high-resolution structures of the D70A and D75N mutants revealed a covalent bond between C6 of UMP and the Lys72 side chain after the -CN moiety's release. The same covalent bond was observed when the native enzyme was incubated with 6-azido-UMP and 6-iodo-UMP; in contrast, the K72A mutant transformed 6-iodo-UMP to barbituric acid ribosyl 5'-monophosphate. These results demonstrate that, given a suitable environment, native orotidine 5'-monophosphate decarboxylase and several of its mutants are not restricted to the physiologically relevant decarboxylation; they are able to catalyze even nucleophilic substitution reactions but consistently maintain distortion on the C6 substituent as an important feature of catalysis.

Association between anticonvulsant drugs and teeth-grinding in children and adolescents with cerebral palsy.

PubMed

Ortega, A O L; Dos Santos, M T B R; Mendes, F M; Ciamponi, A L

2014-09-01

The relation between teeth-grinding and the use of drugs acting on the central nervous system of cerebral palsy (CP) patients has not yet been described. The aim of this research was to evaluate the presence or absence of teeth-grinding (sleep and/or awake periods) in normal and in CP children and adolescents, as well as the association of teeth-grinding and use of anticonvulsant drugs. The sample consisted of 207 children and adolescents, divided into three groups: G1, individuals with CP who did not take anticonvulsant drugs; G2, individuals with CP administered medications on a regular basis; and CG, normal individuals. Logistic regression analyses were performed to evaluate the association of teeth-grinding with some variables. No significant statistical differences were observed regarding the presence or absence of teeth-grinding when G1 and G2 were compared. However, compared with the CG, a statistically significant difference was determined, with the CG showing fewer children presenting teeth-grinding (P < 0·001). Among those children/adolescents prescribed drug therapy, the barbiturate group showed a greater frequency of teeth-grinding. CP children and adolescents show a greater and significant presence of grinding of the teeth compared with normal individuals. Subjects taking barbiturate drugs showed greater presence of teeth-grinding, than those who were taking medications from the other groups of anticonvulsant drugs. © 2014 John Wiley & Sons Ltd.

Acute migraine medication adherence, migraine disability and patient satisfaction: A naturalistic daily diary study.

PubMed

Seng, Elizabeth K; Robbins, Matthew S; Nicholson, Robert A

2017-09-01

Objective To examine the influence of acute migraine medication adherence on migraine disability and acute medication satisfaction. Methods Adults with migraine completed three months of daily electronic diaries assessing headache symptoms, acute medication taken, acute medication satisfaction, and daily migraine disability. Repeated measures mixed-effects models examined the effect of initial medication type [migraine-specific medication (MSM) vs. over-the-counter analgesic (OTC) vs. an opiate/barbiturate], the severity of pain at dosing, and their interaction with daily migraine disability and satisfaction with acute medication. Results Participants (N = 337; 92.5% female; 91.1% Caucasian, non-Hispanic; 84.0% with episodic migraine) recorded 29,722 diary days. Participants took acute medication on 96.5% of 8090 migraine days. MSM was most frequently taken first (58%), followed by OTC (29.9%) and an opiate/barbiturate (12.1%). Acute medication was most frequently taken when pain was mild (41.2%), followed by moderate (37.7%) and severe pain (11.4%). Initially dosing with MSM while pain was mild was associated with the lowest daily disability [medication × pain at dosing F (4, 6336.12) = 58.73, p < .001] and highest acute medication satisfaction [medication × pain at dosing F (4, 3867.36) = 24.00, p < .001]. Conclusion Using an MSM (triptan or ergot) first was associated with the lowest migraine disability and highest acute medication satisfaction.

Anxiolytic-like effect of Carvacrol (5-isopropyl-2-methylphenol) in mice: involvement with GABAergic transmission.

PubMed

Melo, Francisca Helvira Cavalcante; Venâncio, Edith Teles; de Sousa, Damião Pergentino; de França Fonteles, Marta Maria; de Vasconcelos, Silvânia Maria Mendes; Viana, Glauce Socorro Barros; de Sousa, Francisca Cléa Florenço

2010-08-01

Carvacrol (5-isopropyl-2-methylphenol) is a monoterpenic phenol present in the essencial oil of many plants. It is the major component of the essential oil fraction of oregano and thyme. This work presents the behavioral effects of carvacrol in animal models of elevated plus maze (EPM), open field, Rotarod and barbiturate-induced sleeping time tests in mice. Carvacrol (CVC) was administered orally, in male mice, at single doses of 12.5; 25 and 50 mg/kg while diazepam 1 or 2 mg/kg was used as standard drug and flumazenil (2.5 mg/kg) was used to elucidate the possible anxiolytic mechanism of CVC on the plus maze test. The results showed that CVC, at three doses, had no effect on the spontaneous motor activity in the Rotarod test nor in the number of squares crossed in the open-field test. However, CVC decreased the number of groomings in the open-field test. In the plus maze test, CVC, at three doses significantly increased all the observed parameters in the EPM test and flumazenil was able to reverse the effects of diazepam and CVC. Therefore, CVC did not alter the sleep latency and sleeping time in the barbiturate-induced sleeping time test. These results show that CVC presents anxiolytic effects in the plus maze test which are not influenced by the locomotor activity in the open-field test.

Succinate and artificial maintenance of normal body temperature synergistically correct lethal disorders in thiopental coma rat.

PubMed

Ivnitsky, Jury Ju; Rejniuk, Vladimir L; Schäfer, Timur V; Malakhovsky, Vladimir N

2006-01-20

Under modeling of thiopental coma influence of sodium succinate and (or) external warming for the support of normal body temperature (isothermal regimen) on the gas exchange, blood gas content, acid-base status and survival rate was studied in rats. In the absence of therapy hypothermia was developed (-9.4 degrees C), O(2) consumption decreased by a factor 5, oxygenation of arterial blood (pO(2)) did not change while that of venous blood increased, where with arteriovenous oxygen tension gradient decreased by half. Blood tension of carbon dioxide (pCO(2)) increased twice, respiratory and metabolic acidosis was developed. Survival rate under absence of a therapy was 42%, with isolated use of isothermal regimen or succinate therapy alike-50%; with their use in combination drastically increased up to 92%. Succinate increased arteriovenous gradient of pO(2), decreased deficit of buffer bases, increased bicarbonate concentration. At isothermal regimen accumulation of CO(2) in the blood was diminished, its excretion was increased, pH of blood approached normal values. Combined use of both therapy agents increased O(2) consumption and potentiated their positive influence on acid-base status. The implication is that hypothermia restrains effect of succinate in barbiturate coma; prevention of hypothermia in combination with succinate administration is highly effective method of experimental therapy of barbiturate intoxication.

Liposome-based mucus-penetrating particles (MPP) for mucosal theranostics: demonstration of diamagnetic chemical exchange saturation transfer (diaCEST) magnetic resonance imaging (MRI).

PubMed

Yu, Tao; Chan, Kannie W Y; Anonuevo, Abraham; Song, Xiaolei; Schuster, Benjamin S; Chattopadhyay, Sumon; Xu, Qingguo; Oskolkov, Nikita; Patel, Himatkumar; Ensign, Laura M; van Zjil, Peter C M; McMahon, Michael T; Hanes, Justin

2015-02-01

Mucus barriers lining mucosal epithelia reduce the effectiveness of nanocarrier-based mucosal drug delivery and imaging ("theranostics"). Here, we describe liposome-based mucus-penetrating particles (MPP) capable of loading hydrophilic agents, e.g., the diaCEST MRI contrast agent barbituric acid (BA). We observed that polyethylene glycol (PEG)-coated liposomes containing ≥7 mol% PEG diffused only ~10-fold slower in human cervicovaginal mucus (CVM) compared to their theoretical speeds in water. 7 mol%-PEG liposomes contained sufficient BA loading for diaCEST contrast, and provided improved vaginal distribution compared to 0 and 3mol%-PEG liposomes. However, increasing PEG content to ~12 mol% compromised BA loading and vaginal distribution, suggesting that PEG content must be optimized to maintain drug loading and stability. Non-invasive diaCEST MRI illustrated uniform vaginal coverage and longer retention of BA-loaded 7 mol%-PEG liposomes compared to unencapsulated BA. Liposomal MPP with optimized PEG content hold promise for drug delivery and imaging at mucosal surfaces. This team of authors characterized liposome-based mucus-penetrating particles (MPP) capable of loading hydrophilic agents, such as barbituric acid (a diaCEST MRI contrast agent) and concluded that liposomal MPP with optimized PEG coating enables drug delivery and imaging at mucosal surfaces. Copyright © 2015 Elsevier Inc. All rights reserved.

Tandem Aldol-Michael Reactions in Aqueous Diethylamine Medium: A Greener and Efficient Approach to Bis-Pyrimidine Derivatives

PubMed Central

Al-Majid, Abdullah M.; Barakat, Assem; AL-Najjar, Hany J.; Mabkhot, Yahia N.; Ghabbour, Hazem A.; Fun, Hoong-Kun

2013-01-01

A simple protocol, involving the green synthesis for the construction of novel bis-pyrimidine derivatives, 3a–i and 4a–e are accomplished by the aqueous diethylamine media promoted tandem Aldol-Michael reaction between two molecules of barbituric acid derivatives 1a,b with various aldehydes. This efficient synthetic protocol using an economic and environmentally friendly reaction media with versatility and shorter reaction time provides bis-pyrimidine derivatives with high yields (88%–99%). PMID:24317435

JPRS Report, Latin America, Reference Aid, Glossary of Spanish and Portuguese Narcotics Terms.

DTIC Science & Technology

1989-05-04

devils, seconal, barbiturates, amphetamines, LSD a "deal"—to make a connection to obtain drugs (Ar) to deal bread, dough , money "dirty money...drug addict federal police; feds, "G" men PCP; angel dust; phencyclidine bread, dough , money weapon (Ar) a fix, a jab to inject, to shoot up...used to cut heroin); manida, mannite, milk sugar brick (usually a kilogram of hashish or marijuana) bread, dough , money money laundering to

Synthesis of zwitterionic salts of pyridinium-Meldrum acid and barbiturate through unique four-component reactions.

PubMed

Wang, Qi-Fang; Hui, Li; Hou, Hong; Yan, Chao-Guo

2010-03-08

An efficient synthetic procedure for the preparation of the unusual charge-separated pyridinium-Meldrum acid and N,N-dimethylbarbiturate acid zwitterionic salts was developed though a unique one-pot four-component reaction involving pyridine, aromatic aldehyde, Meldrum acid or N,N-dimethylbarbituric acid, and p-nitrobenzyl bromide in acetonitrile. By varying combinations of four components involving nitrogen-containing heterocycles, we conveniently established reactive alpha-halomethylene compounds, aldehydes and beta-dicarbonyl compounds a library of zwitterionic salts.

Virtual Reality Pain Control During Burn Wound Debridement of Combat-Related Burn Injuries Using Robot-Like Arm Mounted VR Goggles

DTIC Science & Technology

2011-07-01

naturally contracts as it heals. Physical therapy stretches help to counteract contraction, increasing skin elasticity, and en- hancing range of motion.3...excru- ciating pain during medical procedures such as wound clean- ing and physical therapy .4 Although opioids are the cornerstone analgesic for patients...Used at low doses, ketamine is a non-barbiturate intravenous anesthetic that is used as part of a multi-modal therapy . Ketamine does not cause

Merocyanine-type dyes from barbituric acid derivatives.

PubMed

Rezende, M C; Campodonico, P; Abuin, E; Kossanyi, J

2001-05-01

The preparation and the solvatochromic behavior of two dyes, obtained by condensation of N,N'-dimethylbarbituric acid with dimethylaminobenzaldehyde and with 4,4'-bis(N,N-dimethylamino)benzophenone (Michler's ketone) are described. The latter dye is rather sensitive to the polarity of the medium, and in particular, to the hydrogen-bond-donor ability of protic solvents. The solvatochromism of both compounds is discussed in terms of the pi* and E(T)(30) solvent polarity scales and their differences in behavior interpreted with the aid of semiempirical calculations.

Synthesis and properties of 2-(4-substituted)butyl derivatives of some 2,3-dihydro-1,3-dioxo-1H-pyrrolo[3,4-c]pyridines.

PubMed

Sladowska, H; Szkatuła, D; Filipek, B; Maciag, D; Sapa, J; Zygmunt, M

2001-02-01

The synthesis of 2-(4-substituted)butyl derivatives of 4-alkoxy-2,3-dihydro-6-methyl-1,3-dioxo-1H-pyrrolo[3,4-c]pyridine (10-15) and the results of preliminary pharmacological screening are described in this paper. All the compounds tested showed a strong analgesic action, suppressed spontaneous locomotor activity and prolonged barbiturate sleep. Except 10, all significantly decreased systolic and diastolic blood pressure.

Accurate and computationally efficient prediction of thermochemical properties of biomolecules using the generalized connectivity-based hierarchy.

PubMed

Sengupta, Arkajyoti; Ramabhadran, Raghunath O; Raghavachari, Krishnan

2014-08-14

In this study we have used the connectivity-based hierarchy (CBH) method to derive accurate heats of formation of a range of biomolecules, 18 amino acids and 10 barbituric acid/uracil derivatives. The hierarchy is based on the connectivity of the different atoms in a large molecule. It results in error-cancellation reaction schemes that are automated, general, and can be readily used for a broad range of organic molecules and biomolecules. Herein, we first locate stable conformational and tautomeric forms of these biomolecules using an accurate level of theory (viz. CCSD(T)/6-311++G(3df,2p)). Subsequently, the heats of formation of the amino acids are evaluated using the CBH-1 and CBH-2 schemes and routinely employed density functionals or wave function-based methods. The calculated heats of formation obtained herein using modest levels of theory and are in very good agreement with those obtained using more expensive W1-F12 and W2-F12 methods on amino acids and G3 results on barbituric acid derivatives. Overall, the present study (a) highlights the small effect of including multiple conformers in determining the heats of formation of biomolecules and (b) in concurrence with previous CBH studies, proves that use of the more effective error-cancelling isoatomic scheme (CBH-2) results in more accurate heats of formation with modestly sized basis sets along with common density functionals or wave function-based methods.

Functional Chemical Groups that May Likely Become a Source for the Synthesis of Novel Central Nervous System (CNS) Acting Drugs.

PubMed

Saganuwan, Saganuwan A

2017-01-01

Central Nervous System (CNS) disorders are on increase perhaps due to genetic, enviromental, social and dietetic factors. Unfortunately, a large number of CNS drugs have adverse effects such as addiction, tolerance, psychological and physical dependence. In view of this, literature search was carried out with a view to identify functional chemical groups that may serve as lead molecules for synthesis of compounds that may have CNS activity. The search revealed that heterocycles that have heteroatoms such as nitrogen (N), sulphur (S) and oxygen (O) form the largest class of organic compounds. They replace carbon in a benzene ring to form pyridine. Compounds with furan, thiophene, pyrrole, pyridine, azole, imidazole, indole, purine, pyrimidine, esters, carboxylic acid, aldehyde, pyrylium, pyrone, pyrodine, barbituric acid, barbiturate, quinoline, quinolone, isoquinolone, coumarin, alkylpyridine, picoline, piperidine, diazine, carboxamide, flavonoid glycoside, oxindole, aminophenol, benzimidazole, benzoxazole, benzothiazole, and chromone chemical groups among others may have CNS effects ranging from depression passing through euphoria to convulsion. Examples of the compounds with the functional groups include but not limited to coal tar, pyridostigmine, pralidoxime, quinine, mefloquine, pyrilamine, pyronaridine, ciprofloxacin and piroxicam. A number of them can undergo keto-enol tautomerism. Chiral amines may be used for derivation of chiral carboxylic acids which are components of tautomers. Some tautomers may cause parkinsonism and Stevens Johnson syndrome. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Clinical characteristics of patients who overdose on multiple psychotropic drugs in Tokyo.

PubMed

Hori, Satoshi; Kinoshita, Kosaku

2016-01-01

The purpose of this study was to identify the clinical aspects leading to overdose of multiple psychotropic drugs, in order to determine areas which need attention in the proper treatment of overdose patients. Patients who were treated for overdose of psychotropic drugs at our emergency and critical center over two years were targeted. The clinical data was gathered from the medical records and database of all patients, including age, gender, vital signs, and laboratory data, drugs, and medical complications during hospital stay. In addition primary patient care at the emergency department was examined. Among the 277 patients treated during this study period, 255 (74.0%) used two or more types of psychotropic drugs. Risk factors associated with endotracheal intubation and aspiration pneumonitis included the use of antipsychotics and/or barbiturates as types of overdose drugs. The mean number of days in the ICU was 3.4 days. Seventy-four patients (26.7%) stayed 4 days or more in the ICU of which 16 patients (5.8%) still had suicidal thoughts. A significantly higher incidence of extended ICU stay or endotracheal intubation and aspiration pneumonitis was observed in the group who overdosed on more than 50 or 60 tablets of psychotropic drugs, respectively. Patients who ingested an overdose of more than 60 tablets of psychotropic drugs should be considered a high-risk group requiring intensive care with extended ICU stay. In case of including antipsychotics and/or barbiturates, the patient should be observed carefully due to a higher risk of medical complications.

Assisted suicide by oxygen deprivation with helium at a Swiss right-to-die organisation.

PubMed

Ogden, Russel D; Hamilton, William K; Whitcher, Charles

2010-03-01

In Switzerland, right-to-die organisations assist their members with suicide by lethal drugs, usually barbiturates. One organisation, Dignitas, has experimented with oxygen deprivation as an alternative to sodium pentobarbital. To analyse the process of assisted suicide by oxygen deprivation with helium and a common face mask and reservoir bag. This study examined four cases of assisted suicide by oxygen deprivation using helium delivered via a face mask. Videos of the deaths were provided by the Zurich police. Dignitas provided protocol and consent information. One man and three women were assisted to death by oxygen deprivation. There was wide variation in the time to unconsciousness and the time to death, probably due to the poor mask fit. Swiss law prevented attendants from effectively managing the face mask apparatus. Purposeless movements of the extremities were disconcerting for Dignitas attendants, who are accustomed to assisting suicide with barbiturates. None of the dying individuals attempted self-rescue. The dying process of oxygen deprivation with helium is potentially quick and appears painless. It also bypasses the prescribing role of physicians, effectively demedicalising assisted suicide. Oxygen deprivation with a face mask is not acceptable because leaks are difficult to control and it may not eliminate rebreathing. These factors will extend time to unconsciousness and time to death. A hood method could reduce the problem of mask fit. With a hood, a flow rate of helium sufficient to provide continuous washout of expired gases would remedy problems observed with the mask.

Increased release of norepinephrine and dopamine from canine kidney during bilateral carotid occlusion

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bradley, T.; Hjemdahl, P.; DiBona, G.F.

1987-02-01

The renal overflow of norepinephrine (NE) and dopamine (DA) to plasma from the innervated kidney was studied at rest and during sympathetic nervous system activation by bilateral carotid artery occlusion (BCO) in vagotomized dogs under barbiturate or barbiturate/nitrous oxide anesthesia. BCO elevated arterial pressure and the arterial plasma concentration of NE, DA, and epinephrine (Epi). Renal vascular resistance (renal arterial pressure kept constant) increased by 15 +/- 7% and the net renal venous outflows (renal veno-arterial concentration difference x renal plasma flow) of NE and DA were enhanced. To obtain more correct estimates of the renal contribution to the renalmore » venous catecholamine outflow, they corrected for the renal extraction of arterial catecholamines, assessed as the extractions of (/sup 3/H)NE, (/sup 3/H)DA, or endogenous Epi. The (/sup 3/H)NE corrected renal NE overflow to plasma increased from 144 +/- 40 to 243 +/- 64 pmol-min/sup -1/ during BCO, which, when compared with a previous study of the (/sup 3/H)NE corrected renal NE overflow to plasma evoked by electrical renal nerve stimulation, corresponds to a 40% increase in nerve impulse frequency from approx. 0.6 Hz. If the renal catecholamine extraction was not taken into account the effect of BCO was underestimated. The renal DA overflow to plasma was about one-fifth of the NE overflow both at rest and during BCO, indicating that there was no preferential activation of noradrenergic or putative dopaminergic nerves by BCO.« less

Circadian manifestations of barbiturate habituation, addiction and withdrawal in the rat

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ehret, C. F.; Peraino, C.; Meinert, J. C.

1979-01-01

The present study uses circadian rhythm observations on rats to include diverse habituation and drug ingestion (phenobarbital) circumstances, including a comparison of the effect of pre-entrainment cycles of programmed feeding and illumination and subsequent conditions of exposure of duration sufficient to permit a steady-state in the appearance of circadian patterns derived from core-temperature telemetry and from automated food-consumption measurements. Finally, measurements were permitted to continue long enough after the drug was withdrawn from the diet to allow characterization of an abstinence syndrome, indicative of addiction.

Management of Intracranial Hypertension

PubMed Central

Rangel-Castillo, Leonardo; Gopinath, Shankar; Robertson, Claudia S.

2008-01-01

Effective management of intracranial hypertension involves meticulous avoidance of factors that precipitate or aggravate increased intracranial pressure. When intracranial pressure becomes elevated, it is important to rule out new mass lesions that should be surgically evacuated. Medical management of increased intracranial pressure should include sedation, drainage of cerebrospinal fluid, and osmotherapy with either mannitol or hypertonic saline. For intracranial hypertension refractory to initial medical management, barbiturate coma, hypothermia, or decompressive craniectomy should be considered. Steroids are not indicated and may be harmful in the treatment of intracranial hypertension resulting from traumatic brain injury. PMID:18514825

Pediatric intensive care treatment of uncontrolled status epilepticus.

PubMed

Wilkes, Ryan; Tasker, Robert C

2013-04-01

The critically ill mechanically ventilated child with ongoing seizures that are refractory to any treatment presents a distinct challenge in pediatric neurocritical care. The evidence base from randomized controlled trials on which anti-epileptic drug (AED) strategy should be used is inadequate. This review of refractory and super-refractory status epilepticus summarizes recent pediatric case series regarding definitions, the second-tier AED therapies once initial anticonvulsants have failed, and the experience of high-dose midazolam, barbiturate anesthesia, and volatile anesthetics for uncontrolled status epilepticus. Copyright © 2013 Elsevier Inc. All rights reserved.

The Hydrogen Bonded Structures of Two 5-Bromobarbituric Acids and Analysis of Unequal C5–X and C5–X′ Bond Lengths (X = X′ = F, Cl, Br or Me) in 5,5-Disubstituted Barbituric Acids

PubMed Central

Gelbrich, Thomas; Braun, Doris E.; Oberparleiter, Stefan; Schottenberger, Herwig; Griesser, Ulrich J.

2017-01-01

The crystal structure of the methanol hemisolvate of 5,5-dibromobarbituric acid (1MH) displays an H-bonded layer structure which is based on N–H⋯O=C, N–H⋯O(MeOH) and (MeOH)O–H⋯O interactions. The barbiturate molecules form an H-bonded substructure which has the fes topology. 5,5′-Methanediylbis(5-bromobarbituric acid) 2, obtained from a solution of 5,5-dibromobarbituric acid in nitromethane, displays a N–H⋯O=C bonded framework of the sxd type. The conformation of the pyridmidine ring and the lengths of the ring substituent bonds C5–X and C5–X′ in crystal forms of 5,5-dibromobarbituric acid and three closely related analogues (X = X′ = Br, Cl, F, Me) have been investigated. In each case, a conformation close to a C5-endo envelope is correlated with a significant lengthening of the axial C5–X′ in comparison to the equatorial C5–X bond. Isolated molecule geometry optimizations at different levels of theory confirm that the C5-endo envelope is the global conformational energy minimum of 5,5-dihalogenbarbituric acids. The relative lengthening of the axial bond is therefore interpreted as an inherent feature of the preferred envelope conformation of the pyrimidine ring, which minimizes repulsive interactions between the axial substituent and pyrimidine ring atoms. PMID:28670485

[Significance of CRF and dopamine receptors in amygdala for reinforcing effects of opiates and opioids on self-stimulation of lateral hypothalamus in rats].

PubMed

Shabanov, P D; Lebedev, A A; Liubimov, A V; Kornilov, V A

2011-01-01

Bipolar electrodes were implanted in the lateral hypothalamus in a group of 44 Wistar male rats in order to study self-stimulation reaction in the Skinner box. Simultaneously, microcanules were implanted into the central nucleus of the amygdala to inject the drugs (1 microl per injection). The blockade of corticoliberin (CRF) receptors (astressin, 1 microg) or Na+influx currents (xycaine or lidocain 1 microg) by the intrastructural administration of drugs into the amygdala decreased self-stimulation reaction of the lateral hypothalamus in rats by 29-55%. The inhibition of D1 and D2 dopamine receptors in the amygdala with SCH23390 (1 microg) or sulpiride (1 microg) respectively, also reduced self-stimulation but to a lower degree. On the background of blockade of CRF (astressin) and dopamine (sulpiride) receptors as well as sodium influx ionic currents (lidocain) in the amygdala neurons, psychomotor stimulant amphetamine (1 mg/kg) and barbiturate sodium ethaminal (5 mg/kg) retained their psychoactivating effect on self-stimulation (+30-37%), while fentanyl (0.1 mg/kg) and leu-enkephaline (0.1 mg/kg) did not produce this effect. Fentanyl moderately activated self-stimulation only after the blockade of D1 dopamine receptors with SCH23390. After the blockade of CRF receptors, leu-enkephaline strengthened its depressant effect on self-stimulation reaction (-89%). Therefore, if the modulating action of amygdala on the hypothalamus is eliminated, the enhancing effects of opiates (fentanyl) and opioids (leu-encephaline) are blocked, but the effects of psychomotor stimulant amphetamine and barbiturate sodium ethaminal are retained.

Proceedings of the drug testing laboratory managers symposium, 28 January--1 February 1974. Final report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Noe, E.R.; Romanchick, W.A.; Ainsworth, C.A. III

1975-06-01

This report deals with broad concepts of managing mass screening programs for drugs of abuse; e.g., morphine, barbiturate, amphetamine, cocaine, and methaqualone. The interactions of the screening process and of the rehabilitation program were covered. Psychotherapy and group therapy are both utilized in rehabilitation programs. The semiautomated radioimmunoassay (RIA) screening procedures are both sensitive and specific at nanogram quantities. Future evaluations of a wafer disk transferral system and of a latex test for morphine are presented. The unique quality control system employed by military drug abuse testing laboratories is discussed. (Author) (GRA)

Mapping General Anesthetic Sites in Heteromeric γ-Aminobutyric Acid Type A Receptors Reveals a Potential For Targeting Receptor Subtypes.

PubMed

Forman, Stuart A; Miller, Keith W

2016-11-01

IV general anesthetics, including propofol, etomidate, alphaxalone, and barbiturates, produce important actions by enhancing γ-aminobutyric acid type A (GABAA) receptor activation. In this article, we review scientific studies that have located and mapped IV anesthetic sites using photoaffinity labeling and substituted cysteine modification protection. These anesthetics bind in transmembrane pockets between subunits of typical synaptic GABAA receptors, and drugs that display stereoselectivity also show remarkably selective interactions with distinct interfacial sites. These results suggest strategies for developing new drugs that selectively modulate distinct GABAA receptor subtypes.

Protometric thermometric titrations of sparingly soluble compounds in water in the presence of n-octanol.

PubMed

Burgot, G; Burgot, J-L

2002-10-15

Thermometric titrimetry permits titration of acido-basic compounds in water in the presence of n-octanol. n-Octanol permits the solubilization of protolytes and moreover may also displace the equilibria of the titration reactions. Hydrochlorides of highly insoluble derivatives such as phenothiazine derivatives can be titrated with satisfactory accuracy and precision by sodium hydroxide despite their high pK(a) values. Likewise barbiturate salts can be titrated by hydrochloric acid. In the case of some salts, the methodology may permit the sequential titration of the ion and counter ion. Copyright 2002 Elsevier Science B.V.

Effectiveness of lorazepam-assisted interviews in an adolescent with dissociative amnesia: A case report★

PubMed Central

Seo, Yuna; Shin, Mi-Hee; Kim, Sung-Gon; Kim, Ji-Hoon

2013-01-01

To facilitate gathering information during a psychiatric interview, some psychiatrists advocate augmenting the interview using drugs. Rather than barbiturates, benzodiazepines have been used for drug-assisted interviews. Dissociative amnesia is one of the indications for these interviews. Herein, we present the case of a 15-year-old female who was diagnosed as having dissociative amnesia because of conflicts with her friends. She was administered a lorazepam-assisted interview to aid recovery of her memories. In this case, a small dose of lorazepam was sufficient to recover her memories without any adverse effects. PMID:25206490

Effectiveness of lorazepam-assisted interviews in an adolescent with dissociative amnesia: A case report.

PubMed

Seo, Yuna; Shin, Mi-Hee; Kim, Sung-Gon; Kim, Ji-Hoon

2013-01-15

To facilitate gathering information during a psychiatric interview, some psychiatrists advocate augmenting the interview using drugs. Rather than barbiturates, benzodiazepines have been used for drug-assisted interviews. Dissociative amnesia is one of the indications for these interviews. Herein, we present the case of a 15-year-old female who was diagnosed as having dissociative amnesia because of conflicts with her friends. She was administered a lorazepam-assisted interview to aid recovery of her memories. In this case, a small dose of lorazepam was sufficient to recover her memories without any adverse effects.

A study of pre-operative sedatives

PubMed Central

Parkhouse, James; Mahoney, Joan

1968-01-01

A state-registered nurse acted as a whole-time investigator following patients through the pre-operative night in hospital and questioning them in the morning, to assess the relative merits of different medications. Two new sedatives were compared with a standard barbiturate and a placebo, and information was collected from patients who elected to have no medication to help them sleep. Subjective assessment enabled the placebo to be distinguished from the active medications, although there was little difference between these. The importance of psychological factors is discussed in relation to those patients who had no medication. PMID:4869880

Barbiturate Induction for the Prevention of Emergence Agitation after Pediatric Sevoflurane Anesthesia

PubMed Central

Nakahara, Haruna; Kimoto, Ayako; Beppu, Yuki; Yoshimura, Maki; Kojima, Toshiyuki; Fukano, Taku

2015-01-01

OBJECTIVES: Emergence agitation (EA) is a common and troublesome problem in pediatric patients recovering from general anesthesia. The incidence of EA is reportedly higher after general anesthesia maintained with sevoflurane, a popular inhalational anesthetic agent for pediatric patients. We conducted this prospective, randomized, double-blind study to test the effect of an intravenous ultra-short–acting barbiturate, thiamylal, administered during induction of general anesthesia on the incidence and severity of EA in pediatric patients recovering from Sevoflurane anesthesia. METHODS: Fifty-four pediatric patients (1 to 6 years of age) undergoing subumbilical surgeries were randomized into 2 groups. Patients received either intravenous thiamylal 5mg/kg (Group T) or inhalational Sevoflurane 5% (Group S) as an anesthetic induction agent. Following induction, general anesthesia was maintained with Sevoflurane and nitrous oxide (N2O) in both groups. To control the intra- and post-operative pain, caudal block or ilioinguinal/iliohypogastric block was performed. The incidence and severity of EA were evaluated by using the Modified Objective Pain Scale (MOPS: 0 to 6) at 15 and 30 min after arrival in the post-anesthesia care unit (PACU). RESULTS: Fifteen minutes after arrival in the PACU, the incidence of EA in Group T (28%) was significantly lower than in Group S (64%; p = 0.023) and the MOPS in Group T (median 0, range 0 to 6) was significantly lower than in Group S (median 4, range 0 to 6; p = 0.005). The interval from discontinuation of Sevoflurane to emergence from anesthesia was not significantly different between the 2 groups. CONCLUSIONS: Thiamylal induction reduced the incidence and severity of EA in pediatric patients immediately after Sevoflurane anesthesia. PMID:26472953

Epidemiology of overdose episodes from the period prior to hospitalization for drug poisoning until discharge in Japan: An exploratory descriptive study using a nationwide claims database.

PubMed

Okumura, Yasuyuki; Sakata, Nobuo; Takahashi, Kunihiko; Nishi, Daisuke; Tachimori, Hisateru

2017-08-01

Little is known about the nationwide epidemiology of the annual rate, causative substance, and clinical course of overdose-related admission. We aimed to describe the epidemiology of overdose episodes from the period prior to hospitalization for drug poisoning until discharge to home. We assessed all cases of admission due to overdose (21,663 episodes) in Japan from October 2012 through September 2013 using the National Database of Health Insurance Claims and Specific Health Checkups of Japan. The annual rate of overdose admission was 17.0 per 100,000 population. Women exhibited two peaks in admission rates at 19-34 years (40.9 per 100,000) and ≥75 years (27.8 per 100,000). Men exhibited one peak in the admission rate at ≥75 years (23.7 per 100,000). Within 90 days prior to overdose, ≥60% and ≥9% of patients aged 19-49 years received a prescription for benzodiazepines and barbiturates, respectively. In addition, 59% of patients aged ≥75 years received a prescription for benzodiazepines prior to overdose, 47% had a history of congestive heart failure, and 24% had a diagnosis of poisoning by cardiovascular drugs. The proportion of patients with recent psychiatric treatments decreased with age (65.1% in those aged 35-49 years and 13.9% in those aged ≥75 years). The findings emphasize the need for overdose prevention programs that focus on psychiatric patients aged 19-49 years who are prescribed benzodiazepines or barbiturates and on non-psychiatric patients aged ≥75 years who are prescribed benzodiazepines or digitalis. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Phenobarbital blockade of the preovulatory luteinizing hormone surge: association with phase-advanced circadian clock and altered suprachiasmatic nucleus Period1 gene expression

PubMed Central

Legan, Sandra J.; Donoghue, Kathleen M.; Franklin, Kathleen M.; Duncan, Marilyn J.

2009-01-01

The suprachiasmatic nucleus (SCN) controls the timing of the preovulatory luteinizing hormone (LH) surge in laboratory rodents. Barbiturate administration during a critical period on proestrus delays the surge and prolongs the estrous cycle 1 day. Because a nonphotic timing signal (zeitgeber) during the critical period that phase advances activity rhythms can also induce the latter effect, we hypothesized that barbiturates delay the LH surge by phase-advancing its circadian timing signal beyond the critical period. In experiment 1, locomotor rhythms and estrous cycles were monitored in hamsters for 2–3 wk preinjection and postinjection of vehicle or phenobarbital and after transfer to darkness at zeitgeber time (ZT) 6 on proestrus. Phenobarbital delayed estrous cycles in five of seven hamsters, which exhibited phase shifts that averaged twofold greater than those exhibited by vehicle controls or phenobarbital-injected hamsters with normal cycles. Experiment 2 used a similar protocol, but injections were at ZT 5, and blood samples for LH determination were collected from 1200 to 1800 on proestrus and the next day via jugular cannulae inserted the day before proestrus. Phenobarbital delayed the LH surge 1 day in all six hamsters, but it occurred at an earlier circadian time, supporting the above hypothesis. Experiment 3 investigated whether phenobarbital, like other nonphotic zeitgebers, suppresses SCN Period1 and Period2 transcription. Two hours postinjection, phenobarbital decreased SCN expression of only Period1 mRNA, as determined by in situ hybridization. These results suggest that phenobarbital advances the SCN pacemaker, governing activity rhythms and hormone release in part by decreasing its Period1 gene expression. PMID:19297538

Phenytoin: 80 years young, from epilepsy to breast cancer, a remarkable molecule with multiple modes of action.

PubMed

Keppel Hesselink, Jan M; Kopsky, David J

2017-08-01

In 1908 phenytoin (5,5-diphenylhydantoin) was first synthesized as a barbiturate derivative in Germany by professor Heinrich Biltz (1865-1943) and subsequently resynthesized by an American chemist of the pharmaceutical company Parke-Davis in 1923 in Detroit. Screening phenytoin did not reveal comparable sedative side effects as barbiturates and, thus, Parke-Davis discarded this compound as a useful drug. In 1936, phenytoin's anticonvulsive properties were identified via a new animal model for convulsive disorders, developed by Putnam and Merritt, who also evaluated its clinical value in a number of patients in the period 1937-1940. For many diseases, mechanism of action of phenytoin remains obscure. The voltage-gated sodium channel was and is generally regarded as the main target to explain phenytoin's activity as an anticonvulsant and an anti-arrhythmic drug. This target, however, does not explain many of the other clinical properties of phenytoin. We will explore a number of original articles on phenytoin published in its 80 years history and give extra attention to the various hypothesis and experiments done to elucidate its mechanisms of action. Phenytoin has been explored in over 100 different disorders; the last two promising indications tested in the clinic are breast cancer and optic neuritis. Most probably, there are multiple targets active for these various disorders, and the insight into which targets are relevant is still very incomplete. It is remarkable that many pharmacological studies tested one dose only, mostly 50 or 100 μM, doses which most probably are higher than the non-plasma bound phenytoin plasma levels obtained during treatment.

Piracetam and TRH analogues antagonise inhibition by barbiturates, diazepam, melatonin and galanin of human erythrocyte D-glucose transport

PubMed Central

Naftalin, Richard J; Cunningham, Philip; Afzal-Ahmed, Iram

2004-01-01

Nootropic drugs increase glucose uptake into anaesthetised brain and into Alzheimer's diseased brain. Thyrotropin-releasing hormone, TRH, which has a chemical structure similar to nootropics increases cerebellar uptake of glucose in murine rolling ataxia. This paper shows that nootropic drugs like piracetam (2-oxo 1 pyrrolidine acetamide) and levetiracetam and neuropeptides like TRH antagonise the inhibition of glucose transport by barbiturates, diazepam, melatonin and endogenous neuropeptide galanin in human erythrocytes in vitro. The potencies of nootropic drugs in opposing scopolamine-induced memory loss correlate with their potencies in antagonising pentobarbital inhibition of erythrocyte glucose transport in vitro (P<0.01). Less potent nootropics, D-levetiracetam and D-pyroglutamate, have higher antagonist Ki's against pentobarbital inhibition of glucose transport than more potent L-stereoisomers (P<0.001). Piracetam and TRH have no direct effects on net glucose transport, but competitively antagonise hypnotic drug inhibition of glucose transport. Other nootropics, like aniracetam and levetiracetam, while antagonising pentobarbital action, also inhibit glucose transport. Analeptics like bemigride and methamphetamine are more potent inhibitors of glucose transport than antagonists of hypnotic action on glucose transport. There are similarities between amino-acid sequences in human glucose transport protein isoform 1 (GLUT1) and the benzodiazepine-binding domains of GABAA (gamma amino butyric acid) receptor subunits. Mapped on a 3D template of GLUT1, these homologies suggest that the site of diazepam and piracetam interaction is a pocket outside the central hydrophilic pore region. Nootropic pyrrolidone antagonism of hypnotic drug inhibition of glucose transport in vitro may be an analogue of TRH antagonism of galanin-induced narcosis. PMID:15148255

The role of liquid chromatography-tandem mass spectrometry (LC-MS/MS) to test blood and urine samples for the toxicological investigation of drug-facilitated crimes.

PubMed

Deveaux, Marc; Chèze, Marjorie; Pépin, Gilbert

2008-04-01

The authors present an overview of the drug-facilitated crime (DFC) phenomenon, especially in France. Recently, there has been an increase in reports of incidents (mainly sexual assaults and robbery) as well as in scientific publications and congress presentations on the topic. From enquiries conducted nationally, a list of drugs reportedly associated with DFC was established and includes benzodiazepines and benzodiazepine-like drugs (zolpidem, zopiclone), minor tranquilizers and neuroleptics, barbiturates, narcotics, hallucinogens, and anaesthetics. Some of these molecules are specific to France in DFC cases. A study using healthy volunteers who had taken benzodiazepines (lorazepam, bromazepam, flunitrazepam, clonazepam), zolpidem and zopiclone, showed that the only way to increase the duration of detection of these drugs is to use liquid chromatography-tandem mass spectrometry (LC-MS/MS) to test blood and urine samples. The very high sensitivity of this method appears to be an essential condition to document the cases, because the drugs tested were still detectable in urine at least 6 days after the ingestion of one therapeutic dose. Limits of detection were always lower than 0.5 ng/mL in urine. The actual list of molecules and metabolites the authors screened for in urine and blood by LC-MS/MS, in every DFC, is given in detail: 25 benzodiazepines and benzodiazepine-like drugs, 11 minor tranquilizers and neuroleptics, 2 barbiturates, 12 narcotics, 4 hallucinogens, and 1 anaesthetic. However, the distinction between continual therapeutic use of a psychotropic drug or illegal narcotic and a single ingestion has to be documented by sequential analysis of hair, again with LC-MS/MS.

[Psychophysiological regin for rehabilition of chronic polydrug users in the Center of the Le Patriarche. 446 cases (author's transl)].

PubMed

Laffont, F; Engelmajer, L; Vourc'h, G; Nahas, G

1980-01-01

From 1974 to 1979, the rehabilitation centers of the association "Le Patriarche" located in the country side of southern France, have received 446 chronic polydrugs users who has consumed at one time or an other cannabis (marihuana, hashish) (87 p. cent), LSD (66 p. cent) and other hallucinogens (35 p. cent), psychodepressants (55 p. cent), psychostimulants (amphetamines, 85 p. cent; cocaïne, 50 p. cent) and opium and its derivatives (brown sugar, 47 p. cent; opiates, 67 p. cent; heroin, 50 p. cent). The dominant addictive drug was heroin and opiates, 52 p. cent, psychodepressants (barbitutiques and benzodiazepines, 33 p. cent, psychostimulants, 15 p. cent. Males were twice as numerous as female. Average age was 21 (range 14-38). Mean duration of drug abuse was 7 years. All these drug abusers display at entrance withdrawal symptoms. These were treated successfully by a drug free, psycho-physiological regimen comprising: 1. An elimination of all psychoactive drugs, including coffee, and alcohol. Tobacco was permitted. 2. Physical therapy (bath, exercise, massage) and forced fluid diuresis. 3. A supportive psychotherapy dispensed by rehabilitated addicts who had undergone successfully a similar regimen. This non-pharmacological method of treating withdrawal symptoms associated with opium, barbiturate and amphetamine addiction, was successful, and was not associated with any major clinical symptoms threatening the vital signs. Mean duration of detoxification was 5 days for opiates, 6 days for amphetamines and 10 days for barbiturates. 78 p. cent of these subjects remained in the centers from 3 months to 2 years, partaking in physical occupational and physiological rehabilitation paograms which allowed then to adopt a drug free life style and prepared them for social reinsertion.

Rates and Correlates of Binge Drinking Among College Students With Disabilities, United States, 2013.

PubMed

West, Steven L; Graham, Carolyn W; Temple, Peter

Our objective was to provide the first comprehensive picture of alcohol use and binge drinking by US college students with disabilities (SWDs), who represent at least 11% (1.6 million) of the US college student population. In fall 2013, we used a stratified random sampling technique to identify and recruit 2440 SWDs from 122 US colleges and universities. A total of 1285 (53%) SWDs from 61 (50%) colleges and universities completed a survey of alcohol and other drug use and the use of substances by student peers. We conducted 4 multiple logistic regression analyses to compare binge-drinking and non-binge-drinking SWDs by potential correlates of such use and a final model that included only significant variables. SWDs aged <21 vs ≥21 (odds ratio [OR] = 0.90; 95% confidence interval [CI], 0.82-0.99) who spent more time vs less time socializing (OR = 1.24; 95% CI, 1.11-1.38), who spent less time vs more time studying (OR = -0.89; 95% CI, -0.80 to -0.99), and who used vs did not use marijuana (OR = 1.44; 95% CI, 1.18-1.75) or amphetamines (OR = 1.82; 95% CI, 1.15-2.89) were significantly more likely to binge drink. SWDs who reported using barbiturates were less likely to binge drink than were those who did not use barbiturates (OR = -0.36; 95% CI, -0.21 to -0.61). In the final model, use of amphetamines (OR = 1.74; 95% CI, 1.15-2.65) or marijuana (OR = 1.60; 95% CI, 1.32-1.94) was the highest predictor of binge drinking. SWDs' reported rates of binge drinking, although high, were not as high as those of nondisabled college students. Nevertheless, prevention efforts should be targeted toward college SWDs.

Successful use of haemodialysis to treat phenobarbital overdose.

PubMed

Hoyland, Kimberley; Hoy, Michael; Austin, Richard; Wildman, Martyn

2013-11-21

A 50-year-old woman presented with coma caused by a phenobarbital overdose, requiring intubation and admission to critical care. She was an international visitor and had been prescribed the drug for night-sedation. Phenobarbital is a long-acting barbiturate, which in an overdose can cause central nervous system depression, respiratory failure and haemodynamic instability; these patients can remain obtunded for many days. After initial supportive therapy, she was dialysed to help in the elimination of the drug. Haemodialysis resulted in a markedly reduced plasma level of phenobarbital, which decreased the length of intubation and stay in the critical care unit and aided full recovery.

Successful use of haemodialysis to treat phenobarbital overdose

PubMed Central

Hoyland, Kimberley; Hoy, Michael; Austin, Richard; Wildman, Martyn

2013-01-01

A 50-year-old woman presented with coma caused by a phenobarbital overdose, requiring intubation and admission to critical care. She was an international visitor and had been prescribed the drug for night-sedation. Phenobarbital is a long-acting barbiturate, which in an overdose can cause central nervous system depression, respiratory failure and haemodynamic instability; these patients can remain obtunded for many days. After initial supportive therapy, she was dialysed to help in the elimination of the drug. Haemodialysis resulted in a markedly reduced plasma level of phenobarbital, which decreased the length of intubation and stay in the critical care unit and aided full recovery. PMID:24265338

Interactions between clinically used drugs and oral contraceptives.

PubMed Central

Bolt, H M

1994-01-01

Metabolism of contraceptive compounds may be influenced by various drugs. Of clinical importance is induction by barbiturates, by diphenylhydantoin, and especially by rifampicin, of enzymes that are responsible for degradation of estrogens. The major target is the hepatic microsomal estrogen-2-hydroxylase (cytochrome P450 3A4). Another type of interaction of drugs with disposition and effectiveness of estrogens is impairment of their enterohepatic circulation. This may be due to absorption of biliary estrogen conjugates (e.g., by cholestyramine) or to insufficient cleavage of the conjugate by intestinal bacteria, the latter being observed after administration of antibiotics (e.g., ampicillin, neomycin). PMID:7698081

Opiate addiction in adult offspring through possible imprinting after obstetric treatment.

PubMed Central

Jacobson, B; Nyberg, K; Grönbladh, L; Eklund, G; Bygdeman, M; Rydberg, U

1990-01-01

OBJECTIVE--To test the hypothesis that opiate addiction in adults might stem partly from an imprinting process during birth when certain drugs are given to the mother. DESIGN--Retrospective study by logistic regression of opiate addicts with siblings as controls. SETTING--Stockholm, Sweden. SUBJECTS--200 Opiate addicts born in Stockholm during 1945-66, comprising 41 identified during interviews of probands for an earlier study; 75 patients whose death from opiate addiction had been confirmed during 1978-88; and 84 accepted for the methadone programme. 262 Siblings (controls) born in Stockholm during the same period, 24 of whom were excluded for drug addiction or being brought up outside the family. Birth records were unavailable for eight, leaving 230 siblings and 139 corresponding probands. MAIN OUTCOME MEASURES--Administration of opiates, barbiturates, and nitrous oxide (for greater than 1 h) to mothers of all subjects during labour within 10 hours before birth as a risk factor for adult opiate addiction. RESULTS--In subjects who had subsequently become addicts a significant proportion of mothers had received opiates or barbiturates, or both, compared with unmatched siblings (25% v 16%, chi 2 = 5.83, df = 1, p = 0.02), and these mothers had received nitrous oxide for longer and more often. After controlling for hospital of birth, order of birth, duration of labour, presentation other than vertex, surgical intervention, asphyxia, meconium stained amniotic fluid, and birth weight the relative risk for offspring subsequently becoming an adult opiate addict increased with the number of administrations of any of the three drugs. When the addicts were matched with their own siblings the estimated relative risk was 4.7 (95% confidence interval 1.8 to 12.4, p for trend = 0.002) for three administrations compared with when no drug was given. CONCLUSIONS--The results are compatible with the imprinting hypothesis. Therefore, for obstetric pain relief methods are preferable that do not permit substantial passage of drugs through the placenta. PMID:2249068

Pharmacologic Treatment Reduces Pressure Times Time Dose and Relative Duration of Intracranial Hypertension.

PubMed

Colton, Katharine; Yang, S; Hu, P F; Chen, H H; Bonds, B; Stansbury, L G; Scalea, T M; Stein, D M

2016-05-01

Past work has shown the importance of the "pressure times time dose" (PTD) of intracranial hypertension (intracranial pressure [ICP] > 19 mm Hg) in predicting outcome after severe traumatic brain injury. We used automated data collection to measure the effect of common medications on the duration and dose of intracranial hypertension. Patients >17 years old, admitted and requiring ICP monitoring between 2008 and 2010 at a single, large urban tertiary care facility, were retrospectively enrolled. Timing and dose of ICP-directed therapy were recorded from paper and electronic medical records. The ICP data were collected automatically at 6-second intervals and averaged over 5 minutes. The percentage of time of intracranial hypertension (PTI) and PTD (mm Hg h) were calculated. A total of 98 patients with 664 treatment instances were identified. Baseline PTD ranged from 27 (before administration of propofol and fentanyl) to 150 mm Hg h (before mannitol). A "small" dose of hypertonic saline (HTS; ≤250 mL 3%) reduced PTD by 38% in the first hour and 37% in the second hour and reduced the time with ICP >19 by 38% and 39% after 1 and 2 hours, respectively. A "large" dose of HTS reduced PTD by 40% in the first hour and 63% in the second (PTI reduction of 36% and 50%, respectively). An increased dose of propofol or fentanyl infusion failed to decrease PTD but reduced PTI between 14% (propofol alone) and 30% (combined increase in propofol and fentanyl, after 2 hours). Barbiturates failed to decrease PTD but decreased PTI by 30% up to 2 hours after administration. All reductions reported are significantly changed from baseline, P < .05. Baseline PTD values before drug administration reflects varied patient criticality, with much higher values seen before the use of mannitol or barbiturates. Treatment with HTS reduced PTD and PTI burden significantly more than escalation of sedation or pain management, and this effect remained significant at 2 hours after administration. © The Author(s) 2014.

A Comparison of Pharmacologic Therapeutic Agents Used for the Reduction of Intracranial Pressure After Traumatic Brain Injury.

PubMed

Alnemari, Ahmed M; Krafcik, Brianna M; Mansour, Tarek R; Gaudin, Daniel

2017-10-01

In neurotrauma care, a better understanding of treatments after traumatic brain injury (TBI) has led to a significant decrease in morbidity and mortality in this population. TBI represents a significant medical problem, and complications after TBI are associated with the initial injury and postevent intracranial processes such as increased intracranial pressure and brain edema. Consequently, appropriate therapeutic interventions are required to reduce brain tissue damage and improve cerebral perfusion. We present a contemporary review of literature on the use of pharmacologic therapies to reduce intracranial pressure after TBI and a comparison of their efficacy. This review was conducted by PubMed query. Only studies discussing pharmacologic management of patients after TBI were included. This review includes prospective and retrospective studies and includes randomized controlled trials as well as cohort, case-control, observational, and database studies. Systematic literature reviews, meta-analyses, and studies that considered conditions other than TBI or pediatric populations were not included. Review of the literature describing the current pharmacologic treatment for intracranial hypertension after TBI most often discussed the use of hyperosmolar agents such as hypertonic saline and mannitol, sedatives such as fentanyl and propofol, benzodiazepines, and barbiturates. Hypertonic saline is associated with faster resolution of intracranial hypertension and restoration of optimal cerebral hemodynamics, although these advantages did not translate into long-term benefits in morbidity or mortality. In patients refractory to treatment with hyperosmolar therapy, induction of a barbiturate coma can reduce intracranial pressure, although requires close monitoring to prevent adverse events. Current research suggests that the use of hypertonic saline after TBI is the best option for immediate decrease in intracranial pressure. A better understanding of the efficacy of each treatment option can help to direct treatment algorithms during the critical early hours of trauma care and continue to improve morbidity and mortality after TBI. Copyright © 2017 Elsevier Inc. All rights reserved.

Nuclear medicine technology progress report for quarter ending September 30, 1980

DOE Office of Scientific and Technical Information (OSTI.GOV)

Knapp, F.F. Jr.

1981-03-01

Brain uptake of several /sup 75/Se- and /sup 123m/Te-labelled barbiturates is being studied. These new agents, substituted at the C-5 position, freely pass through the intact blood-brain barrier. Barbiturates labelled with gamma-emitting radionuclides may be an attractive new class of agents for measurement of regional cerebral blood flow. The diffusion chamber assay system has been used to assess the chronic effects of As/sub 2/O/sub 3/ toxicity. A small osmotically actuated minipump was used to deliver aqueous As/sub 2/O/sub 3/ at a continuous delivery rate to animals having intraperitoneally implanted diffusion chambers containing human lung cells (Flow 200). In these preliminarymore » studies, a 49 to 53% inhibition of cell growth was observed over a five-day period when animals received As/sub 2/O/sub 3/ at a dose of 1.7 to 2 mg (kg-d). These initial studies suggest that the minipump may be a useful means of studying the chronic effects of substances on cell proliferation in conjunction with the diffusion chamber assay system. A microscale synthesis of gold antirheumatoid agents was developed. This method involves reaction of thiohexose derivatives such as thioglucosetetraacetate (..beta..-D-TGTA) with trialkylphosphinegold halide intermediates (R/sub 3/PAu-Cl) in the presence of pyridine to give the coupling products R/sub 3/PAu(..beta..-D-TGTA) in good yield (>75%). Using this method, the triethyl analog Et/sub 3/PAu(..beta..-D-TGTA) and triphenyl analog (phi/sub 3/PAu(..beta..-D-TGTA)) have been prepared and characterized.This method will be used to prepare the /sup 195/Au-labeled agents. The platinum antitumor agent cis-dichloro-trans-dihydroxy-bis-(isopropylamine)-platinum (IV) (CHIP) has been purified. This system is efficient for separation of CHIP from impurities produced during the synthetic sequence and will be used to prepare /sup 195m/Pt-CHIP for biological evaluation. (ERB)« less

Comparisons of pilot performance in simulated and actual flight. [effects of ingested barbiturates

NASA Technical Reports Server (NTRS)

Billings, C. E.; Gerke, R. J.; Wick, R. L., Jr.

1975-01-01

Five highly experienced professional pilots performed instrument landing system approaches under simulated instrument flight conditions in a Cessna 172 airplane and in a Link-Singer GAT-1 simulator while under the influence of orally administered secobarbital (0, 100, and 200 mg). Tracking performance in two axes and airspeed control were evaluated continuously during each approach. Error and RMS variability were about half as large in the simulator as in the airplane. The observed data were more strongly associated with the drug level in the simulator than in the airplane. Further, the drug-related effects were more consistent in the simulator. Improvement in performance suggestive of learning effects were seen in the simulator, but not in actual flight.

A new synthetic approach to functionalize pyrimido[4,5-b]quinoline-2,4(1H,3H)-diones via a three-component one-pot reaction.

PubMed

Aknin, Karen; Desbène-Finck, Stéphanie; Helissey, Philippe; Giorgi-Renault, Sylviane

2010-02-01

Functionalized pyrimido[4,5-b]quinoline-2,4 (1H,3H)-diones were synthesized by a three-component one-pot reaction involving barbituric acid, aldehydes, and anilines. The use of commercially available anilines allowed the facile syntheses of pyrimido[4,5-b]quinolinediones substituted in all the positions on the benzene ring with electron donor or electron withdrawing groups. This straightforward method circumvents the preparation of unstable substituted 2-aminobenzaldehydes that limits the scope of previously described syntheses. Furthermore, access to the 5-substituted derivatives is now also possible starting from aliphatic or aromatic aldehydes. Our strategy and methodology offer significant and practical improvements over other methodologies.

Pentobarbital quantitation using EMIT serum barbiturate assay reagents: application to monitoring of high-dose pentobarbital therapy.

PubMed

Pape, B E; Cary, P L; Clay, L C; Godolphin, W

1983-01-01

Pentobarbital serum concentrations associated with a high-dose therapeutic regimen were determined using EMIT immunoassay reagents. Replicate analyses of serum controls resulted in a within-assay coefficient of variation of 5.0% and a between-assay coefficient of variation of 10%. Regression analysis of 44 serum samples analyzed by this technique (y) and a reference procedure (x) were y = 0.98x + 3.6 (r = 0.98; x = ultraviolet spectroscopy) and y = 1.04x + 2.4 (r = 0.96; x = high-performance liquid chromatography). Clinical evaluation of the results indicates the immunoassay is sufficiently sensitive and selective for pentobarbital to allow accurate quantitation within the therapeutic range associated with high-dose therapy.

Effect of peptidase inhibition on the pattern of intraspinally released immunoreactive substance P detected with antibody microprobes.

PubMed

Duggan, A W; Schaible, H G; Hope, P J; Lang, C W

1992-05-08

Antibody microprobes bearing antibodies to the C-terminus of substance P (SP) were used to measure release of immunoreactive (ir) SP in the dorsal horn of barbiturate anaesthetized spinal cats. Electrical stimulation of unmyelinated primary afferents of the ipsilateral tibial nerve produced a relatively localised release of ir SP in the superficial dorsal horn. Prior microinjection of the peptidase inhibitors kelatorphan and enalaprilat in the dorsal horn resulted in ir SP being detected over the whole of the dorsal horn and the overlying dorsal column. This pattern had previously been observed with evoked release of ir neurokinin A and supports the proposal that a slow degradation results in a neuropeptide accessing many sites remote from sites of release.

Effects of polychlorinated biphenyls and nutritional restriction on barbituate-induced sleeping times and selected blood characteristics in raccoons (Procyon lotor)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Montz, W.E.; Card, W.C.; Kirkpatrick, R.L.

1982-05-01

Hepatic microsomal enzyme activity was induced in wild-trapped raccoons (Procyon lotor) and selected blood characteristics were measured in an effort to detect responses due to PCB ingestion, nutritional restriction, and their interactions. Barbiturate-induced sleeping times were used as an index of hepatic microsomal activity because they have been used reliably by other workers. Blood characteristics examined in the study were nonesterified fatty acids (NEFA), cholesterol, and three ketone bodies (D-(-)-3-hydroxybutyrate, acetoacetate, and acetone). Results show a reduction in sleeping times, elevated NEFA and D-(-)-3-hydroxybutyrate concentrations, and lower cholesterol concentrations in PCB-treated groups. A highly significant interaction between PCB treatment andmore » nutritional restriction was observed in acetoacetate concentrations. (JMT)« less

Screening selves: sciences of memory and identity on film, 1930-1960.

PubMed

Winter, Alison

2004-11-01

Chemicals that could be used scientifically to force an individual to tell the truth - dubbed truth sera - were first described in the early 1920s. Ever since, the notion of "truth drugs" has remained tenaciously within popular culture. One of the most important reasons for the survival of the notion of a pharmaceutical technology of authenticity was the role of the barbiturates sodium amytal and sodium pentothal in psychiatric research and treatment during the 1930s through the 1950s. This article traces that history, giving special emphasis to the role of motion pictures. The article argues that researchers were seeking to develop a technology of authenticity (rather than of the truth per se). It examines how they used motion pictures to help them develop and disseminate this technology.

Peter Bourne's drug policy and the perils of a public health ethic, 1976-1978.

PubMed

Clark, Claire D; Dufton, Emily

2015-02-01

As President Jimmy Carter's advisor for health issues, Peter Bourne promoted a rational and comprehensive drug strategy that combined new supply-side efforts to prevent drug use with previously established demand-side addiction treatment programs. Using a public health ethic that allowed the impact of substances on overall population health to guide drug control, Bourne advocated for marijuana decriminalization as well as increased regulations for barbiturates. A hostile political climate, a series of rumors, and pressure from both drug legalizers and prohibitionists caused Bourne to resign in disgrace in 1978. We argue that Bourne's critics used his own public health framework to challenge him, describe the health critiques that contributed to Bourne's resignation, and present the story of his departure as a cautionary tale for today's drug policy reformers.

Central nervous system side effects associated with zolpidem treatment.

PubMed

Toner, L C; Tsambiras, B M; Catalano, G; Catalano, M C; Cooper, D S

2000-01-01

Zolpidem is one of the newer medications developed for the treatment of insomnia. It is an imidazopyridine agent that is an alternative to the typical sedative-hypnotic agents. Zolpidem use is gaining favor because of its efficacy and its side effect profile, which is milder and less problematic than that of the benzodiazepines and barbiturates used to treat insomnia. Still, side effects are not uncommon with zolpidem use. We report a series of cases in which the patients developed delirium, nightmares and hallucinations during treatment with zolpidem. We will review its pharmacology, discuss previous reports of central nervous system side effects, examine the impact of drug interactions with concurrent use of antidepressants, examine gender differences in susceptibility to side effects, and explore the significance of protein binding in producing side effects.

Central effects of citral, myrcene and limonene, constituents of essential oil chemotypes from Lippia alba (Mill.) n.e. Brown.

PubMed

do Vale, T Gurgel; Furtado, E Couto; Santos, J G; Viana, G S B

2002-12-01

Citral, myrcene and limonene (100 and 200 mg/kg body wt., i.p.), constituents of essential oils from Lippia alba chemotypes, decreased not only the number of crossings but also numbers for rearing and grooming, as measured by the open-field test in mice. Although muscle relaxation detected by the rota rod test was seen only at the highest doses of citral (200 mg/kg body wt.) and myrcene (100 and 200 mg/kg body wt.), this effect was observed even at the lowest dose of limonene (50 mg/kg body wt.). Also, citral and myrcene (100 and 200 mg/kg body wt.) increased barbiturate sleeping time as compared to control. Limonene was also effective at the highest dose, and although citral did not increase the onset of sleep, it increased the duration of sleep, which is indicative of a potentiation of sleeping time. Citral (100 and 200 mg/kg body wt.) increased 2.3 and 3.5 times, respectively, the barbiturate sleeping time in mice. Similar effects were observed for myrcene and limonene at the highest dose (200 mg/kg body wt.) which increased the sleeping time around 2.6 times. In the elevated-plus maze, no effect was detected with citral up to 25 mg/kg body wt., while at a high dose it decreased by 46% the number of entries in the open arms. A smaller but significant effect was detected with limonene (5 mg/kg body wt.). While myrcene (10 mg/kg body wt.) decreased only by 22% the number of entries in the open arms, this parameter was decreased by 48% at the highest dose. Our study showed that citral, limonene and myrcene presented sedative as well as motor relaxant effects. Although only at the highest dose, they also produced a potentiation of the pentobarbital-induced sleeping time in mice, which was more intense in the presence of citral. In addition, neither of them showed an anxiolytic effect, but rather a slight anxiogenic type of effect at the higher doses.

Molecular structure and spectroscopic investigations combined with hypoglycemic/anticancer and docking studies of a new barbituric acid derivative

NASA Astrophysics Data System (ADS)

Barakat, Assem; Soliman, Saied M.; Elshaier, Yaseen A. M. M.; Ali, M.; Al-Majid, Abdullah Mohammed; Ghabbour, Hazem A.

2017-04-01

The one-pot synthesis reaction of barbituric acid derivative, 1,3-cyclohexandione, and 4-fluorobenzaldehyde in water mediated by NHEt2 as base afforded 4 with excellent yield. The synthesized compound was characterized by spectrophotometric tools as well as X-ray single crystal diffraction technique. The stability of the nine possible isomers of the synthesized compound was studied using the B3LYP method and 6-31G(d,p) basis set. The electronic and spectroscopic properties of the most stable isomer were predicted. The UV-Vis absorption spectrum displayed two bands at 203 and 257 nm in the solvent chloroform. The latter was calculated at 235.6 nm (f = 0.1995) in the gas phase due to H-2→L (42%) and H-1→L+2 (14%) excitations. In solution, using chloroform as a solvent, a slight bathochromic shift to 237.6 nm with an increase in the absorption intensity (f = 0.2898) was predicted. The molecular orbital energy level diagram of this transition band was characterized mainly by π-π* transitions. The 13C and 1H NMR chemical shifts correlated well with the experimental data. The correlations had higher correlation coefficients (R2) when solvent effects were considered. The atomic charges were calculated using natural population analysis and the charged regions were presented using a molecular electrostatic potential (MEP) map. The synthesized compound was examined as a hypoglycemic agent via inhibition of α-glucosidase and β-glucuronidase enzymes. Its inhibitory activity against α-glucosidase was 10 times greater than the inhibitory activity of the standard drug acarbose (IC50 77.9 ± 0.3 μM and 840 ± 1.73 μM, respectively). Moreover, the target compound was evaluated for anticancer activity against MCF-7, H460, 3T3, and Hela cell lines. It demonstrated inhibitory activity against the MCF-7 and H460 cell lines with IC50 5.80 ± 0.12 and 19.6 ± 0.5 μM, respectively, in comparison to doxorubicin. The docking study was performed using the OpenEye program.

Thiopental Anesthesia and Tannic Acid Diagnostic Enemas

PubMed Central

Singh, Jasbir; Boyd, Eldon M.

1966-01-01

The administration to albino rats of tannic acid as a retention enema (in doses of 0.2 g./kg. body weight and over) prolonged the duration of anesthesia induced by thiopental given immediately before, or 72 hours after, the tannic acid. This dose of tannic acid corresponds, on the basis of body weight, to a radiodiagnostic enema of 2 1. of 0.25% tannic acid in barium sulfate suspension given to a child weighing 25 kg. By excluding certain hypothermic effects of tannic acid, it was concluded that thiopental potentiation was probably due to impairment by the tannic acid of the liver's ability to detoxify the barbiturate. The results suggest that a drug which is detoxified in the liver should be administered three to five days after a tannic acid-barium sulfate radiodiagnostic enema only with considerable caution. PMID:5947612

Anaphylaxis due to thiopental sodium anesthesia.

PubMed Central

Dolovich, J; Evans, S; Rosenbloom, D; Goodacre, R; Rafajac, F O

1980-01-01

Anaphylaxis due to an anesthetic is one type of cardiovascular emergency that can occur during general anesthesia. Anaphylactic reactions to muscle relaxants have been documented. Barbiturates, used as sedatives, are well known to produce cutaneous reactions, but anaphylaxis after their ingestion seems to be rare. Generalized allergic reactions to thiopental sodium during anesthesia are mentioned in the product monograph for Penthothal sodium, and rare case reports of anaphylactic reactions to infused thiopental have appeared, generally in the anesthesiology literature. Documentation of the immunologic responses to thiopental sodium has been limited to the demonstration of an allergic reaction to thiopental by skin testing in some cases. This report describes a woman who, after having tolerated thiopental sodium and other general anesthetics, became sensitive to this agent and had a severe acute reaction at the time of induction of general anesthesia. PMID:6167340

Toxicity of aerosol propellants in the respiratory and circulatory systems. VII. Influence of pulmonary emphysema and anesthesia in the rat.

PubMed

Watanabe, T; Aviado, D M

1975-01-01

Experimental induction of pulmonary emphysema caused an increase in sensitivity of the rat to toxicity from inhalation of propellants. The emphysematous rat showed an exaggerated reduction in pulmonary compliance in response to inhalation of trichlorofluoromethane (FC 11). In emphysematous and non emphysematous rats without anesthesia the inhalation of FC 11 caused tachycardia, arrhythmias and other abnormalities in the electrocardiogram. The tachycardiac response was eliminated by induction of barbiturate anesthesia, which increased the sensitivity of the heart to occurrence of abnormalities in the electrocardiogram in response to inhalation of FC 11 as well as of dichlorodifluoromethane (FC 12) and difluoroethane (FC 152a). The acceleration in heart rate in response to inhalation of FC 11, hypoxia or hypercapnea was prevented by prior treatment with a beta-blocking drug.

Narcotic addiction, pregnancy, and the newborn.

PubMed

Fricker, H S; Segal, S

1978-04-01

Between 1954 and 1973, 101 heroin-addicted mothers gave birth to 149 babies at Vancouver General Hospital. Thirty-seven percent of the infants had low birth weights and two thirds were born preterm. Average birth weight was 2,710 gm as compared with an overall average of 3,420 gm for this hospital. Tobacco and alcohol abuse, and poor maternal nutrition probably contributed to the growth retardation. Withdrawal symptoms were observed in 68% of the babies, and this may have been aggravated by multiple drug use, which was prevalent, including alcohol, barbiturates, and "soft drugs." Neonatal mortality rate of 6.7% and a stillbirth rate of 4% resulted in a perinatal mortality rate of 10.7%. Prematurity, respiratory distress syndrome, and other perinatal complications related to an unfavorable social background accounted for most neonatal deaths, but none was attributable directly to narcotic withdrawal.

Exacerbation of benign familial neonatal epilepsy induced by massive doses of phenobarbital and midazolam.

PubMed

Maeda, Tomoki; Shimizu, Miki; Sekiguchi, Kazuhito; Ishii, Atsushi; Ihara, Yukiko; Hirose, Shinichi; Izumi, Tatsuro

2014-08-01

Barbiturates and benzodiazepines are the first-line anticonvulsants for neonatal seizures. However, in immature brains, those drugs may lead to paradoxical neuronal excitation. A patient with benign familial neonatal epilepsy developed epileptic encephalopathy after massive doses of phenobarbital that were followed by a continuous infusion of midazolam on postnatal day 3. Electroencephalography revealed rhythmic delta activity in clusters with migrating epileptic foci. After discontinuation of both drugs, the patient's consciousness promptly improved and her electroencephalography normalized on postnatal day 5. This baby developed persistent electroencephalographic seizures due to massive doses of phenobarbital and midazolam. Clinicians should be aware of this anticonvulsant-induced paradoxical neuronal excitation and the uncoupling phenomenon, especially in individuals with benign familial neonatal epilepsy, who have low seizure thresholds. Copyright © 2014 Elsevier Inc. All rights reserved.

Evidence for involvement of the astrocytic benzodiazepine receptor in the mechanism of action of convulsant and anticonvulsant drugs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bender, A.S.; Hertz, L.

1988-01-01

The anticonvulsant drugs carbamazepine, phenobarbital, trimethadione, valproic acid and ethosuximide at pharmacologically relevant concentrations inhibit (/sup 3/H)diazepam binding to astrocytes in primary cultures but have much less effect on a corresponding preparation of neurons. Phenytoin as well as pentobarbital (which is not used chronically as an anticonvulsant) are equipotent in the two cell types. The convulsants picrotoxinin and pentylenetetrazol, the convulsant benzodiazepine RO 5-3663 and the two convulsant barbiturates DMBB and CHEB similarly inhibit diazepam binding to astrocytes but have little effect on neurons. On the basis of these findings it is suggested that these convulsants and anticonvulsants owe atmore » least part of their effect to an interaction with the astrocytic benzodiazepine receptor, perhaps by interference with a calcium channel.« less

Peter Bourne’s Drug Policy and the Perils of a Public Health Ethic, 1976–1978

PubMed Central

Dufton, Emily

2015-01-01

As President Jimmy Carter’s advisor for health issues, Peter Bourne promoted a rational and comprehensive drug strategy that combined new supply-side efforts to prevent drug use with previously established demand-side addiction treatment programs. Using a public health ethic that allowed the impact of substances on overall population health to guide drug control, Bourne advocated for marijuana decriminalization as well as increased regulations for barbiturates. A hostile political climate, a series of rumors, and pressure from both drug legalizers and prohibitionists caused Bourne to resign in disgrace in 1978. We argue that Bourne’s critics used his own public health framework to challenge him, describe the health critiques that contributed to Bourne’s resignation, and present the story of his departure as a cautionary tale for today’s drug policy reformers. PMID:25521893

The relationship of college students' use of marijuana to parental attitudes and drug-taking behavior.

PubMed

Turner, C J; Willis, R J

1980-10-01

This study was part of an extensive survey of drug use patterns at a small private college in suburban New Jersey during the fall, 1975. Selected items from a questionnaire developed by the Inter-University Drug Survey Council of Metropolitan New York were cross-tabulated in order to examine the relationship between 379 college students' use of marijuana and their parents' attitudes and behavior relative to drug use. Significant results at the 0.01 level were found between (1) time of first marijuana use and parental attitudes toward alcohol and marijuana; (2) time of first marijuana use and parental use of barbiturates, marijuana, and pain-killers; (3) current frequency of marijuana use and parental attitudes toward alcohol and marijuana; and (4) current frequency of marijuana use and parental use of pain-killers.

Efficacy, end points and eventualities: sumatriptan/naproxen versus butalbital/paracetamol/caffeine in the treatment of migraine.

PubMed

Fox, Anthony W

2012-09-01

Migraine is a widespread, relapsing, remittent syndrome. No animal model predicts whether test medications will be clinically useful. Using a modern, well-controlled, sophisticated study design, Derosier et al. demonstrates not only that a butalbital formulation has modest efficacy as an acute treatment for migraine but also that a sumatriptan-naproxen combination is superior. These conclusions are reached using a variety of internally consistent secondary efficacy end points. The primary end point chosen (highly conservative and fashionable in some academic circles) was a technical failure (and not a negative experimental finding). Migraine is intrinsically pleiomorphic: diverse treatment options help match patient with therapy. This study does not justify blanket bans on (admittedly hazardous) barbiturate therapies, and regulators should not impose end point conservatism to an extent that will stifle further progress.

Effects of anticonvulsants in vivo on high affinity choline uptake in vitro in mouse hippocampal synaptosomes.

PubMed Central

Miller, J. A.; Richter, J. A.

1985-01-01

The effects of several anticonvulsant drugs on sodium-dependent high affinity choline uptake (HACU) in mouse hippocampal synaptosomes was investigated. HACU was measured in vitro after in vivo administration of the drug to mice. HACU was inhibited by drugs which have in common the ability to facilitate gamma-aminobutyric acid (GABA) transmission, pentobarbitone, phenobarbitone, barbitone, diazepam, chloridiazepoxide, and valproic acid. Dose-response relationships were determined for these drugs and the drugs' potencies at inhibiting HACU correlated well with their anticonvulsant potencies. Clonazepam, ethosuximide, carbamazepine, and barbituric acid had no effect on HACU in the doses used while phenytoin and trimethadione stimulated HACU. These results suggest that certain anticonvulsants may elicit a part of their anticonvulsant activity by modulating cholinergic neurones. This effect may be mediated through a GABA mechanism. PMID:3978310

Effectiveness of urine surveillance as an adjunct to outpatient psychotherapy for drug abusers.

PubMed

Milby, J B; Clarke, C; Toro, C; Thornton, S; Rickert, D

1980-10-01

Twenty-nine polydrug abusers were randomly assigned to three out-patient treatment groups after inpatient detoxification. The groups were outpatient psychotherapy (1) with urine surveillance, (2) without surveillance, and (3) waiting list control. Tests were administered before and 3 months after outpatient treatment began. All groups made positive changes during treatment including significant reduction in drugs abused and numbers of subjects reporting less time spent in illegal activity. Notable significant differences were Group 3's reduction in social introversion vs Groups 1 and 2, and Group 1's retaining fewer drug-using friends and showing greatest reduction in barbiturate use frequency vs Groups 2 and 3. Experimenters concluded urine surveillance was somewhat helpful as an adjunct to outpatient psychotherapy but suggested its effect could be amplified by employing more rigorous surveillance procedures, especially if contingency contracting were utilized.

Cerebellar pressor response in the dog

NASA Technical Reports Server (NTRS)

Dormer, K. J.; Stone, H. L.

1976-01-01

A fastigial pressor response has been elicited in the anesthetized mongrel dog. Stimulation within the rostral portions of this nucleus results in mean arterial pressure rises up to 150 mmHg above control. A proportional tachycardia is simultaneously evoked which may rapidly attain heart rates of 190 beats/min above control levels. Peak tachycardias immediately subside and often the heart rate declines below control values during stimulation while arterial pressure remains elevated. When either the carotid sinuses were isolated by ligation or a bilateral vagotomy was performed, the fastigial tachycardia was sustained. The response could still be attained when submaximal doses of alpha-chloralose anesthesia or high levels of barbiturates (30-40 mg/kg) were given. Both portions of the response result from widespread sympathetic activation; however, buffering of the response through the baroreceptor reflexes is only demonstrated in the cardiac segment of the response.

The Metabolism of the Volatile Amines

PubMed Central

Tobe, Barry A.; Goldman, Bernard S.

1963-01-01

The effects of certain drugs on metabolism of ammonia by the liver and kidneys in dogs were investigated by a technique in which both hepatic inflow and outflow bloods could be repeatedly sampled in unanesthetized healthy animals. Specific representatives of the classes of the drugs studied included thiopental (barbiturates), morphine (opiates and analgesics), promazine (tranquillizers), and chlorothiazide (oral diuretics). The three drugs commonly used as sedatives were all found to impair the ability of the liver to metabolize ammonia. The diuretic, by contrast, increased the amount of ammonia put into the systemic system by the kidneys. Ethanol appeared to have little or no direct effect on ammonia metabolism. The possibility exists that the occurrence of acute hepatic encephalopathy in patients with severe liver disease may be avoided in many cases if these drugs are administered with proper care. Results also indicated that current concepts of the pharmacological action of sedatives, opiates and tranquillizers may require revision. ImagesFig. 2 PMID:14069611

Structural determinants for the inhibitory ligands of orotidine-5′-monophosphate decarboxylase

DOE Office of Scientific and Technical Information (OSTI.GOV)

Meza-Avina, Maria Elena; Wei, Lianhu; Liu, Yan

2010-06-14

In recent years, orotidine-5{prime}-monophosphate decarboxylase (ODCase) has gained renewed attention as a drug target. As a part of continuing efforts to design novel inhibitors of ODCase, we undertook a comprehensive study of potent, structurally diverse ligands of ODCase and analyzed their structural interactions in the active site of ODCase. These ligands comprise of pyrazole or pyrimidine nucleotides including the mononucleotide derivatives of pyrazofurin, barbiturate ribonucleoside, and 5-cyanouridine, as well as, in a computational approach, 1,4-dihydropyridine-based non-nucleoside inhibitors such as nifedipine and nimodipine. All these ligands bind in the active site of ODCase exhibiting distinct interactions paving the way to designmore » novel inhibitors against this interesting enzyme. We propose an empirical model for the ligand structure for rational modifications in new drug design and potentially new lead structures.« less

Part-body and multibody effects on absorption of radio-frequency electromagnetic energy by animals and by models of man

NASA Technical Reports Server (NTRS)

Gandhi, O. P.; Hagmann, M. J.; Dandrea, J. A.

1979-01-01

Fine structure in the whole-body resonant curve for radio-frequency energy deposition in man can be attributed to part-body resonances. As for head resonance, which occurs near 350 MHz in man, the absorptive cross section is nearly three times the physical cross section of the head. The arm has a prominent resonance at 150 MHz. Numerical solutions, antenna theory, and experimental results on animals have shown that whole-body energy deposition may be increased by 50 percent or more because of multiple bodies that are strategically located in the field. Empirical equations for SARs are also presented along with test data for several species of laboratory animals. Barbiturate anesthesia is sufficiently disruptive of thermoregulation that delta Ts of colonic temperature yield energy dose values in several mammals that compare quite favorably with those based on whole-body calorimetry.

Seizure and electroencephalographic changes in the newborn period induced by opiates and corrected by naloxone infusion.

PubMed

da Silva, O; Alexandrou, D; Knoppert, D; Young, G B

1999-03-01

To describe the association between opioid administration in the newborn period and neurologic abnormalities. Case reports of two infants who presented with seizure activity and abnormal electroencephalograms associated with opiate administration, and reversed by naloxone. The first was a preterm infant who developed a burst-suppression pattern on the electroencephalogram while receiving a continuous infusion of morphine and muscle paralysis. Naloxone injection during the electroencephalogram recording reversed the burst-suppression pattern. The second was a term infant receiving fentanyl infusion for pain control following surgery, who presented with motor seizure that was only partially controlled with barbiturates. An abnormal electroencephalogram recording during the opiate infusion improved with naloxone administration. Our observations indicate a potential for neurologic abnormalities, including induction of seizure activity and electroencephalogram abnormalities, suggesting caution when opiates are used for sedation and/or pain control in the newborn period.

Procedure for detecting and confirming pentobarbital residues in dog food by gas chromatography/mass spectrometry.

PubMed

Adam, L A; Reeves, V B

1998-01-01

The method described detects and confirms presence of pentobarbital residues in dry, extruded feeds at concentrations of 5-20 ppb. Dried feed is ground to a uniform powder and shaken overnight in methanol. A portion of the methanolic extract is evaporated, and the residue is reconstituted in phosphate-buffered saline. The aqueous extract is cleaned with a solid-phase extraction cartridge designed to extract barbiturate residues from biological matrixes. Dimethyl sulfoxide, tetramethylammonium hydroxide, and iodomethane are added to derivatize pentobarbital, 1,3-Dimethyl-pentobarbital is then acidified with dilute hydrochloric acid and extracted with isooctane. The organic layer is transferred and evaporated under a stream of nitrogen. The residue is reconstituted in a small volume of ethyl acetate for analysis by gas chromatography/mass spectrometry. The limit of detection is approximately 0.7 ppb. The method was validated with pentobarbital-fortified feed samples containing high concentrations of meat and bone meal.

Ten-minute analysis of drugs and metabolites in saliva by surface-enhanced Raman spectroscopy

NASA Astrophysics Data System (ADS)

Shende, Chetan; Inscore, Frank; Maksymiuk, Paul; Farquharson, Stuart

2005-11-01

Rapid analysis of drugs in emergency room overdose patients is critical to selecting appropriate medical care. Saliva analysis has long been considered an attractive alternative to blood plasma analysis for this application. However, current clinical laboratory analysis methods involve extensive sample extraction followed by gas chromatography and mass spectrometry, and typically require as much as one hour to perform. In an effort to overcome this limitation we have been investigating metal-doped sol-gels to both separate drugs and their metabolites from saliva and generate surface-enhanced Raman spectra. We have incorporated the sol-gel in a disposable lab-on-a-chip format, and generally no more than a drop of sample is required. The detailed molecular vibrational information allows chemical identification, while the increase in Raman scattering by six orders of magnitude or more allows detection of microg/mL concentrations. Measurements of cocaine, its metabolite benzoylecgonine, and several barbiturates are presented.

Psychophysiology of arterial baroreceptors and the etiology of hypertension.

PubMed

Rau, H; Elbert, T

2001-01-01

Arterial baroreceptors are sensitive to blood pressure dependent blood vessel dilation. They play a key role in the short term regulation of blood pressure. Their impact on psychological and psychophysiological aspects is of increasing interest. The review focuses on experimental techniques for the controlled baroreceptor manipulation. Results from the application of these techniques show that baroreceptor activation influences the cardiovascular system as well as central nervous functioning: Behavioral and electrophysiological measures of arousal, low level reflexes and pain responses are modulated through baroreceptor manipulation. The observation of an overall dampening ('barbiturate like') effect of baroreceptor activity led Dworkin et al. formulate the theory of learned hypertension: Subjects might experience blood pressure dependent baroreceptor activation as stress and pain relieving. High blood pressure periods become negatively reinforced. Phasic high blood pressure might develop as a coping strategy. Data from a longitudinal human study supporting this theory are reported.

Vibrational spectra and normal coordinate analysis of diazepam, phenytoin and phenobarbitone

NASA Astrophysics Data System (ADS)

Gunasekaran, S.; Thilak Kumar, R.; Ponnusamy, S.

2006-12-01

Vibrational spectroscopy is an important tool for the structural investigation of the organic molecules. In the present investigation, a normal coordinate analysis has been carried out on some anti-epileptic drugs, viz. diazepam, phenytoin and phenobarbitone. Diazepam is a derivative of benzodiazepine, phenytoin is a derivative of hydanation and pheonobarbitone is a barbiturate. The infrared spectra of the compounds are recorded in the region 4000-400 cm -1 and Raman spectra are recorded in the region 3500-50 cm -1. From the structural point of view, diazepam, phenytoin and phenobarbitone have been assumed to C s point group. A systematic set of symmetry coordinates has been constructed for these compounds and Wilson's FG matrix method has been applied for the normal coordinate analysis using general quadratic valance force field. The potential energy distribution is also calculated to check the vibrational band assignments.

Anaesthesia for Barotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cass, N. M.

An evaluation was made of various anesthetic techniques and agents employed in the newly developed high-pressure oxygen radiotherapeutic method. Results are reported for 334 courses of anesthesia given to patients prior to treatment with megavoltage x rays under high oxygen pressure. Reasons for anesthesia during barotherapy are discussed. The optimal anesthetic technique combines heavy premedication with pentobarbitone. Promethazine (25 mg) is given orally 4 hr before treatment. Two hours before treatment papaveretum and scopolamine are given hypodermically. On arrival in the treatment suite, patients are given pentobarbitone (Nembutal) intravenously. Since light hypnosis with barbiturates increases reflex response to pain, pethidinemore » was given intravenously in doses of 50 to 150 mg. Four % cocaine in adrenaline (1: 100,000 solution) is then applied to the nostrils, and the trachea and larynx sprayed with 4% lignocaine. In 334 anesthetic courses there were no deaths and minimal complications. Epileptiform convulsions occurred during three compressions. (BRB)« less

Phenobarbital and temperature profile during hypothermia for hypoxic-ischemic encephalopathy

PubMed Central

Sant’Anna, Guilherme; Laptook, Abbot R.; Shankaran, Seetha; Bara, Rebecca; McDonald, Scott A.; Higgins, Rosemary D.; Tyson, Jon E.; Ehrenkranz, Richard A.; Das, Abhik; Goldberg, Ronald N.; Walsh, Michele C.

2012-01-01

Data from the whole body hypothermia trial was analyzed to examine the effects of phenobarbital administration prior to cooling (+PB) on the esophageal temperature (Te) profile, during the induction phase of hypothermia. A total of 98 infants were analyzed. At enrollment, +PB infants had a higher rate of severe HIE and clinical seizures and lower Te and cord pH than infants that have not received PB (−PB). There was a significant effect of PB itself and an interaction between PB and time in the Te profile. Mean Te in the +PB group was lower than in the −PB group and the differences decreased over time. In +PB infants the time to surpass target Te of 33.5°C and to reach the minimum Te during overshoot were shorter. In conclusion, the administration of PB prior to cooling was associated with changes that may reflect a reduced thermogenic response associated with barbiturates. PMID:21960671

Neurophysiological model of the normal and abnormal human pupil

NASA Technical Reports Server (NTRS)

Krenz, W.; Robin, M.; Barez, S.; Stark, L.

1985-01-01

Anatomical, experimental, and computer simulation studies were used to determine the structure of the neurophysiological model of the pupil size control system. The computer simulation of this model demonstrates the role played by each of the elements in the neurological pathways influencing the size of the pupil. Simulations of the effect of drugs and common abnormalities in the system help to illustrate the workings of the pathways and processes involved. The simulation program allows the user to select pupil condition (normal or an abnormality), specific site along the neurological pathway (retina, hypothalamus, etc.) drug class input (barbiturate, narcotic, etc.), stimulus/response mode, display mode, stimulus type and input waveform, stimulus or background intensity and frequency, the input and output conditions, and the response at the neuroanatomical site. The model can be used as a teaching aid or as a tool for testing hypotheses regarding the system.

IDENTIFICATION AND MANAGEMENT OF ALCOHOL WITHDRAWAL SYNDROME

PubMed Central

Mirijello, Antonio; D’Angelo, Cristina; Ferrulli, Anna; Vassallo, Gabriele; Antonelli, Mariangela; Caputo, Fabio; Leggio, Lorenzo; Gasbarrini, Antonio; Addolorato, Giovanni

2016-01-01

Symptoms of alcohol withdrawal syndrome may develop within 6–24 hours after the abrupt discontinuation or decrease of alcohol consumption. Symptoms can vary from autonomic hyperactivity and agitation to delirium tremens. The gold-standard treatment for alcohol withdrawal syndrome is represented by benzodiazepines. Among them, different agents (i.e., long-acting or short-acting) and different regimens (front-loading, fixed dose or symptom-triggered) may be chosen on the basis of patient characteristics. Severe withdrawal could require ICU admission and the use of barbiturates or propofol. Other drugs, such as alpha2-agonists (clonidine and dexmetedomidine) and beta-blockers can be used as adjunctive treatments to control neuroautonomic hyperactivity. Furthermore, neuroleptics can help control hallucinations. Finally, other medications for the treatment for alcohol withdrawal syndrome have been investigated with promising results. These include carbamazepine, valproate, sodium oxybate, baclofen, gabapentin, and topiramate. The usefulness of these agents will be discussed in the text. PMID:25666543

Exposure to an environment containing the aromatic red cedar, Juniperus virginiana: procarcinogenic, enzyme-inducing and insecticidal effects.

PubMed

Sabine, J R

1975-11-01

(1) Shavings from the Eastern Red Cedar (Juniperus virginiana) were examined for three diverse biological properties, i.e. enzyme induction, procarcinogenicity and insecticidal activity. (2) The ability of a cedar environment to stimulate liver drug-metabolizing enzymes in mice was confirmed by lowered values for barbiturate sleeping time. (3) In susceptible strains of mice (C3H-Avy, C3H-AvyfB and CBA/J) the use of cedar shavings as bedding increased significantly the incidence of spontaneous tumors of the liver and mammary gland, and also reduced the average time at which tumors appeared. (4) Cedar and some of its derivatives (Oil of Cedarwood, cedrene, cedrol) disrupted the reproductive and developmental cycle of a number of insects, including the Peanut Trash Bug (Elasmolomus sordidus), the Indian Meal Moth (Plodia interpunctella) and the Forage Mite (Tyrophagus putrescentiae).

(/sup 3/H)Batrachotoxinin A 20 alpha-benzoate binding to voltage-sensitive sodium channels: a rapid and quantitative assay for local anesthetic activity in a variety of drugs

DOE Office of Scientific and Technical Information (OSTI.GOV)

McNeal, E.T.; Lewandowski, G.A.; Daly, J.W.

1985-03-01

(/sup 3/H)Batrachotoxinin A benzoate ((/sup 3/H)BTX-B) binds with high affinity to sites on voltage-dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex. In this preparation, local anesthetics competitively antagonize the binding of (/sup 3/H)BTX-B. The potencies of some 40 classical local anesthetics and a variety of catecholamine, histamine, serotonin, adenosine, GABA, glycine, acetylcholine, and calcium antagonists, tranquilizers, antidepressants, barbiturates, anticonvulsants, steroids, vasodilators, antiinflammatories, anticoagulants, analgesics, and other agents have been determined. An excellent correlation with the known local anesthetic activity of many of these agents indicate that antagonism of binding of (/sup 3/H)BTX-B binding provides a rapid,more » quantitative, and facile method for the screening and investigation of local anesthetic activity.« less

The Thermodynamics of General and Local Anesthesia

PubMed Central

Græsbøll, Kaare; Sasse-Middelhoff, Henrike; Heimburg, Thomas

2014-01-01

General anesthetics are known to cause depression of the freezing point of transitions in biomembranes. This is a consequence of ideal mixing of the anesthetic drugs in the membrane fluid phase and exclusion from the solid phase. Such a generic law provides physical justification of the famous Meyer-Overton rule. We show here that general anesthetics, barbiturates, and local anesthetics all display the same effect on melting transitions. Their effect is reversed by hydrostatic pressure. Thus, the thermodynamic behavior of local anesthetics is very similar to that of general anesthetics. We present a detailed thermodynamic analysis of heat capacity profiles of membranes in the presence of anesthetics. Using this analysis, we are able to describe experimentally observed calorimetric profiles and predict the anesthetic features of arbitrary molecules. In addition, we discuss the thermodynamic origin of the cutoff effect of long-chain alcohols and the additivity of the effect of general and local anesthetics. PMID:24853743

Coma blisters in children: case report and review of the literature.

PubMed

Bosco, Laura; Schena, Donatella; Colato, Chiara; Biban, Paolo; Girolomoni, Giampiero

2013-12-01

Coma-induced blisters is a rare condition associated with prolonged impairment of conscious level, which is relatively well-known in adults following overdose with barbiturates. However, it has been very rarely described in children. A case of coma-bullae occurring in an 11-year-old child with meningoencephalitis is herein reported. The bullous lesions occurred on the limbs and trunks, and evolved into necrotic ulcers in a few days. No correlation with any drug overdosage was found. A skin biopsy revealed epidermal and eccrine sweat gland necrosis with abundant neutrophils, and thrombosis of the vessels in the lower dermis. A comprehensive review of the literature showed that only 5 cases of coma-bullae in children have been published so far. Coma blistering resolves spontaneously within days or weeks. Diagnosis of coma-bullae may require careful clinical-pathologic correlation to exclude other blistering diseases in children.

Efficient Synthesis and Antimicrobial Evaluation of Pyrazolopyranopyrimidines in the Presence of SBA-Pr-SO3H as a Nanoporous Acid Catalyst

PubMed Central

Mohammadi Ziarani, Ghodsi; Aleali, Faezeh; Lashgari, Negar; Badiei, Alireza; Abolhasani Soorki, Ali

2018-01-01

A simple, efficient, and environmentally friendly method has been developed for the synthesis of a series of tricyclic fused pyrazolopyranopyrimidines via a one-pot three-component reaction of barbituric acids, aromatic aldehydes, and 3-methyl-5-pyrazolone in the presence of SBA-Pr-SO3H. SBA-15 mesoporous silica material functionalized with propyl sulfonic acid groups was used as a heterogeneous Brønsted acid catalyst with hexagonal structure, high surface area, thick walls, and large uniform pores. All reactions were performed under reflux conditions in water in the presence of a catalytic amount of SBA-Pr-SO3H. High yields, mild reaction conditions, short reaction times, and simple work-up procedures are some advantages of this method. The antimicrobial activities of the synthesized compounds were also evaluated and some products exhibited significant antibacterial activities at low concentrations. PMID:29881410

Drugs of abuse that cause developing neurons to commit suicide.

PubMed

Farber, Nuri B; Olney, John W

2003-12-30

When neuronal activity is abnormally suppressed during the developmental period of synaptogenesis, the timing and sequence of synaptic connections is disrupted, and this causes nerve cells to receive an internal signal to commit suicide, a form of cell death known as "apoptosis". By altering glutamate and GABA transmission alcohol suppresses neuronal activity, causing millions of nerve cells to commit suicide in the developing brain. This proapoptotic effect of alcohol provides a likely explanation for the diminished brain size and lifelong neurobehavioral disturbances associated with the human fetal alcohol syndrome. These findings have public health significance, not only in relation to fetal alcohol syndrome, but also in relation to several other drugs of abuse and various drugs used in obstetric and pediatric medicine, because these additional drugs (e.g. phencyclidine, ketamine, benzodiazepines, barbiturates) also suppress neuronal activity and drive developing neurons to commit suicide.

Saccadic eye movements analysis as a measure of drug effect on central nervous system function.

PubMed

Tedeschi, G; Quattrone, A; Bonavita, V

1986-04-01

Peak velocity (PSV) and duration (SD) of horizontal saccadic eye movements are demonstrably under the control of specific brain stem structures. Experimental and clinical evidence suggest the existence of an immediate premotor system for saccade generation located in the paramedian pontine reticular formation (PPRF). Effects on saccadic eye movements have been studied in normal volunteers with barbiturates, benzodiazepines, amphetamine and ethanol. On two occasions computer analysis of PSV, SD, saccade reaction time (SRT) and saccade accuracy (SA) was carried out in comparison with more traditional methods of assessment of human psychomotor performance like choice reaction time (CRT) and critical flicker fusion threshold (CFFT). The computer system proved to be a highly sensitive and objective method for measuring drug effect on central nervous system (CNS) function. It allows almost continuous sampling of data and appears to be particularly suitable for studying rapidly changing drug effects on the CNS.

The Thermodynamics of General and Local Anesthesia

NASA Astrophysics Data System (ADS)

Græsbøll, Kaare; Sasse-Middelhoff, Henrike; Heimburg, Thomas

2014-05-01

General anesthetics are known to cause depression of the freezing point of transitions in biomembranes. This is a consequence of ideal mixing of the anesthetic drugs in the membrane fluid phase and exclusion from the solid phase. Such a generic law provides physical justification of the famous Meyer-Overton rule. We show here that general anesthetics, barbiturates and local anesthetics all display the same effect on melting transitions. Their effect is reversed by hydrostatic pressure. Thus, the thermodynamic behavior of local anesthetics is very similar to that of general anesthetics. We present a detailed thermodynamic analysis of heat capacity profiles of membranes in the presence of anesthetics. This analysis is able to describe experimentally observed calorimetric profiles and permits prediction of the anesthetic features of arbitrary molecules. In addition, we discuss the thermodynamic origin of the cutoff-effect of long-chain alcohols and the additivity of the effect of general and local anesthetics.

Structural and electronic properties of barbituric acid and melamine-containing ribonucleosides as plausible components of prebiotic RNA: implications for prebiotic self-assembly.

PubMed

Kaur, Sarabjeet; Sharma, Purshotam; Wetmore, Stacey D

2017-11-22

The RNA world hypothesis assumes that RNA was the first informational polymer that originated from prebiotic chemical soup. However, since the reaction of d-ribose with canonical nucleobases (A, C, G and U) fails to yield ribonucleosides (rNs) in substantial amounts, the spontaneous origin of rNs and the subsequent synthesis of RNA remains an unsolved mystery. To this end, it has been suggested that RNA may have evolved from primitive genetic material (preRNA) composed of simpler prebiotic heterocycles that spontaneously form glycosidic bonds with ribose. As an effort toward evaluating this hypothesis, the present study uses density functional theory (DFT) to assess the suitability of barbituric acid (BA) and melamine (MM) to act as prebiotic nucleobases, both of which have recently been shown to spontaneously form a glycosidic bond with ribose and organize into supramolecular assemblies in solution. The significant strength of hydrogen bonds involving BA and MM indicates that such interactions may have played a crucial role in their preferential selection over competing heterocycles that interact solely through stacking interactions from the primordial soup during the early phase of evolution. However, the greater stability of stacked dimers involving BA or MM and the canonical nucleobases compared to those consisting solely of BA and/or MM points towards the possible evolution of intermediate informational polymers consisting of prebiotic and canonical nucleobases, which could have eventually evolved into RNA. Analysis of the associated rNs reveals an anti conformational preference for the biologically-relevant β-anomer of both BA and MM rNs, which will allow complementary WC-like hydrogen bonding that can stabilize preRNA polymers. Large calculated deglycosylation barriers suggest BA rNs containing C-C glycosidic bonds are relevant in challenging prebiotic environments such as volcanic geotherms, while lower barriers indicate the MM rNs containing C-N-C glycosidic linkages may have been more likely synthesized from simple precursors such as urea-ice in icy (polar) regions. Together, our quantum chemical data clarifies the physicochemical interactions and stability of potential prebiotically-relevant constituents of BA and MM polymeric assemblies, and complements information from previous experimental studies to bolster the candidature of these heterocycles as prebiotic nucleobases.

Actions of general anaesthetics on 5-HT3 receptors in N1E-115 neuroblastoma cells.

PubMed Central

Jenkins, A.; Franks, N. P.; Lieb, W. R.

1996-01-01

1. NIE-115 mouse neuroblastoma cells were studied under voltage clamp in the whole-cell patch-clamp configuration. Peak currents induced by bath application of 5-hydroxytryptamine (5-HT) were inwardly rectifying, reversed at 0.4 +/- 0.2 mV (mean +/- s.e.mean), and were approximately half-inhibited (at 1 microM 5-HT) by 2 nM of the 5-HT3 selective antagonist MDL-72222 (3-tropanyl-3,5-dichlorobenzoate). 2. Peak inward currents activated by a low concentration of 5-HT at a holding potential of -50 mV were potentiated by volatile general anaesthetics. At their human minimum alveolar concentrations (MACs), the degree of potentiation increased in the order isoflurane < halothane < enflurane < methoxyflurane. Potentiation by methoxyflurane was independent of membrane potential in the range -70 mV to +40 mV. The reversal potential was the same in the presence and absence of methoxyflurane. 3. Methoxyflurane shifted the 5-HT dose-response curve to lower 5-HT concentrations, without significantly changing the Hill coefficient or maximum response. The EC50 concentration for 5-HT decreased from 1.86 +/- 0.02 microM to 1.07 +/- 0.11 microM (means +/- s.e.mean) due to the presence of 1 MAC (270 microM) methoxyflurane. 4. In contrast to the volatile anaesthetics, the barbiturate anaesthetic, thiopentone, inhibited the 5-HT3 receptor. Hill analysis of thiopentone dose-response data gave an average IC50 = 117 +/- 8 microM thiopentone and Hill coefficient = 1.6 +/- 0.2 (means +/- s.e.mean). These parameters were not significantly different for data obtained at 5-HT concentrations above and below the control EC50 concentration for 5-HT, consistent with non-competitive inhibition. 5. The n-alcohols occupied an intermediate position between the volatile and barbiturate anaesthetics. The lower alcohols (butanol and hexanol) potentiated 5-HT responses at low alcohol concentrations but inhibited them at high concentrations. In contrast, the higher alcohols (octanol, decanol, dodecanol, tridecanol, tetradecanol and pentadecanol) produced no potentiation, but only inhibition, at all alcohol concentrations. 6. Inhibition of the 5-HT3 receptor by the n-alcohols exhibited a cutoff in potency similar to those previously found for tadpoles, luciferase enzymes and a neuronal nicotinic acetylcholine receptor channel. PMID:8730747

The ketogenic diet as broad-spectrum treatment for super-refractory pediatric status epilepticus: challenges in implementation in the pediatric and neonatal intensive care units.

PubMed

Cobo, Nicole H; Sankar, Raman; Murata, Kristina K; Sewak, Sarika L; Kezele, Michele A; Matsumoto, Joyce H

2015-02-01

Refractory status epilepticus carries significant morbidity and mortality. Recent reports have promoted the use of the ketogenic diet as an effective treatment for refractory status epilepticus. We describe our recent experience with instituting the ketogenic diet for 4 critically ill children in refractory status epilepticus, ranging in age from 9 weeks to 13.5 years after failure of traditional treatment. The ketogenic diet allowed these patients to be weaned off continuous infusions of anesthetics without recurrence of status epilepticus, though delayed ketosis and persistently elevated glucose measurements posed special challenges to effective initiation, and none experienced complete seizure cessation. The ease of sustaining myocardial function with fatty acid energy substrates compares favorably over the myocardial toxicity posed by anesthetic doses of barbiturates and contributes to the safety profile of the ketogenic diet. The ketogenic diet can be implemented successfully and safely for the treatment of refractory status epilepticus in pediatric patients. © The Author(s) 2014.

Evaluation of nootropic potential of Ocimum sanctum Linn. in mice.

PubMed

Joshi, Hanumanthachar; Parle, Milind

2006-02-01

Dementia is one of the age related mental problems and a characteristic symptom of various neurodegenerative disorders including Alzheimer's disease. Certain drugs like diazepam, barbiturates and alcohol disrupt learning and memory in animals and man. However, a new class of drugs known as nootropic agents is now used in situations where there is organic disorder in learning abilities. The present work was undertaken to assess the potential of O. sanctum extract as a nootropic and anti-amnesic agent in mice. Aqueous extract of dried whole plant of O. sanctum ameliorated the amnesic effect of scopolamine (0.4 mg/kg), diazepam (1 mg/kg) and aging induced memory deficits in mice. Elevated plus maze and passive avoidance paradigm served as the exteroceptive behavioral models. O. sanctum extract decreased transfer latency and increased step down latency, when compared to control (piracetam treated), scopolamine and aged groups of mice significantly. O. sanctum preparations could of beneficial in the treatment of cognitive disorders such as dementia and Alzheimer's disease.

Shelf Life Prediction for Canned Gudeg using Accelerated Shelf Life Testing (ASLT) Based on Arrhenius Method

NASA Astrophysics Data System (ADS)

Nurhayati, R.; Rahayu NH, E.; Susanto, A.; Khasanah, Y.

2017-04-01

Gudeg is traditional food from Yogyakarta. It is consist of jackfruit, chicken, egg and coconut milk. Gudeg generally have a short shelf life. Canning or commercial sterilization is one way to extend the shelf life of gudeg. This aims of this research is to predict the shelf life of Andrawinaloka canned gudeg with Accelerated Shelf Life Test methods, Arrhenius model. Canned gudeg stored at three different temperature, there are 37, 50 and 60°C for two months. Measuring the number of Thio Barbituric Acid (TBA), as a critical aspect, were tested every 7 days. Arrhenius model approach is done with the equation order 0 and order 1. The analysis showed that the equation of order 0 can be used as an approach to estimating the shelf life of canned gudeg. The storage of Andrawinaloka canned gudeg at 30°C is predicted untill 21 months and 24 months for 25°C.

[Drug consumption and occupational violence in working women of Monterrey, N. L., Mexico].

PubMed

Alonso Castillo, Maria Magdalena; Caufield, Catherine; Gómez Meza, Marco Vinicio

2005-01-01

The purpose of this study was to explore drug consumption and occupational violence in a sample of 669 adult women, working and living in 13 basic geostatistical areas of Monterrey, Nuevo León, México, using a descriptive correlational design with a qualitative approach. Results indicated that 37.1% of women consumed alcohol, 29.1% tobacco, 0.4% marihuana, 0.1% inhalants, and, among medical drugs, 5% consumed tranquilizers, and 1% other substances (barbiturates, antidepressive agents, Tylenol/codeine). The c2 test found no significant difference between sociodemographic and occupational factors and drug consumption (p<.05), except for the work form (c2=18.08, gl=4, p=.001). However, violence rate showed a positive association with drug consumption (p<.05). This study found 126 cases of violence, 34 of which narrated their experience. Drug consumption and violence perception was identified in 2 categories: Conceptualization of Occupational Violence and Relationship between Violence and Drug Consumption.

NEONATAL ABSTINENCE SYNDROME: PHARMACOLOGIC STRATEGIES FOR THE MOTHER AND INFANT

PubMed Central

Kraft, Walter K.; Stover, Megan W.; Davis, Jonathan M.

2015-01-01

Opioid use in pregnancy has increased dramatically over the past decade. Since prenatal opioid use is associated with numerous obstetrical and neonatal complications, this now has become a major public health problem. In particular, in utero opioid exposure can result in neonatal abstinence syndrome (NAS) which is a serious condition characterized by central nervous system hyperirritability and autonomic nervous system dysfunction. The present review seeks to define current practices regarding the approach to the pregnant mother and neonate with prenatal opiate exposure. Although the cornerstone of prenatal management of opioid dependence is opioid maintenance therapy, the ideal agent has yet to be definitively established. Pharmacologic management of NAS is also highly variable and may include an opioid, barbiturate, and/or α-agonist. Genetic factors appear to be associated with the incidence and severity of NAS. Establishing pharmacogenetic risk factors for the development of NAS has the potential for creating opportunities for “personalized genomic medicine” and novel, individualized therapeutic interventions. PMID:26791055

Psychiatric effects of antiepileptic drugs in adults.

PubMed

Dussaule, Claire; Bouilleret, Viviane

2018-06-01

Epileptic and psychiatric diseases share overlaps. Indeed, anxiety and depression are common comorbidities in epilepsy, and patients with psychiatric disease are at risk of epilepsy. Some antiepileptic drugs (AED) have psychiatric side effects; conversely, some AED could be used to treat psychiatric pathologies. Based on current literature data, the aim of this study is to determine the psychiatric effects induced by the most frequently prescribed AED in epileptic adults. Some AED will have positive mood or anxiolytic effects like sodium channel blockers, valproate and benzodiazepines; conversely, others might induce negative psychiatric effect, especially depression, anxiety or aggression, like levetiracetam, perampanel, topiramate, zonisamide, and barbiturates. The main risk factor for presenting these side effects is a personal history of psychiatric pathology. We therefore recommend monitoring the occurrence of psychiatric side effects, especially when using the most at risk AED and/or in case of psychiatric history. Moreover, in this latter case, it is preferable to use AED with positive psychiatric effects. The use of anxiety and depression scales could be useful detection tools.

The treatment of anxiety states by drugs and other means.

PubMed

Linford Rees, W

1979-10-27

The place of pharmacotherapy, behaviour therapy and biofeedback techniques in the general strategy of treating anxiety states is critically discussed. The dangers and disadvantages of barbiturates are described and the value and limitations of other drugs are considered. Beta-adrenergic receptor blocking drugs have a limited but valuable role in some patients, neuroleptics have a strictly limited place in treatment, and the role of antidepressants of various kinds is considered when anxiety is part of a depressive illness. The benzodiazepines are the most important group of drugs available for the treatment of anxiety states. The differences between various benzodiazepines are presented, with particular reference to their onset of action, half-life and the relevance of active metabolites of some of these drugs. A knowledge of the pharmacokinetics of the benzodiazepine drugs is of practical importance to the clinician. Emphasis is placed on the doctor-patient relationship and psychotherpeutic management in which drugs and other treatment serve as tactical aids in the general strategy of care.

Toxic nephropathy after low-dose methoxyflurane anesthesia: drug interaction with secobarbital?

PubMed

Churchill, D; Yacoub, J M; Siu, K P; Symes, A; Gault, M H

1976-02-21

Vasopressin-resistant nonoliguric renal insufficiency developed in a 57-year-old man after 2 1/2 hours of low-dose methoxyflurane anesthesia. Secobarbital, 100 mg daily, had been taken for 1 month before. Of 13 patients in whom the influence of methoxyflurane on renal function was being studied, he was the only one to have taken a drug that induces microsomal enzymes. Blood values of methoxyflurane in this patient were lower than group means on all five occasions during anesthesia. Postoperatively his serum inorganic fluoride value reached 114 mumol/l -- more than two standard deviations greater than the group mean. Peak values for serum urea nitrogen, creatinine and uric acid and postvasopressin urine osmolality, and the lowest creatinine clearance in this patient also differed by more than 2 SD from the group mean, and the peak amount of oxalate excreted in his urine was double the group mean. Pretreatment with the barbiturate appears to have altered methoxyflurane metabolism and led to toxic concentrations of metabolites in the blood.

Toxic nephropathy after low-dose methoxyflurane anesthesia: drug interaction with secobarbital?

PubMed Central

Churchill, D.; Yacoub, J. M.; Siu, K. P.; Symes, A.; Gault, M. H.

1976-01-01

Vasopressin-resistant nonoliguric renal insufficiency developed in a 57-year-old man after 2 1/2 hours of low-dose methoxyflurane anesthesia. Secobarbital, 100 mg daily, had been taken for 1 month before. Of 13 patients in whom the influence of methoxyflurane on renal function was being studied, he was the only one to have taken a drug that induces microsomal enzymes. Blood values of methoxyflurane in this patient were lower than group means on all five occasions during anesthesia. Postoperatively his serum inorganic fluoride value reached 114 mumol/l -- more than two standard deviations greater than the group mean. Peak values for serum urea nitrogen, creatinine and uric acid and postvasopressin urine osmolality, and the lowest creatinine clearance in this patient also differed by more than 2 SD from the group mean, and the peak amount of oxalate excreted in his urine was double the group mean. Pretreatment with the barbiturate appears to have altered methoxyflurane metabolism and led to toxic concentrations of metabolites in the blood. PMID:1253070

Catatonia is not schizophrenia and it is treatable.

PubMed

Appiani, Francisco J; Castro, Gonzalo S

2017-06-10

Catatonia is a cluster of motor features that appears in many recognized psychiatric illnesses, that according to the DSM-5 it is not linked as a subtype to schizophrenia anymore. The classic signs are mutism, a rigid posture, fixed staring, stereotypic movements, and stupor, which are all part of a broad psychopathology that may be found in affective, thought, neurological, toxic, metabolic and immunological disorders. Despite the many etiologies, catatonia may be a life-threatening condition with a specific treatment. Benzodiazepines are the first line therapeutic option for catatonia, being lorazepam the first-choice drug. Eighty percent of the patients are relieved by the use of barbiturates or benzodiazepines, while in those who fail, an improvement is achieved by electroconvulsive therapy (ECT). With more than 60years of use in catatonic patients, ECT has proven to be an effective and safe tool for the treatment of this frequent and sometimes forgotten syndrome. Copyright © 2017 Elsevier B.V. All rights reserved.

Independent predictors of delay in emergence from general anesthesia.

PubMed

Maeda, Shigeru; Tomoyasu, Yumiko; Higuchi, Hitoshi; Ishii-Maruhama, Minako; Egusa, Masahiko; Miyawaki, Takuya

2015-01-01

Some patients with intellectual disabilities spend longer than others in emergence from ambulatory general anesthesia for dental treatment. Although antiepileptic drugs and anesthetics might be involved, an independent predictor for delay of the emergence remains unclear. Thus, a purpose of this study is to identify independent factors affecting the delay of emergence from general anesthesia. This was a retrospective cohort study in dental patients with intellectual disabilities. Patients in need of sedative premedication were removed from participants. The outcome was time until emergence from general anesthesia. Stepwise multivariate regression analysis was used to extract independent factors affecting the outcome. Antiepileptic drugs and anesthetic parameters were included as predictor variables. The study included 102 cases. Clobazam, clonazepam, and phenobarbital were shown to be independent determinants of emergence time. Parameters relating to anesthetics, patients' backgrounds, and dental treatment were not independent factors. Delay in emergence time in ambulatory general anesthesia is likely to be related to the antiepileptic drugs of benzodiazepine or barbiturates in patients with intellectual disability.

Independent Predictors of Delay in Emergence From General Anesthesia

PubMed Central

Maeda, Shigeru; Tomoyasu, Yumiko; Higuchi, Hitoshi; Ishii-Maruhama, Minako; Egusa, Masahiko; Miyawaki, Takuya

2015-01-01

Some patients with intellectual disabilities spend longer than others in emergence from ambulatory general anesthesia for dental treatment. Although antiepileptic drugs and anesthetics might be involved, an independent predictor for delay of the emergence remains unclear. Thus, a purpose of this study is to identify independent factors affecting the delay of emergence from general anesthesia. This was a retrospective cohort study in dental patients with intellectual disabilities. Patients in need of sedative premedication were removed from participants. The outcome was time until emergence from general anesthesia. Stepwise multivariate regression analysis was used to extract independent factors affecting the outcome. Antiepileptic drugs and anesthetic parameters were included as predictor variables. The study included 102 cases. Clobazam, clonazepam, and phenobarbital were shown to be independent determinants of emergence time. Parameters relating to anesthetics, patients' backgrounds, and dental treatment were not independent factors. Delay in emergence time in ambulatory general anesthesia is likely to be related to the antiepileptic drugs of benzodiazepine or barbiturates in patients with intellectual disability. PMID:25849468

Discriminative-stimulus effects of zolpidem, triazolam, pentobarbital, and caffeine in zolpidem-trained humans.

PubMed

Rush, C R; Baker, R W; Rowlett, J K

2000-02-01

Six non-drug-abusing humans were trained to discriminate 15 mg zolpidem in the present experiment. After participants acquired discrimination, a range of doses of zolpidem (2.5-15.0 mg), triazolam (0.0625-0.3750 mg), pentobarbital (25-150 mg), caffeine (100-600 mg), and placebo were tested to determine whether they shared discriminative-stimulus effects with 15 mg zolpidem. The participant-rated and performance-impairing effects of zolpidem, triazolam, pentobarbital, and caffeine were assessed concurrently. Triazolam and pentobarbital dose dependently increased zolpidem-appropriate responding. Caffeine occasioned low levels of zolpidem-appropriate responding. Zolpidem, triazolam, and pentobarbital, but not caffeine, generally produced a similar constellation of participant-rated drug effects (e.g., increased scores for the Pentobarbital, Chlorpromazine, and Alcohol Group subscale on the Addiction Research Center Inventory) and dose dependently impaired performance. These results suggest that humans can reliably discriminate zolpidem. Despite its unique benzodiazepine-receptor binding profile, the discriminative-stimulus, participant-rated, and performance-impairing effects of zolpidem are similar to those of the barbiturates and benzodiazepines.

KETAMINE ABREACTION : A NEW APPROACH TO NARCOANALYSIS

PubMed Central

Golechha, G.R.; Sethi, I.C.; Misra, S.L.; Jayaprakash, N.P.

1986-01-01

SUMMARY Ketamine is a parenterally administered non barbiturate anaesthetic agent, in use for more than a decade. It is a safer than Na Pentothal. Administered intramuscularly, in dose of 6 to 15 mgm/Kg body wt. it produces dissociative anaesthesia. But, in smaller sub anaesthetic doses it may act as an abreactant. We report in this study the abreaction effect of Ketamine in dose of .5 to 1.5 mgm/kg body wt. given intramuscularly in 30 selected psychiatric cases requiring narcoanalysis for diagnostic or therapeutic purpose. The results are compared with another ten cases subjected to pentothal interview and five cases subjected to narcoanalysis with intravenous Na Amytal and methidrine. Our findings suggest that Ketamine has property of an efficacious abreactant in doses of 1 to 1.5 mgm/kg body wt. administered intramuscularly and can successfully be used for narcoanalysis in properly selected cases as a good substitute for intravenous pentothal or sodium amytal with methidrine. The relative cardio respiratory safety and ease of administration are its two added advantages. PMID:21927193

Synthesis and characterization of Cu(II)-based anticancer chemotherapeutic agent targeting topoisomerase Iα: in vitro DNA binding, pBR322 cleavage, molecular docking studies and cytotoxicity against human cancer cell lines.

PubMed

Tabassum, Sartaj; Zaki, Mehvash; Afzal, Mohd; Arjmand, Farukh

2014-03-03

New metal-based anticancer chemotherapeutic drug candidates [Cu(phen)L](NO₃)₂ (1) and [Zn(phen)L](NO₃)₂ (2) were synthesized from ligand L (derived from pharmacophore scaffold barbituric acid and pyrazole). In vitro DNA binding studies of the L, 1 and 2 were carried out by various biophysical techniques revealing electrostatic mode. Complex 1 cleaves pBR322 DNA via oxidative pathway and recognizes major groove of DNA double helix. The molecular docking study was carried out to ascertain the mode of action towards the molecular target DNA and enzymes. The complex 1 exhibited remarkably good anticancer activity on a panel of human cancer cell lines (GI₅₀ values < 10 μg/ml), and to elucidate the mechanism of cancer inhibition, Topo-I enzymatic activity was carried out. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Examination of unmet treatment needs among persons with episodic migraine: results of the American Migraine Prevalence and Prevention (AMPP) Study.

PubMed

Lipton, Richard B; Buse, Dawn C; Serrano, Daniel; Holland, Starr; Reed, Michael L

2013-09-01

Despite the expanding therapeutic armamentarium, many people with episodic migraine (EM) have unmet acute treatment needs. To determine the relative frequency of prespecified types of "unmet treatment needs" in persons with EM in a US population-based sample. Eligible participants completed the 2009 American Migraine Prevalence and Prevention Study survey and met International Classification of Headache Disorders-2nd edition (ICHD-2) criteria for migraine with an average headache day frequency of <15 days per month (EM). We identified 5 domains of unmet treatment needs: (1) dissatisfaction with current acute treatment using 3 summary items from the Patient Perception of Migraine Questionnaire-revised edition (PPMQ-R); (2) moderate or severe headache-related disability defined by a Migraine Disability Assessment Scale score of ≥11; (3) excessive use of opioids or barbiturates defined as use on ≥4 days/month or by meeting Diagnostic and Statistical Manual for Mental Disorders-4th edition criteria for dependence; (4) recurrent use of the emergency department or urgent care clinic for headache defined by ≥2 visits in the preceding year for headache; and (5) history of cardiovascular events indicating a possible contraindication to triptan use. For each respondent, we identified their unmet treatment needs in each category and classified them as having no unmet needs or 1 or more unmet needs. Of 5591 respondents with EM, 2274 (40.7%) had 1 or more unmet needs; 1467 (26.2%) had exactly 1 unmet need, and 807 (14.4%) had 2 or more unmet needs. Among those with at least 1 unmet need, 1069 (47.0%) had moderate or severe headache-related disability, 851 (37.4%) were dissatisfied with their acute treatment regimen, 728 (32.0%) had excessive opioid or barbiturate use and/or probable dependence, 595 (26.2%) had a history of cardiovascular events, and 129 (5.7%) reported ≥2 visits in the preceding year to the emergency department/urgent care clinic for headache. Persons with more headache days, depression, or generalized anxiety were more likely to have unmet treatment needs. In a population sample of individuals with EM, more than 40% have at least 1 unmet need in the area of acute treatment. The leading reasons for unmet needs, which include headache-related disability and dissatisfaction with current acute treatment, suggest opportunities for improving outcomes for persons with EM. © 2013 American Headache Society.

Cortical neurons and networks are dormant but fully responsive during isoelectric brain state.

PubMed

Altwegg-Boussac, Tristan; Schramm, Adrien E; Ballestero, Jimena; Grosselin, Fanny; Chavez, Mario; Lecas, Sarah; Baulac, Michel; Naccache, Lionel; Demeret, Sophie; Navarro, Vincent; Mahon, Séverine; Charpier, Stéphane

2017-09-01

A continuous isoelectric electroencephalogram reflects an interruption of endogenously-generated activity in cortical networks and systematically results in a complete dissolution of conscious processes. This electro-cerebral inactivity occurs during various brain disorders, including hypothermia, drug intoxication, long-lasting anoxia and brain trauma. It can also be induced in a therapeutic context, following the administration of high doses of barbiturate-derived compounds, to interrupt a hyper-refractory status epilepticus. Although altered sensory responses can be occasionally observed on an isoelectric electroencephalogram, the electrical membrane properties and synaptic responses of individual neurons during this cerebral state remain largely unknown. The aim of the present study was to characterize the intracellular correlates of a barbiturate-induced isoelectric electroencephalogram and to analyse the sensory-evoked synaptic responses that can emerge from a brain deprived of spontaneous electrical activity. We first examined the sensory responsiveness from patients suffering from intractable status epilepticus and treated by administration of thiopental. Multimodal sensory responses could be evoked on the flat electroencephalogram, including visually-evoked potentials that were significantly amplified and delayed, with a high trial-to-trial reproducibility compared to awake healthy subjects. Using an analogous pharmacological procedure to induce prolonged electro-cerebral inactivity in the rat, we could describe its cortical and subcortical intracellular counterparts. Neocortical, hippocampal and thalamo-cortical neurons were all silent during the isoelectric state and displayed a flat membrane potential significantly hyperpolarized compared with spontaneously active control states. Nonetheless, all recorded neurons could fire action potentials in response to intracellularly injected depolarizing current pulses and their specific intrinsic electrophysiological features were preserved. Manipulations of the membrane potential and intracellular injection of chloride in neocortical neurons failed to reveal an augmented synaptic inhibition during the isoelectric condition. Consistent with the sensory responses recorded from comatose patients, large and highly reproducible somatosensory-evoked potentials could be generated on the inactive electrocorticogram in rats. Intracellular recordings revealed that the underlying neocortical pyramidal cells responded to sensory stimuli by complex synaptic potentials able to trigger action potentials. As in patients, sensory responses in the isoelectric state were delayed compared to control responses and exhibited an elevated reliability during repeated stimuli. Our findings demonstrate that during prolonged isoelectric brain state neurons and synaptic networks are dormant rather than excessively inhibited, conserving their intrinsic properties and their ability to integrate and propagate environmental stimuli. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

"The soft embalmer of the still midnight": a problem of prescribing hypnotics in general practice.

PubMed Central

1976-01-01

Was it euthanasia or was it even murder? That is the rather dramatic question with which the case history ends. However, none of those taking part in this conference had any doubts that it was neither murder nor euthanasia. But all had doubts as to whether the patient received the best care which the medical and allied professions can command. The barrister declared that in law there would have been no case to answer but the consensus of opinion of the other participants was that as no real diagnosis had been made the treatment was essentially superficial - ensuring sleep for the patient by prescribing barbiturates. The most fundamental criticism of the management of this patient was that individuals looked after her rather than an interdisciplinary team, some member of which might properly have sought to overrule Dorothy (the patient's daughter) when she took her mother away from a nursing home. However, what makes this case conference fascinating is not the facts of the case or the treatment so much as the avenues for moral and social discussion opened for the reader. PMID:966261

Management of refractory status epilepticus in adults

PubMed Central

Rossetti, Andrea O.; Lowenstein, Daniel H.

2011-01-01

Summary Refractory status epilepticus (RSE) can be defined as status epilepticus that continues despite treatment with benzodiazepines and one antiepileptic drug. RSE should be treated promptly to prevent morbidity and mortality; however, scarce evidence is available to support the choice of specific treatments. Major independent outcome predictors are age (not modifiable) and etiology (that should be actively targeted). Recent recommendations for adults, relying upon limited evidence, suggest that RSE treatment aggressiveness should be tailored to the clinical situation: to minimize ICU-related complications, focal RSE without major consciousness impairment might initially be approached more conservatively; conversely, early induction of pharmacological coma is advisable in generalized-convulsive forms. At this stage, midazolam, propofol or barbiturates represent the most used alternatives. Several other treatments, such as additional anesthetics, other antiepileptic or immunomodulatory compounds, or non-pharmacological approaches (electroconvulsive treatment, hypothermia), have been used in protracted RSE. Treatment lasting weeks or months may sometimes result in a good outcome, as in selected cases after cerebral anoxia and encephalitis. Well-designed prospective studies of this condition are urgently needed. PMID:21939901

Postulated deficiency of hepatic heme and repair by hematin infusions in the "inducible" hepatic porphyrias.

PubMed Central

Watson, C J; Pierach, C A; Bossenmaier, I; Cardinal, R

1977-01-01

There is compelling, indirect evidence of hepatic heme deficiency due primarily to the respective genetic errors of the three inducible hepatic porphyrias, acute intermittent porphyria, porphyria variegata, and hereditary coproporphyria. The induction is enhanced by exogenous inducers such as barbiturate, estrogens and other "porphyrogenic" chemicals and factors, including glucose deprivation. The newer knowledge of the induction of delta-aminolevulinic acid synthetase [delta-aminolevulinate synthase; succinyl--CoA:glycine C-succinyltransferase (decarboxylating), EC 2.3.1.37] in relation to inadequate heme, and repression by heme, stimulated early trials of hematin infusions to overcome the acute relapse in the foregoing inducible porphyrias. Recently this experience has been considerably expanded, 143 infusions of hematin having been given in 22 cases. Studies of the effect on the serum concentrations of delta-aminolevulinic acid and porphobilinogen have shown a highly significant decline, often to 0, especially of delta-aminolevulinic acid. A distinct relationship to the clinical severity of the attack has been evident in the frequency and magnitude of decline of serum delta-aminolevulinic acid and porphobilinogen. This was regularly associated with objective clinical improvement. PMID:266732

Drug-induced apnea.

PubMed

Boutroy, M J

1994-01-01

Drugs have been in the past and will in the future still be liable to induce apnea in neonates, infants and older children. At these different stages of development, the child may be abnormally vulnerable to respiratory disorders and apnea, and doses of drugs, without any abnormal side effects in adult patients, can be harmful in younger subjects. Drugs responsible for apnea during development are numerous, but more than half of the problems are induced by sedatives and hypnotics, among which phenothiazines, barbiturates, benzodiazepines (included transplacentally acquired) and general anesthetics are a few. Other pharmacological families are apnea inducers in the neonatal period and childhood: analgesics and opioid narcotics, agents acting at the levels of neuromuscular function and autonomic ganglia, and cardiovascular agents. The pathogenesis of these apneas depends on the disturbance of any mechanism responsible for the respiratory activity: medullary centers and brain stem structures, afferent influx to CNS, sleep stages, upper airways, lungs and respiratory muscles. At key stages such as birth and infancy, drugs may emphasize the particular sensitivity of the mechanisms responsible for inducing apnea. This might explain unexpected respiratory disorders during development.

Trace drug analysis by surface-enhanced Raman spectroscopy

NASA Astrophysics Data System (ADS)

Farquharson, Stuart; Lee, Vincent Y.

2000-12-01

Drug overdose involves more than 10 percent of emergency room (ER) cases, and a method to rapidly identify and quantify the abused drug is critical to the ability of the ER physician to administer the appropriate care. To this end, we have been developing a surface-enhanced Raman (SER) active material capable of detecting target drugs at physiological concentrations in urine. The SER-active material consists of a metal-doped sol-gel that provides not only a million fold increase in sensitivity but also reproducible measurements. The porous silica network offers a unique environment for stabilizing SER active metal particles and the high surface area increase the interaction between the analyte and metal particles. The sol-gel has been coated on the inside walls of glass samples vials, such that urine specimens may simply be introduced for analysis. Here we present the surface-enhanced Raman spectra of a series of barbiturates, actual urine specimens, and a drug 'spiked' urine specimen. The utility of pH adjustment to suppress dominant biochemicals associated with urine is also presented.

Clinically favourable effects of ketamine as an anaesthetic for electroconvulsive therapy: a retrospective study.

PubMed

Kranaster, Laura; Kammerer-Ciernioch, Jutta; Hoyer, Carolin; Sartorius, Alexander

2011-12-01

In a retrospective chart review, we examined the effects of ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, as electroconvulsive therapy (ECT) anaesthetic in patients suffering from therapy-resistant depression. We included 42 patients who received ECT treatment with either ketamine (n = 16) or the barbiturate thiopental (n = 26). We analysed the number of sessions until completion of ECT treatment (used as a surrogate parameter for outcome), psychopathology as assessed by pre- and post-ECT Mini-Mental State Examination (MMSE) and Hamilton Rating Scale for Depression (HAM-D) scores as well as ECT and seizure parameters (stimulation dose, seizure duration and concordance, urapidil dosage for post-seizure blood pressure management). The ketamine group needed significantly fewer ECT sessions and had significantly lower HAM-D and higher MMSE scores afterwards. As expected, the ketamine group needed more urapidil for blood pressure control. Taking into account the limits inherent in a retrospective study design and the rather small sample size, our results nonetheless point towards synergistic effects of ECT and ketamine anaesthesia, less cognitive side effects and good tolerability of ketamine.

A comparison of male users and nonusers of marijuana on the perceived harmfulness of drugs.

PubMed

Primavera, L H; Pascal, R

1986-01-01

Subjects (n = 108) who volunteered to participate in a study in which they expected to smoke marijuana were asked, as part of a screening procedure, to rate the harmfulness of a number of illicit drugs including marijuana. Subjects were separated into three groups according to their reported history of use of marijuana. The three groups were: naive users (at least 1 but no more than 25 incidences of use in a lifetime), light users (1 to 3 incidences of use per week), and heavy users (at least 5 incidences of use per week). Groups did not differ in terms of their perceived harmfulness of any of the drugs. Cluster analyses of the results for each group and for the total group indicated three distinct clusters: the drugs perceived to be the most harmful were heroin, morphine, and LSD; drugs perceived to be less harmful were cocaine, amphetamines, barbiturates, and nicotine; and the drugs perceived to be the least harmful were caffeine and marijuana, with marijuana being judged the least harmful of all the drugs.

Recreational drugs. Societal and professional issues.

PubMed

Solari-Twadell, P A

1991-06-01

Recreational drug use presents a challenge to society and, in particular, the profession of nursing. Recreational drug use must be appreciated for the implications it presents for the episodes of abuse and development of chronic health problems. The effects and recreational use of volatile substances, cannabis, opioids, barbiturates, benzodiazepines, amphetamines, cocaine, psychedelics, and designer drugs as well as alcohol, caffeine, and nicotine must be acknowledged and understood if options for change are to be considered. The resultant cost of recreational drug use as well as health care implications, public safety, and prevention are significant issues society is faced with today. These issues will continue to be significant unless the current posture toward recreational drug use and abuse is addressed. The profession of nursing continues to be faced with the problems associated with recreational drug use not only through caring for clients, but immediately by the effects of recreational drug use on individual professional nurses. To respond effectively, nursing education and nursing research must be challenged to create an emphasis on this focus. Only through this type of multifocal approach will long-term substantial change be affected for the betterment of future generations.

Differential response of orthologous L,L-diaminopimelate aminotransferases (DapL) to enzyme inhibitory antibiotic lead compounds.

PubMed

McKinnie, Shaun M K; Rodriguez-Lopez, Eva M; Vederas, John C; Crowther, Jennifer M; Suzuki, Hironori; Dobson, Renwick C J; Leustek, Thomas; Triassi, Alexander J; Wheatley, Matthew S; Hudson, André O

2014-01-01

L,L-Diaminopimelate aminotransferase (DapL) is an enzyme required for the biosynthesis of meso-diaminopimelate (m-DAP) and L-lysine (Lys) in some bacteria and photosynthetic organisms. m-DAP and Lys are both involved in the synthesis of peptidoglycan (PG) and protein synthesis. DapL is found in specific eubacterial and archaeal lineages, in particular in several groups of pathogenic bacteria such as Leptospira interrogans (LiDapL), the soil/water bacterium Verrucomicrobium spinosum (VsDapL) and the alga Chlamydomonas reinhardtii (CrDapL). Here we present the first comprehensive inhibition study comparing the kinetic activity of DapL orthologs using previously active small molecule inhibitors formerly identified in a screen with the DapL of Arabidopsis thaliana (AtDapL), a flowering plant. Each inhibitor is derived from one of four classes with different central structural moieties: a hydrazide, a rhodanine, a barbiturate, or a thiobarbituate functionality. The results show that all five compounds tested were effective at inhibiting the DapL orthologs. LiDapL and AtDapL showed similar patterns of inhibition across the inhibitor series, whereas the VsDapL and CrDapL inhibition patterns were different from that of LiDapL and AtDapL. CrDapL was found to be insensitive to the hydrazide (IC₅₀ >200 μM). VsDapL was found to be the most sensitive to the barbiturate and thiobarbiturate containing inhibitors (IC₅₀ ∼5 μM). Taken together, the data shows that the homologs have differing sensitivities to the inhibitors with IC₅₀ values ranging from 4.7 to 250 μM. In an attempt to understand the basis for these differences the four enzymes were modeled based on the known structure of AtDapL. Overall, it was found that the enzyme active sites were conserved, although the second shell of residues close to the active site were not. We conclude from this that the altered binding patterns seen in the inhibition studies may be a consequence of the inhibitors forming additional interactions with residues proximal to the active site, or that the inhibitors may not act by binding to the active site. Compounds that are specific for DapL could be potential biocides (antibiotic, herbicide or algaecide) that are nontoxic to animals since animals do not contain the enzymes necessary for PG or Lys synthesis. This study provides important information to expand our current understanding of the structure/activity relationship of DapL and putative inhibitors that are potentially useful for the design and or discovery of novel biocides. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

[POISONING BY PSYCHOPHARMACOLOGICAL DRUGS IN AZERBAIJAN: THE RESULTS OF 8-YEAR PROSPECTIVE OBSERVATION].

PubMed

Afandiyev, I; Azizov, V

2017-11-01

Acute poisoning of chemical etiology is a significant global public health problem. The aim of this study was the analysis of the toxicoepidemiological structure of psychopharmacological drugs poisoning in Azerbaijan. We collected and analyzed the data on all cases of acute poisoning by psychopharmacological drugs (codes of categories T42/T43 ICD-10) undergoing inpatient treatment at the Center of Clinical Toxicology in Baku, Azerbaijan in 2009-2016. The total number of patients with acute intoxication by psychopharmacological drugs was 3,413, which was 48.3% of all cases of poisoning by drugs, medicaments and biological substances (T36-T50). The predominance of women was registered in all age groups. 1114 patients or 32.6% were in 15-24 years old age group. The highest percentage of poisonings at category T42 of ICD-10 were benzodiazepine-type drugs (35.8%), and at category T43 - antipsychotic and neuroleptic drugs (19.2%). In the structure of benzodiazepine poisoning, the first and second ranked places belonged to phenazepam (71.0%) and clonazepam - 16.6%. In addition, another 120 cases (5.5%) of poisonings in the T42 cohort were caused by "Z drugs", which have similar therapeutic effect to benzodiazepines (zolpidem and zopiclone). Among the antipsychotic and neuroleptic poisonings, thioridazine, trifluoperazine, levomepromazine, chlorpromazine, and periciazine accounted for 91% of all cases of intoxication in this cohort. Barbiturates, in view of their toxicity and narrow range of therapeutic dosages, now lost their importance as antiepileptic and hypnotic drugs. Only 4.9% of all cases of poisoning, classified under category T42, was due to the use of barbiturates (mainly phenobarbital). Poisonings with iminostilbenes were presented by carbamazepine poisoning only. Most patients in this cohort received this anticonvulsant drug as prescribed by a doctor. Acute intoxications by tricyclic antidepressants in 91.5% were presented by cases of amitriptyline poisoning. Intoxication by serotonin reuptake inhibitors antidepressants, were relatively rare (3.8% of all cases of poisoning in T43). Among the poisonings with butyrophenone and thioxanthene neuroleptics, the first ranked place was occupied by cases of haloperidol poisoning, which accounted for 82.6% in this cohort. In the group of intoxications with other antipsychotic and neuroleptic drugs, the first ranked place belonged to the poisoning with clozapine - a total of 83 cases or 47.2% in cohort. Poisonings by psychopharmacological drugs occupy the first ranking place among poisoning by drugs, medicaments and biological substances (T36-T50). Increased control over the prescription and sale of psychopharmacological drugs, a reduction the number of tablets in one package, as well as increased attention to vulnerable groups of the population could be help to reduce the percentage of these poisonings in Azerbaijan.

Problem drinking and the dimension of involvement with drugs: a Guttman scalogram analysis of adolescent drug use.

PubMed Central

Donovan, J E; Jessor, R

1983-01-01

Analyses of data from two nationwide surveys of high school students, one carried out in 1974 and the other in 1978, suggest that problem drinking may be seen as yet another step along an underlying dimension of involvement with both licit and illicit drugs. The dimension of involvement with drugs consists of the following levels: nonuse of alcohol or illicit drugs; nonproblem use of alcohol; marijuana use; problem drinking; use of pills (amphetamines, barbiturates, hallucinogenic drugs); and the use of "hard drugs" such as cocaine or heroin. The dimension possesses excellent Guttman-scale properties in both national samples as well as in subsamples differing in gender and ethnic background. The ordering of the levels of involvement was confirmed by the ordering of the alcohol-drug involvement groups based on their mean scores on measures of psychosocial proneness for involvement in problem behavior. The excessive use of a licit drug, i.e., problem drinking, appears to indicate greater involvement in drug use than does the use of an illicit drug, marijuana. This finding points to the importance of distinguishing between use and problem use of drugs in efforts to understand adolescent drug involvement. PMID:6837819

Acute poisoning with emamectin benzoate.

PubMed

Yen, Tzung-Hai; Lin, Ja-Liang

2004-01-01

Emamectin benzoate is the 4'-deoxy-4'-epi-methyl-amino benzoate salt of avermectin B1 (abamectin), which is similar structurally to natural fermentation products of Streptomyces avermitilis. Emamectin benzoate is being developed as a newer broad-spectrum insecticide for vegetables and has a very low application rate. The mechanism of action involves stimulation of high-affinity GABA receptors and a consequent increase in membrane chloride ion permeability. Animal studies indicate a wide margin of safety because mammalian species are much less sensitive due to lower GABA receptor affinities and relative impermeability of the blood-brain barrier. Notably, the literature has not reported human exposure resulting in toxicity. This paper describes a case of acute poisoning with Proclaim insecticide (Syngenta, Taiwan), consisting of 2.15% w/w emamectin benzoate in 2, 6-bis (1, 1-dimethylethyl)-4-methyl-phenol and 1-hexanol. The clinical manifestation was transient gastrointestinal upset with endoscopy-proven gastric erosion and superficial gastritis, mild central nervous system depression, and aspiration pneumonia. No specific antidote exists for emamectin benzoate intoxication; this patient was treated successfully with gastric lavage, administration of activated charcoal, and empiric antibiotics. Drugs that enhance GABA activity such as barbiturates and benzodiazepines were avoided.

[Detection of drugs in meconium].

PubMed

Dahlem, P; Bucher, H U; Ursprung, T; Mieth, D; Gautschi, K

1992-06-01

The number of newborn infants exposed to drugs in utero is on the increase in many European countries. As drug use reported by addicted pregnant women is unreliable there is a need for an accurate test to determine the drugs to which an infant has been exposed in utero. The purpose of this study was to evaluate the reliability of toxicology testing in meconium compared with traditional urine testing. From twenty newborn infants born to drug-dependent mothers, meconium and urine were collected as soon as possible after birth and tested for drugs with the same radioimmunoassay. Five neonates were premature (Gestational weeks less than 37), six were small and three microcephalic for gestational age. Meconium was positive for drugs in 19 infants (95%) (Methadone 9, Morphine 9, Cocaine 6, Cannabis 4). Urine testing revealed the presence of drugs in 13 babies (65%) (Methadone 9, Morphine 6, Cocaine 4, Cannabis 1, Barbiturates 1). Five infants did not have any drug withdrawal, five had mild and ten severe withdrawal symptoms necessitating treatment with chlorpromazine and in four instances additional pethidine. Meconium is not only easier to collect but also at least as reliable as urine for drug detection in neonates.

Spectroscopic and Computational Investigations of Ligand Binding to IspH: Discovery of Non-diphosphate Inhibitors

DOE Office of Scientific and Technical Information (OSTI.GOV)

O'Dowd, Bing; Williams, Sarah; Wang, Hongxin

Isoprenoid biosynthesis is an important area for anti-infective drug development. One isoprenoid target described is (E)-1-hydroxy-2-methyl-but-2-enyl 4-diphosphate (HMBPP) reductase (IspH), which forms isopentenyl diphosphate and dimethylallyl diphosphate from HMBPP in a 2H + /2e - reduction. IspH contains a 4 Fe-4 S cluster, and in this work, we first investigated how small molecules bound to the cluster by using HYSCORE and NRVS spectroscopies. The results of these, as well as other structural and spectroscopic investigations, led to the conclusion that, in most cases, ligands bound to IspH 4 Fe-4 S clusters by η 1 coordination, forming tetrahedral geometries at themore » unique fourth Fe, ligand side chains preventing further ligand (e.g., H 2 O, O 2 ) binding. Based on these ideas, we used in silico methods to find drug-like inhibitors that might occupy the HMBPP substrate binding pocket and bind to Fe, leading to the discovery of a barbituric acid analogue with a K i value of ≈500 nm against Pseudomonas aeruginosa IspH.« less

2-Methylpyridinium/pyridinium 5-(2,4-dinitrophenyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-olates as potent anticonvulsant agents—synthesis and crystal structure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mangaiyarkarasi, G.; Kalaivani, D., E-mail: kalaivbalaj@yahoo.co.in

2013-12-15

The molecular salt, 2-methylpyridinium 5-(2,4-dinitrophenyl)-2,6-dioxo-1,2,3,6-tetrahydropy-rimidin-4-olate) (I), is prepared from the ethanolic solution of 1-chloro-2,4-dinitrobenzene, pyrimidine-2,4,6-(1H,3H,5H)-trione (barbituric acid) and 2-methylpyridine at room temperature, and the molecular salt, pyridinium 5-(2,4-dinitrophenyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-olate (II), is prepared from the same reactants, by dissolving them in hot DMSO and ethanol mixture at 70°C. The structures of I and II are characterized by visible, IR, {sup 1}H-NMR, {sup 13}C-NMR and elemental analysis and confirmed by single crystal X-ray analysis. Both the salts crystallize in triclinic crystal system with sp. gr. P-bar1. They possess noticeable anticonvulsant activity even at low concentration (25 mg/kg). Acute toxicity studies of these complexesmore » indicate that LD{sub 50} values are greater than 1500 mg/kg and the tested animals do not show any behavioural changes.« less

Reduction in radiation-induced brain injury by use of pentobarbital or lidocaine protection

DOE Office of Scientific and Technical Information (OSTI.GOV)

Oldfield, E.H.; Friedman, R.; Kinsella, T.

1990-05-01

To determine if barbiturates would protect brain at high doses of radiation, survival rates in rats that received whole-brain x-irradiation during pentobarbital- or lidocaine-induced anesthesia were compared with those of control animals that received no medication and of animals anesthetized with ketamine. The animals were shielded so that respiratory and digestive tissues would not be damaged by the radiation. Survival rates in rats that received whole-brain irradiation as a single 7500-rad dose under pentobarbital- or lidocaine-induced anesthesia was increased from between from 0% and 20% to between 45% and 69% over the 40 days of observation compared with the othermore » two groups (p less than 0.007). Ketamine anesthesia provided no protection. There were no notable differential effects upon non-neural tissues, suggesting that pentobarbital afforded protection through modulation of ambient neural activity during radiation exposure. Neural suppression during high-dose cranial irradiation protects brain from acute and early delayed radiation injury. Further development and application of this knowledge may reduce the incidence of radiation toxicity of the central nervous system (CNS) and may permit the safe use of otherwise unsafe doses of radiation in patients with CNS neoplasms.« less

Actions of insecticides on the insect GABA receptor complex

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bermudez, I.; Hawkins, C.A.; Taylor, A.M.

1991-01-01

The actions of insecticides on the insect gamma-aminobutyric acid (GABA) receptor were investigated using (35S)t-butylbicyclophosphorothionate (( 35S)TBPS) binding and voltage-clamp techniques. Specific binding of (35S)TBPS to a membrane homogenate derived from the brain of Locusta migratoria locusts is characterised by a Kd value of 79.3 {plus minus} 2.9 nM and a Bmax value of 1770 {plus minus} 40 fmol/mg protein. (35S)TBPS binding is inhibited by mM concentrations of barbiturates and benzodiazepines. In contrast dieldrin, ivermectin, lindane, picrotoxin and TBPS are inhibitors of (35S)TBPS binding at the nanomolar range. Bicuculline, baclofen and pyrethroid insecticides have no effect on (35S)TBPS binding. Thesemore » results are similar to those obtained in electrophysiological studies of the current elicited by GABA in both Locusta and Periplaneta americana central neurones. Noise analysis of the effects of lindane, TBPS, dieldrin and picrotoxin on the cockroach GABA responses reveals that these compounds decrease the variance of the GABA-induced current but have no effect on its mean open time. All these compounds, with the exception of dieldrin, significantly decrease the conductance of GABA-evoked single current.« less

Drugs and personality: comparison of drug users, nonusers, and other clinical groups on the 16PF.

PubMed

Spotts, J V; Shontz, F C

1991-10-01

This article reviews published 16PF research on drug users. It also compares the 16PF scores of a new sample of nonusers with scores of matched groups of heavy, chronic users of cocaine, amphetamine, opiates, and barbiturates/sedative hypnotics, as well as combined groups of stimulant users, depressant users, and a combined group of users of all substances. No significant differences were found among drug user groups, but the profile of the nonuser group was distinctive. K-Means Cluster Analyses, as well as Cattell's Similarity and Pearson Product Moment Correlation Coefficients, were used to compare profiles of these new samples with the 19 groups described in an earlier meta-analysis of published 16PF studies. Data from the new samples did not cluster with data from other published research, although certain specific similarities appeared in more detailed correlational analyses. Methodological problems are discussed, and it is recommended that in future studies drug user groups be more carefully selected and defined, sample descriptions be more thorough and complete, complete profile information be routinely provided, and efforts be made to explore the utility of the Cattell CAQ in studies of drug users/misusers.

Details on suicide among US physicians: data from the National Violent Death Reporting System.

PubMed

Gold, Katherine J; Sen, Ananda; Schwenk, Thomas L

2013-01-01

Physician suicide is an important public health problem as the rate of suicide is higher among physicians than the general population. Unfortunately, few studies have evaluated information about mental health comorbidities and psychosocial stressors which may contribute to physician suicide. We sought to evaluate these factors among physicians versus non-physician suicide victims. We used data from the United States National Violent Death Reporting System to evaluate demographics, mental health variables, recent stressors and suicide methods among physician versus non-physician suicide victims in 17 states. The data set included 31,636 suicide victims of whom 203 were identified as physicians. Multivariable logistic regression found that having a known mental health disorder or a job problem which contributed to the suicide significantly predicted being a physician. Physicians were significantly more likely than non-physicians to have antipsychotics, benzodiazepines and barbiturates present on toxicology testing but not antidepressants. Mental illness is an important comorbidity for physicians who complete a suicide but postmortem toxicology data shows low rates of medication treatment. Inadequate treatment and increased problems related to job stress may be potentially modifiable risk factors to reduce suicidal death among physicians. Copyright © 2013 Elsevier Inc. All rights reserved.

Cyanogenic glycosides in plant-based foods available in New Zealand.

PubMed

Cressey, Peter; Saunders, Darren; Goodman, Janet

2013-01-01

Cyanogenic glycosides occur in a wide range of plant species. The potential toxicity of cyanogenic glycosides arises from enzymatic degradation to produce hydrogen cyanide, which may result in acute cyanide poisoning and has also been implicated in the aetiology of several chronic diseases. One hundred retail foods were sampled and analysed for the presence of total hydrocyanic acid using an acid hydrolysis-isonicotinic/barbituric acid colourimetric method. Food samples included cassava, bamboo shoots, almonds and almond products, pome fruit products, flaxseed/linseed, stone fruit products, lima beans, and various seeds and miscellaneous products, including taro leaves, passion fruit, spinach and canned stuffed vine leaves. The concentrations of total hydrocyanic acid (the hydrocyanic acid equivalents of all cyanogenic compounds) found were consistent with or lower than concentrations reported in the scientific literature. Linseed/flaxseed contained the highest concentrations of total hydrocyanic acid of any of the analysed foods (91-178 mg kg(-1)). Linseed-containing breads were found to contain total hydrocyanic acid at concentrations expected from their linseed content, indicating little impact of processing on the total hydrocyanic acid content. Simulation modelling was used to assess the risk due to the total hydrocyanic acid in fruit juice and linseed-containing bread. 

A hybrid approach to urine drug testing using high-resolution mass spectrometry and select immunoassays.

PubMed

McMillin, Gwendolyn A; Marin, Stephanie J; Johnson-Davis, Kamisha L; Lawlor, Bryan G; Strathmann, Frederick G

2015-02-01

The major objective of this research was to propose a simplified approach for the evaluation of medication adherence in chronic pain management patients, using liquid chromatography time-of-flight (TOF) mass spectrometry, performed in parallel with select homogeneous enzyme immunoassays (HEIAs). We called it a "hybrid" approach to urine drug testing. The hybrid approach was defined based on anticipated positivity rates, availability of commercial reagents for HEIAs, and assay performance, particularly analytical sensitivity and specificity for drug(s) of interest. Subsequent to implementation of the hybrid approach, time to result was compared with that observed with other urine drug testing approaches. Opioids, benzodiazepines, zolpidem, amphetamine-like stimulants, and methylphenidate metabolite were detected by TOF mass spectrometry to maximize specificity and sensitivity of these 37 drug analytes. Barbiturates, cannabinoid metabolite, carisoprodol, cocaine metabolite, ethyl glucuronide, methadone, phencyclidine, propoxyphene, and tramadol were detected by HEIAs that performed adequately and/or for which positivity rates were very low. Time to result was significantly reduced compared with the traditional approach. The hybrid approach to urine drug testing provides a simplified and analytically specific testing process that minimizes the need for secondary confirmation. Copyright© by the American Society for Clinical Pathology.

Sensitivity to ethanol hypnosis and modulation of chloride channels does not cosegregate with pentobarbital sensitivity in HS mice.

PubMed

Allan, A M; Harris, R A

1989-06-01

Several findings suggest that barbiturates and alcohol produce their sedative effects through a common neural and possibly a common genetic mechanism. We tested this hypothesis by examining the correlation between ethanol and pentobarbital sedative effects in individual animals from a genetically heterogeneous population. The duration of pentobarbital-induced hypnosis (sleep-time) was unrelated to the sleep-time produced by ethanol in heterogeneous stock (HS) mice. Therefore, the present study also examined the effect of ethanol, pentobarbital, and flunitrazepam on muscimol-stimulated chloride flux into brain membranes prepared from HS mice selected for differences in pentobarbital- and ethanol-induced sleep-time. Brain membranes from mice selected for differences in ethanol sleep-time were differentially responsive to ethanol- and flunitrazepam-, but not to pentobarbital-induced augmentation of muscimol-stimulated chloride flux. No differences in augmentation of chloride flux by ethanol, pentobarbital, or flunitrazepam were found in membranes prepared from mice differentially sensitive to pentobarbital hypnosis. The ability of muscimol to stimulate chloride uptake was not related to ethanol or pentobarbital sensitivity. These findings suggest that sensitivity to ethanol is not likely to be genetically linked to pentobarbital sensitivity.

Update of Inpatient Treatment for Refractory Chronic Daily Headache.

PubMed

Lai, Tzu-Hsien; Wang, Shuu-Jiun

2016-01-01

Chronic daily headache (CDH) is a group of headache disorders, in which headaches occur daily or near-daily (>15 days per month) and last for more than 3 months. Important CDH subtypes include chronic migraine, chronic tension-type headache, hemicrania continua, and new daily persistent headache. Other headaches with shorter durations (<4 h/day) are usually not included in CDH. Common comorbidities of CDH are medication overuse headache and various psychiatric disorders, such as depression and anxiety. Indications of inpatient treatment for CDH patients include poor responses to outpatient management, need for detoxification for overuse of specific medications (particularly opioids and barbiturates), and severe psychiatric comorbidities. Inpatient treatment usually involves stopping acute pain, preventing future attacks, and detoxifying medication overuse if present. Multidisciplinary integrated care that includes medical staff from different disciplines (e.g., psychiatry, clinical psychology, and physical therapy) has been recommended. The outcomes of inpatient treatment are satisfactory in terms of decreasing headache intensity or frequency, withdrawal from medication overuse, reducing disability, and improving life quality, although long-term relapse is not uncommon. In conclusion, inpatient treatment may be useful for select patients with refractory CDH and should be incorporated in a holistic headache care program.

Legacy of a Chemical Factory Site: Contaminated Groundwater Impacts Stream Macroinvertebrates.

PubMed

Rasmussen, Jes J; McKnight, Ursula S; Sonne, Anne Th; Wiberg-Larsen, Peter; Bjerg, Poul L

2016-02-01

Legislative and managing entities of EU member states face a comprehensive task because the chemical and ecological impacts of contaminated sites on surface waters must be assessed. The ecological assessment is further complicated by the low availability or, in some cases, absence of ecotoxicity data for many of the compounds occurring at contaminated sites. We studied the potential impact of a contaminated site, characterised by chlorinated solvents, sulfonamides, and barbiturates, on benthic macroinvertebrates in a receiving stream. Most of these compounds are characterised by low or unknown ecotoxicity, but they are continuously discharged into the stream by way of a long-lasting source generating long-term chronic exposure of the stream biota. Our results show that taxonomical density and diversity of especially sediment dwelling taxa were reduced by >50 % at the sampling sites situated in the primary inflow zone of the contaminated GW. Moreover, macroinvertebrate communities at these sampling sites could be distinguished from those at upstream control sites and sites situated along a downstream dilution gradient using multidimensional scaling. Importantly, macroinvertebrate indices currently used did not identify this impairment, thus underpinning an urgent need for developing suitable tools for the assessment of ecological effects of contaminated sites in streams.

[Development and application of electroanalytical methods in biomedical fields].

PubMed

Kusu, Fumiyo

2015-01-01

To summarize our electroanalytical research in the biomedical field over the past 43 years, this review describes studies on specular reflection measurement, redox potential determination, amperometric acid sensing, HPLC with electrochemical detection, and potential oscillation across a liquid membrane. The specular reflection method was used for clarifying the adsorption of neurotransmitters and their related drugs onto a gold electrode and the interaction between dental alloys and compound iodine glycerin. A voltammetric screening test using a redox potential for the antioxidative effect of flavonoids was proposed. Amperometric acid sensing based on the measurement of the reduction prepeak current of 2-methyl-1,4-naphthoquinone (VK3) or 3,5-di-tert-buty1-1,2-benzoquinone (DBBQ) was applied to determine acid values of fats and oils, titrable acidity of coffee, and enzyme activity of lipase, free fatty acids (FFAs) in serum, short-chain fatty acids in feces, etc. The electrode reactions of phenothiazines, catechins, and cholesterol were applied to biomedical analysis using HPLC with electrochemical detection. A three-channel electrochemical detection system was utilized for the sensitive determination of redox compounds in Chinese herbal medicines. The behavior of barbituric acid derivatives was examined based on potential oscillation measurements.

Alcohol Withdrawal Syndrome: Benzodiazepines and Beyond

PubMed Central

Sachdeva, Ankur; Chandra, Mina

2015-01-01

Alcohol dependence is an increasing and pervasive problem. Alcohol withdrawal symptoms are a part of alcohol dependence syndrome and are commonly encountered in general hospital settings, in most of the departments. Alcohol withdrawal syndrome ranges from mild to severe. The severe complicated alcohol withdrawal may present with hallucinations, seizures or delirium tremens. Benzodiazepines have the largest and the best evidence base in the treatment of alcohol withdrawal, and are considered the gold standard. Others, such as anticonvulsants, barbiturates, adrenergic drugs, and GABA agonists have been tried and have evidence. Supportive care and use of vitamins is essential in the management. Symptom triggered regime is favoured over fixed tapering dose regime, although monitoring through scales is cumbersome. This article aims to review the evidence base for appropriate clinical management of the alcohol withdrawal syndrome. We searched Pubmed for articles published in English on ‘Alcohol withdrawal syndrome’ in humans during the last 10 years. A total of 1182 articles came up. Articles not relevant to clinical utility and management were excluded based on the titles and abstract available. Full text articles, meta-analyses, systematic reviews and randomized controlled trials were obtained from this list and were considered for review. PMID:26500991

Physiologically based pharmacokinetic modeling of a homologous series of barbiturates in the rat: a sensitivity analysis.

PubMed

Nestorov, I A; Aarons, L J; Rowland, M

1997-08-01

Sensitivity analysis studies the effects of the inherent variability and uncertainty in model parameters on the model outputs and may be a useful tool at all stages of the pharmacokinetic modeling process. The present study examined the sensitivity of a whole-body physiologically based pharmacokinetic (PBPK) model for the distribution kinetics of nine 5-n-alkyl-5-ethyl barbituric acids in arterial blood and 14 tissues (lung, liver, kidney, stomach, pancreas, spleen, gut, muscle, adipose, skin, bone, heart, brain, testes) after i.v. bolus administration to rats. The aims were to obtain new insights into the model used, to rank the model parameters involved according to their impact on the model outputs and to study the changes in the sensitivity induced by the increase in the lipophilicity of the homologues on ascending the series. Two approaches for sensitivity analysis have been implemented. The first, based on the Matrix Perturbation Theory, uses a sensitivity index defined as the normalized sensitivity of the 2-norm of the model compartmental matrix to perturbations in its entries. The second approach uses the traditional definition of the normalized sensitivity function as the relative change in a model state (a tissue concentration) corresponding to a relative change in a model parameter. Autosensitivity has been defined as sensitivity of a state to any of its parameters; cross-sensitivity as the sensitivity of a state to any other states' parameters. Using the two approaches, the sensitivity of representative tissue concentrations (lung, liver, kidney, stomach, gut, adipose, heart, and brain) to the following model parameters: tissue-to-unbound plasma partition coefficients, tissue blood flows, unbound renal and intrinsic hepatic clearance, permeability surface area product of the brain, have been analyzed. Both the tissues and the parameters were ranked according to their sensitivity and impact. The following general conclusions were drawn: (i) the overall sensitivity of the system to all parameters involved is small due to the weak connectivity of the system structure; (ii) the time course of both the auto- and cross-sensitivity functions for all tissues depends on the dynamics of the tissues themselves, e.g., the higher the perfusion of a tissue, the higher are both its cross-sensitivity to other tissues' parameters and the cross-sensitivities of other tissues to its parameters; and (iii) with a few exceptions, there is not a marked influence of the lipophilicity of the homologues on either the pattern or the values of the sensitivity functions. The estimates of the sensitivity and the subsequent tissue and parameter rankings may be extended to other drugs, sharing the same common structure of the whole body PBPK model, and having similar model parameters. Results show also that the computationally simple Matrix Perturbation Analysis should be used only when an initial idea about the sensitivity of a system is required. If comprehensive information regarding the sensitivity is needed, the numerically expensive Direct Sensitivity Analysis should be used.

Rationally Designed Peptidomimetic Modulators of Aβ Toxicity in Alzheimer's Disease

NASA Astrophysics Data System (ADS)

Rajasekhar, K.; Suresh, S. N.; Manjithaya, Ravi; Govindaraju, T.

2015-01-01

Alzheimer's disease is one of the devastating illnesses mankind is facing in the 21st century. The main pathogenic event in Alzheimer's disease is believed to be the aggregation of the β-amyloid (Aβ) peptides into toxic aggregates. Molecules that interfere with this process may act as therapeutic agents for the treatment of the disease. Use of recognition unit based peptidomimetics as inhibitors are a promising approach, as they exhibit greater protease stability compared to natural peptides. Here, we present peptidomimetic inhibitors of Aβ aggregation designed based on the KLVFF (P1) sequence that is known to bind Aβ aggregates. We improved inhibition efficiency of P1 by introducing multiple hydrogen bond donor-acceptor moieties (thymine/barbiturate) at the N-terminal (P2 and P3), and blood serum stability by modifying the backbone by incorporating sarcosine (N-methylglycine) units at alternate positions (P4 and P5). The peptidomimetics showed moderate to good activity in both inhibition and dissolution of Aβ aggregates as depicted by thioflavin assay, circular dichroism (CD) measurements and microscopy (TEM). The activity of P4 and P5 were studied in a yeast cell model showing Aβ toxicity. P4 and P5 could rescue yeast cells from Aβ toxicity and Aβ aggregates were cleared by the process of autophagy.

In Silico Discovery of Novel Potent Antioxidants on the Basis of Pulvinic Acid and Coumarine Derivatives and Their Experimental Evaluation

PubMed Central

Martinčič, Rok; Mravljak, Janez; Švajger, Urban; Perdih, Andrej; Anderluh, Marko; Novič, Marjana

2015-01-01

A pigment from the edible mushroom Xerocomus badius norbadione A, which is a natural derivative of pulvinic acid, was found to possess antioxidant properties. Since the pulvinic acid represents a novel antioxidant scaffold, several other derivatives were recently synthetized and evaluated experimentally, along with some structurally related coumarine derivatives. The obtained data formed the basis for the construction of several quantitative structure-activity and pharmacophore models, which were employed in the virtual screening experiments of compound libraries and for the prediction of their antioxidant activity, with the goal of discovering novel compounds possessing antioxidant properties. A final prioritization list of 21 novel compounds alongside 8 established antioxidant compounds was created for their experimental evaluation, consisting of the DPPH assay, 2-deoxyribose assay, β-carotene bleaching assay and the cellular antioxidant activity assay. Ten novel compounds from the tetronic acid and barbituric acid chemical classes displayed promising antioxidant activity in at least one of the used assays, that is comparable to or even better than some standard antioxidants. Compounds 5, 7 and 9 displayed good activity in all the assays, and were furthermore effective preventers of oxidative stress in human peripheral blood mononuclear cells, which are promising features for the potential therapeutic use of such compounds. PMID:26474393

Non-health care facility anticonvulsant medication errors in the United States.

PubMed

DeDonato, Emily A; Spiller, Henry A; Casavant, Marcel J; Chounthirath, Thitphalak; Hodges, Nichole L; Smith, Gary A

2018-06-01

This study provides an epidemiological description of non-health care facility medication errors involving anticonvulsant drugs. A retrospective analysis of National Poison Data System data was conducted on non-health care facility medication errors involving anticonvulsant drugs reported to US Poison Control Centers from 2000 through 2012. During the study period, 108,446 non-health care facility medication errors involving anticonvulsant pharmaceuticals were reported to US Poison Control Centers, averaging 8342 exposures annually. The annual frequency and rate of errors increased significantly over the study period, by 96.6 and 76.7%, respectively. The rate of exposures resulting in health care facility use increased by 83.3% and the rate of exposures resulting in serious medical outcomes increased by 62.3%. In 2012, newer anticonvulsants, including felbamate, gabapentin, lamotrigine, levetiracetam, other anticonvulsants (excluding barbiturates), other types of gamma aminobutyric acid, oxcarbazepine, topiramate, and zonisamide, accounted for 67.1% of all exposures. The rate of non-health care facility anticonvulsant medication errors reported to Poison Control Centers increased during 2000-2012, resulting in more frequent health care facility use and serious medical outcomes. Newer anticonvulsants, although often considered safer and more easily tolerated, were responsible for much of this trend and should still be administered with caution.

Some endocrinological aspects of barbiturate dependence.

PubMed

Norton, P R

1971-02-01

1. Hypophysectomized rats become dependent on barbitone and show the same withdrawal syndrome as intact animals.2. Barbitone dependent rats have larger thyroid and adrenal glands, a larger liver, smaller gonads and larger secondary sex organs than untreated animals. The levator ani muscle of the males is smaller.3. In contrast, dependent female hypophysectomized rats only showed a decreased gonad weight and increased liver weight.4. Histologically, the thyroid gland of dependent rats appears more active, but the concentration of iodine bound to plasma protein, basal metabolic rate and body temperature are similar in dependent and untreated animals.5. Resting plasma corticosterone concentration appears to be unchanged in barbitone dependent animals, but stress induced increases in the concentration of corticosterone in plasma are less in dependent animals.6. Immature barbitone dependent rats grow at a faster rate than untreated animals, but hypophysectomized rats of similar age receiving barbitone do not.7. The additional body weight gained by barbitone dependent animals is of normal body composition.8. Administration of growth hormone has an identical growth inducing effect in dependent hypophysectomized animals and in untreated hypophysectomized animals.9. Barbitone dependent rats do not exhibit the ;frustration effect' in a double runway. In barbitone dependent rats approach to a potentially ;frustrating' situation is slower than in untreated animals.

Design of inhibitors of orotidine monophosphate decarboxylase using bioisosteric replacement and determination of inhibition kinetics.

PubMed

Poduch, Ewa; Bello, Angelica M; Tang, Sishi; Fujihashi, Masahiro; Pai, Emil F; Kotra, Lakshmi P

2006-08-10

Inhibitors of orotidine monophosphate decarboxylase (ODCase) have applications in RNA viral, parasitic, and other infectious diseases. ODCase catalyzes the decarboxylation of orotidine monophosphate (OMP), producing uridine monophosphate (UMP). Novel inhibitors 6-amino-UMP and 6-cyano-UMP were designed on the basis of the substructure volumes in the substrate OMP and in an inhibitor of ODCase, barbituric acid monophosphate, BMP. A new enzyme assay method using isothermal titration calorimetry (ITC) was developed to investigate the inhibition kinetics of ODCase. The reaction rates were measured by monitoring the heat generated during the decarboxylation reaction of orotidine monophosphate. Kinetic parameters (k(cat) = 21 s(-1) and KM = 5 microM) and the molar enthalpy (DeltaH(app) = 5 kcal/mol) were determined for the decarboxylation of the substrate by ODCase. Competitive inhibition of the enzyme was observed and the inhibition constants (Ki) were determined to be 12.4 microM and 29 microM for 6-aza-UMP and 6-cyano-UMP, respectively. 6-Amino-UMP was found to be among the potent inhibitors of ODCase, having an inhibition constant of 840 nM. We reveal here the first inhibitors of ODCase designed by the principles of bioisosterism and a novel method of using isothermal calorimetry for enzyme inhibition studies.

Pathophysiology of medication overuse headache: Insights and hypotheses from preclinical studies

PubMed Central

Meng, Ian D; Dodick, David; Ossipov, Michael H; Porreca, Frank

2017-01-01

Introduction Medication overuse headache (MOH) is a clinical concern in the management of migraine headache. MOH arises from the frequent use of medications used for the treatment of a primary headache. Medications that can cause MOH include opioid analgesics as well as formulations designed for the treatment of migraine, such as triptans, ergot alkaloids, or drug combinations that include caffeine and barbiturates. Literature review Gathering evidence indicates that migraine patients are more susceptible to development of MOH, and that prolonged use of these medications increases the prognosis for development of chronic migraine, leading to the suggestion that similar underlying mechanisms may drive both migraine headache and MOH. In this review, we examine the link between several mechanisms that have been linked to migraine headache and a potential role in MOH. For example, cortical spreading depression (CSD), associated with migraine development, is increased in frequency with prolonged use of topiramate or paracetamol. Conclusions Increased CGRP levels in the blood have been linked to migraine and elevated CGRP can be casued by prolonged sumatriptan exposure. Possible mechanisms that may be common to both migraine and MOH include increased endogenous facilitation of pain and/or diminished diminished endogenous pain inhibition. Neuroanatomical pathways mediating these effects are examined. PMID:21444643

Gelation-driven selection in dynamic covalent C 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 C/CN exchange.

PubMed

Liang, Chunshuang; Kulchat, Sirinan; Jiang, Shimei; Lehn, Jean-Marie

2017-10-01

Knoevenagel barbiturate derivatives bearing long alkyl chains were proven to form organogels in suitable solvents based on supramolecular interactions. Their reaction with imines allows for component exchange through CC/CN recombination. The effect of various parameters (solvents, chain length, and temperature) on the CC/CN exchange reaction has been studied. Mixing Knoevenagel compound K and imine I-16 in a 1 : 1 ratio generated a constitutional dynamic library containing the four constituents K , I-16 , K'-16 , and I' . The reversible exchange reaction was monitored by 1 H-NMR, showing marked changes in the fractions of the four constituents on sol-gel interconversion as a function of temperature. The library composition changed from statistical distribution of the four constituents in the sol state to selective amplification of the gel forming K'-16 constituent together with that of its agonist I' . The process amounts to self-organization driven component selection in a constitutional dynamic organogel system undergoing gelation. This process displays up-regulation of the gel-forming constituent by component redistribution through reversible covalent connections.

Imprinting of cerebral cytochrome P450s in offsprings prenatally exposed to cypermethrin augments toxicity on rechallenge

NASA Astrophysics Data System (ADS)

Singh, Anshuman; Agrahari, Anita; Singh, Radhadutt; Yadav, Sanjay; Srivastava, Vikas; Parmar, Devendra

2016-11-01

Epigenetic studies were carried in the rat offsprings, born to dams treated with cypermethrin (orally; 5.0 mg/kg) from gestation day (GD) 5 to 21 and rechallenged with cypermethrin (orally; 10 mg/kg for 6 days), at adulthood (12 weeks) to understand the mechanism underlying the overexpression of cerebral cytochrome P450s (CYPs) in exposed offsprings. The data revealed alterations in histone H3 acetylation and DNA methylation in promoter regions of CYP1A- and 2B- isoenzymes in the brain isolated from rechallenged animals. Further, bisulphite sequencing revealed critical CpG methylation changes in BARBIE BOX (Barbiturate response element) and BTE (Basal transcription element) in promoter of CYP2B1 in the brain isolated from rechallenged animals. Western blotting and DNA laddering/fragmentation studies revealed a greater magnitude of increase in the signalling pathways associated with apoptosis in the rechallenged animals. The data have indicated that overexpression of cerebral CYPs could be due to the imprinting of CYPs. Further, increased apoptosis observed in the rechallenged offsprings has suggested that these epigenetic changes in CYPs may predispose the prenatally exposed offsprings to the neurotoxic effects of other centrally acting drugs and chemicals when subsequently rechallenged later at life.

Pharmacology of midazolam.

PubMed

Pieri, L; Schaffner, R; Scherschlicht, R; Polc, P; Sepinwall, J; Davidson, A; Möhler, H; Cumin, R; Da Prada, M; Burkard, W P; Keller, H H; Müller, R K; Gerold, M; Pieri, M; Cook, L; Haefely, W

1981-01-01

8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (midazolam, Ro 21-3981, Dormicum) is an imidazobenzodiazepine whose salts are soluble and stable in aqueous solution. It has a quick onset and, due to rapid metabolic inactivation, a rather short duration of action in all species studied. Midazolam has a similar pharmacologic potency and broad therapeutic range as diazepam. It produces all the characteristic effects of the benzodiazepine class, i.e., anticonvulsant, anxiolytic, sleep-inducing, muscle relaxant, and "sedative" effects. The magnitude of the anticonflict effect of midazolam is smaller than that of diazepam in rats and squirrel monkeys, probably because a more pronounced sedative component interferes with the increase of punished responses. In rodents, surgical anaesthesia is not attained with midazolam alone even in high i.v. doses, whereas this state is obtained in monkeys. The drug potentiates the effect of various central depressant agents. Midazolam is virtually free of effects on the cardiovascular system in conscious animals and produces only slight decreases in cardiac performance in dogs anaesthetized with barbiturates. No direct effects of the drugs on autonomic functions were found, however, stress-induced autonomic disturbances are prevented, probably by an effect on central regulatory systems. All animal data suggest the usefulness of midazolam as a sleep-inducer and i.v. anaesthetic of rapid onset and short duration.

Spontaneous abortion and the prophylactic effect of folic acid supplementation in epileptic women undergoing antiepileptic therapy.

PubMed

Pittschieler, Sabine; Brezinka, Christoph; Jahn, Beate; Trinka, Eugen; Unterberger, Iris; Dobesberger, Judith; Walser, Gerald; Auckenthaler, Andrea; Embacher, Norbert; Bauer, Gerhard; Luef, Gerhard

2008-12-01

Antiepileptic drugs (AEDs) like phenytoin (PHE), carbamazepine (CBZ), barbiturates and valproic acid (VPA) interfere with folic acid absorption and metabolism, which in turn can be the cause of adverse pregnancy outcome. To study the prophylactic effect of folic acid supplementation with regard to spontaneous abortion and preterm delivery (fetal demise after week 20 of gestational age) in pregnant women receiving AED therapy, as well as benefits of most common dosage and preconceptional commencement. Prospective examination of 104 patients, registered in EURAP from 1999-2004 at a single center and a retrospective analysis of data from our epilepsy databank completed with medical records and patients interviews of the Department of Neurology of Innsbruck University Hospital from 1971 to 1999. 388 pregnancies in 244 patients were analyzed. Pregnancies with folic acid supplementation showed significant reduction of spontaneous abortion. With regard to monotherapies, in the group of women taking VPA, supplementation of folic acid had significant benefit. Other examined monotherapies (CBZ, PHE, and PB) known to interfere with folic acid showed no significant results. This study confirms the prophylactic effect of folic acid supplementation on spontaneous abortion. For AED therapy, folic acid supplementation should be part of the therapy of every pregnant epileptic woman, especially for those treated with VPA.

Predicting changes in drug use and treatment entry for local programs: a case study.

PubMed

Flaherty, E W; Olsen, K; Bencivengo, M

1980-01-01

Recent sharp decline in treatment admissions by opiate abusers stimulated the conduct of a study designed to provide timely data to treatment system administrators for the next cycle of program and budgetary planning. The process of designing the study involved definition of required study characteristics, review of four categories of drug abuse research, and generation of seven locally relevant hypotheses. Interviews were conducted with 335 heroin adicts: 196 new admissions to treatment and 139 "street" addicts not currently in treatment. Major findings were a marked reduction in the quality, availability, and price of heroin; very negative perceptions of methadone maintenance, especially by female respondents; decline in heroin popularity and increase in reported use of alcohol, amphetamines, and barbiturates; and differing perceptions of treatment by sex of respondent. Response patterns suggest that users who are not entering treatment are less "strung-out than those entering treatment because of decline in availability and quality of heroin and consequent increased mixing of drugs. The emphasis in the report is on the conduct of a study which can be timely, feasible, and useful to local planners. The study weaknesses and recommended remedies are discussed, as well as the characteristics which made the findings immediately useful to administrators and planners.

Selective inhibition of osmotic water flow by general anesthetics to toad urinary bladder.

PubMed Central

Levine, S D; Levine, R D; Worthington, R E; Hays, R M

1976-01-01

Vasopressin increases the permeability of the total urinary bladder, an analogue of the mammalian renal collecting duct, to water and small solutes, especially the amide urea. We have observed that three general anesthetic agents of clinical importance, the gases methoxyflurane and halothane and the ultrashortacting barbiturate methohexital, reversibly inhibit vasopressin-stimulated water flow, but do not depress permeability to urea, or the the lipophilic solute diphenylhydantoin. In contrast to their effects in vasopressin-treated bladders, the anesthetics do not inhibit cyclic AMP-stimulated water flow, consistent with an effect on vasopressin-responsive adenylate cyclase. The selectivity of the anesthetic-induced depression of water flow suggests that separate adenylate cyclases and cyclic AMP pools may exist for control of water and urea permeabilities in to toad bladder. Furthermore, theophylline's usual stimulatory effect on water flow, but not its effect on urea permeability, was entirely abolished in methoxyflurane-treated bladders, suggesting that separate phosphodiesterases that control water and urea permeabilities are present as well. We conclude that the majority of water and urea transport takes place via separate pathways across the rate-limiting luminal membrane of the bladder cell, and that separate vasopressin-responsive cellular pools of cyclic AMP appear to control permeability to water and to urea. PMID:184113

Citrate-capped superparamagnetic iron oxide (Fe3O4-CA) nanocatalyst for synthesis of pyrimidine derivative compound as antioxidative agent

NASA Astrophysics Data System (ADS)

Cahyana, A. H.; Pratiwi, D.; Ardiansah, B.

2017-04-01

The development of a recyclable catalyst based on magnetic nanoparticles has attracted an increasing interest as the emerging application in the heterogeneous catalyst field. Superparamagnetic iron oxide nanoparticle with citric acid as capping agent was successfully obtained from iron (III) chloride solution via two steps synthesis. The first step involving the formation of magnetite nanoparticle by bioreduction using Sargassum Sp, then its surface was modified by adding citric acid solution in the second step. The structural, surface morphology and magnetic properties of the nanocatalyst were investigated by various instrumentations such as scanning electron microscope with energy dispersive (SEM-EDS), and particle size analyser (PSA). Fe3O4-CA was then applied as reusable catalyst for Knoevenagel condensation of barbituric acid and cinnamaldehyde to produce (E)-5-(3-phenylallylidene)pyrimidine-2,4,6(1H,3H,5H)-trione. The optimum condition of this reaction was achieved by using 7.5% mole of catalyst at 50°C for 6 h to give 83% yield. Some spectroscopy techniques such as UV-Vis, FTIR, LC-MS and 1H-NMR were used to confirm the product’s structure. Furthermore, the synthesized compound has an attractive antioxidant activity based on the in-vitro analysis using DPPH method.

PREVENTION OF SUICIDE

PubMed Central

Bennett, A. E.

1954-01-01

Suicide is the ninth major cause of death in the nation. California, according to the latest comprehensive figures (1949), ranks about 50 per cent above the national average. Yet the importance of suicide as a cause of death is gravely underestimated. At hospitals and other agencies only emergency treatment is given before discharge of persons who attempt suicide, although it is known that many will repeat the attempt. Rarely is psychiatric evaluation carried out or definitive treatment prescribed. Suicidal symptoms are often ignored in other cases. Physicians have a responsibility, as in any disorder, to recognize signs and symptoms of impending suicide and to use all means of prevention. Prevention could be forwarded by the education of physicians and laymen in detecting early signs of depression, in recognizing accident proneness, and in insisting upon legal control of use of barbiturates, a common means of suicide. Lay associations should encourage individuals with suicidal impulses to go to psychiatric clinics for help. Police should learn how to deal with suicidal attempts, and hospitals should include psychiatric examination and advice as to treatment of all such persons. Suicidal attempts should be registered and reported to public health officers in the same way as are other dangerous diseases. More research should be done on case records of these patients, in order to better understand motivations and means of prevention. PMID:13209373

Vestibular afferent responses to linear accelerations in the alert squirrel monkey

NASA Technical Reports Server (NTRS)

Somps, Christopher J.; Schor, Robert H.; Tomko, David L.

1994-01-01

The spontaneous activity of 40 otolith afferents and 44 canal afferents was recorded in 4 alert, intact squirrel monkeys. Polarization vectors and response properties of otolith afferents were determined during static re-orientations relative to gravity and during Earth-horizontal, sinusoidal, linear oscillations. Canal afferents were tested for sensitivity to linear accelerations. For regular otolith afferents, a significant correlation between upright discharge rate and sensitivity to dynamic acceleration in the horizontal plane was observed. This correlation was not present in irregular units. The sensitivity of otolith afferents to both static tilts and dynamic linear acceleration was much greater in irregularly discharging units than in regularly discharging units. The spontaneous activity and static and dynamic response properties of regularly discharging otolith afferents were similar to those reported in barbiturate-anesthetized squirrel monkeys. Irregular afferents also had similar dynamic response properties when compared to anesthetized monkeys. However, this sample of irregular afferents in alert animals had higher resting discharge rates and greater sensitivity to static tilts. The majority of otolith polarization vectors were oriented near the horizontal in the plane of the utricular maculae; however, directions of maximum sensitivity were different during dynamic and static testing. Canal afferents were not sensitive to static tilts or linear oscillations of the head.

Ethics roundtable: 'Open-ended ICU care: can we afford it?'.

PubMed

Crippen, David; Burrows, Dick; Stocchetti, Nino; Mayer, Stephan A; Andrews, Peter; Bleck, Tom; Whetstine, Leslie

2010-01-01

The patient is a 27-year-old previously healthy male with a diagnosis of viral encephalitis with a lymphocytic pleocytosis on cerebrospinal fluid examination. For 3 months, he has been in status epilepticus (SE) on high doses of barbiturates, benzodiazepines, and ketamine and a ketogenic feeding-tube formula. He remains in burst suppression on continuous electroencephalography (EEG). He is trached and has a percutaneous endoscopic gastrostomy (PEG) feeding tube. He has been treated several times for pneumonia, and he is on a warming blanket and is on vasopressors to maintain his blood pressure. His vitals are stable and his lab work is within limits. The sedation is decreased under EEG guidance every 72 hours, after which he goes back into SE and heavy sedation is resumed. The latest magnetic resonance imaging (MRI) shows edema but otherwise no obvious permanent cortical damage. The family wants a realistic assessment of the likely outcome. The neurologist tells them the literature suggests the outlook is poor but not 100% fatal. As long as all of his other organs are functioning on life support, there is always a chance the seizures will stop at some time in the future, and so the neurologist recommends an open-ended intensive care unit (ICU) plan and hopes for that outcome.

Epidemiology of psychoactive drug use amongst adolescents in metropolitan Lagos, Nigeria.

PubMed

Famuyiwa, Oluwole; Aina, Olatunji F; Bankole-Oki, Olufunlayo M

2011-07-01

The study was conducted in response to the lack of epidemiological data in recent time on the use of psychoactive substances by adolescents in metropolitan Lagos-a city unique for its socio-economic profile. We considered some methodological issues omitted in several previous studies. A total of 4,286 school pupils (mean age 15.2) were anonymously administered a Self-Report Questionnaire to ascertain a range of key drug use factors in lifetime and 1-year periods. The rate of use of most of the 14 substances investigated was much higher than reported in any other study on comparable population sample. We found that 61.8 and 32.1% of respondents have used one or more substances in their lifetime and in the past 1 year, respectively. High lifetime rates of use were found for common stimulants: coffee, kolanut, and prescription drugs (barbiturates and minor tranquilisers). The rate of use of proscribed addictive substances, cannabis, heroin, and cocaine, ranged between 4.0 and 4.8%. Missing data and non-response rates were few; however, social acquiescence, under and over reporting, could be mitigant to estimation of rates and patterns of use. We advocate properly articulated school-based educative programmes that can facilitate drug demand reduction.

Identifying and assessing the substance-exposed infant.

PubMed

Clark, Lisa; Rohan, Annie

2015-01-01

As the rate of opioid prescription grows, so does fetal exposure to opioids during pregnancy. With increasing fetal exposure to both prescription and nonprescription drugs, there has been a concurrent increase in identification of Neonatal Withdrawal Syndrome (NWS) and adaptation difficulties after birth. In addition, extended use of opioids, barbiturates, and benzodiazepines in neonatal intensive care has resulted in iatrogenic withdrawal syndromes. There is a lack of evidence to support the use of any one specific evaluation strategy to identify NWS. Clinicians caring for infants must use a multimethod approach to diagnosis, including interview and toxicology screening. Signs of NWS are widely variable, and reflect dysfunction in autonomic regulation, state control, and sensory and motor functioning. Several assessment tools have been developed for assessing severity of withdrawal in term neonates. These tools assist in determining need and duration of pharmacologic therapy and help in titration of these therapies. Considerable variability exists in the pharmacologic and nonpharmacologic approaches to affected babies across settings. An evidence-based protocol for identification, evaluation, and management of NWS should be in place in every nursery. This article provides an overview of identification and assessment considerations for providers who care for babies at risk for or who are experiencing alterations in state, behavior, and responses after prenatal or iatrogenic exposure to agents associated with the spectrum of withdrawal.

Physiologic, Behavioral, and Histologic Responses to Various Euthanasia Methods in C57BL/6NTac Male Mice.

PubMed

Boivin, Gregory P; Bottomley, Michael A; Schiml, Patricia A; Goss, Lori; Grobe, Nadja

2017-01-01

Rodent euthanasia using exposure to increasing concentrations of CO2 has come under scrutiny due to concerns of potential pain during the euthanasia process. Alternatives to CO2, such as isoflurane and barbiturates, have been proposed as more humane methods of euthanasia. In this study, we examined 3 commonly used euthanasia methods in mice: intraperitoneal injection of pentobarbital-phenytoin solution, CO2 inhalation, and isoflurane anesthesia followed by CO2 inhalation. We hypothesized that pentobarbital-phenytoin euthanasia would cause fewer alterations in cardiovascular response, result in less behavioral evidence of pain or stress, and produce lower elevations in ACTH than would the isoflurane and CO2 methods, which we hypothesized would not differ in regard to these parameters. ACTH data suggested that pentobarbital-phenytoin euthanasia may be less stressful to mice than are isoflurane and CO2 euthanasia. Cardiovascular, behavioral, and activity data did not consistently or significantly support isoflurane or pentobarbital-phenytoin euthanasia as less stressful methods than CO2. Euthanasia with CO2 was the fastest method of the 3 techniques. Therefore, we conclude that using CO2 with or without isoflurane is an acceptable euthanasia method. Pathologic alterations in the lungs were most severe with CO2 euthanasia, and alternative euthanasia techniques likely are better suited for studies that rely on analysis of the lungs.

[The clinico-epidemiological premises for antioxidant prevention and treatment in chronic myocardial infarct].

PubMed

Azoicăi, D; Mitu, F; Iacobovici, A; Pavel, M; Jerca, L; Ungureanu, D; Popovici, I; Cojocaru, M; Ivan, A; Gheorghiţă, N

1996-01-01

The improvement of therapeutic and recoverable proceeding to chronic myocardial infarction (IMC) imposes a complex epidemiological estimation of the global cardiovascular risk, of their clinical and biological status. The retrospective evaluation of the risk factors (RF) by epidemiological methods, in 38 hospitalized prevalence of both constitutional and behavioral factors, and the quantification of the risk state, according to graph Euro 194, has pointed on the fact that 50% of IMC cases have presented a global risk of 10-20%. That justified the application of a preventive conduct in order to continually neutralize the associates FR. The biochemical determinations have allowed to frame the dyslipidemic patients, according to the ARCOL classification in the classes D (29.2%), E (25.0%) and B (20.8%) with direct implication in the adopted therapy. The colorimetric dozing with thyo-barbituric acid of the malonly dialdehyde (MAD) each is a product of the lipidic peroxidation, as well as the interpreting or correlation of the registered values with an evolutive clinic stage, and with the existence of some existing diseases (diabetes, chronic hepatitis etc.) along with signification of other dismethabolical parameters (cholesterol, triglycerides, LDLc, apoB) have confirmed the necessity of a complex therapy, including an antioxidative treatment, having the role to directly inhibit or exclude the free radicals resulted after the oxidative stress of the infarct.

ANESTHESIA FOR EYE OPERATIONS IN THE AGED

PubMed Central

Failing, Joseph H.

1955-01-01

Aged persons appear to fear eye operations. Hence both patient and surgeon are more at ease with the use of a general anesthetic, particularly if the anesthetist has visited the patient before the operation and reassured him. Early ambulation, ordinarily so desirable in the aged, is curtailed in most eye operations because the head and eyes must be completely quiet. Since barbiturates are not well tolerated by aged patients, Dramamine is used instead preoperatively. Dramamine adequately sedates but does not cause depression or hallucinations. Morphine is contraindicated because of its pupillary action; Demerol is the drug of choice for preoperative medication. Xylocaine applied directly to the pyriform fossa and vocal cords prevents laryngospasm, coughing and straining. Then, following induction with Pentothal, a Guedel airway is introduced into the oropharynx and through it a continuous flow of oxygen is maintained throughout the procedure. Relaxation of the eyelids is aided by the use of various muscle relaxants, succinylcholine being the relaxant of choice because it is rapidly eliminated. By administering narcotics intravenously during the course of the operation the amount of Pentothal needed can be held to a minimum. To prevent any slowing of the respiration, Nalline is administered in conjunction with the narcotic. In dealing with debilitated patients, Nalline is usually given in conjunction with the preoperative narcotic. Any latent slowing of the respiration can be promptly relieved by an additional dose of Nalline. PMID:13230913

Psychedelic drugs, hippie counterculture, speed and phenobarbital treatment of sedative-hypnotic dependence: a journey to the Haight Ashbury in the Sixties.

PubMed

Wesson, Donald R

2011-01-01

The 1960s were a time of social upheaval, wars, vibrant creativity and missed opportunity. Mainstream culture and a psychedelic drug-using counterculture shared a belief in "better living through chemistry'," but they disagreed about the particular chemistry. The Vietnam war and the cold war with the Soviet Union, racial discrimination, and gender roles fueled political activism. "Yes we can" was not a slogan of the time but political activists clearly believed they could change the beliefs, attitudes and behavior of mainstream culture; and they did. Hippie counterculture on the other hand was largely alienated and strove primarily to develop a separate culture with its own mores, beliefs and lifestyles. Although there was some overlap between hippies and activists, hippies didn't generally have the same sense of political empowerment. Hippie enclaves developed in New York; Boston; Seattle; Austin, Texas and elsewhere; but the epicenter was arguably the Haight-Asbury District of San Francisco. Psychedelic drugs, marijuana and the Vietnam war were among many wedge issues. This paper conjures up a personal history related to the evolution of the hippie counterculture, changing drug use patterns in the Haight-Ashbury, and the origins of a technique of withdrawing patients from barbiturates and other sedative-hypnotics using phenobarbital variously known as the "Phenobarbital Withdrawal Protocol, or the "Smith and Wesson Protocol."

Component analysis of Iranian crack; a newly abused narcotic substance in iran.

PubMed

Farhoudian, Ali; Sadeghi, Mandana; Khoddami Vishteh, Hamid Reza; Moazen, Babak; Fekri, Monir; Rahimi Movaghar, Afarin

2014-01-01

Iranian crack is a new form of narcotic substance that has found widespread prevalence in Iran in the past years. Crack only nominally resembles crack cocaine as it is widely different in its clinical signs. Thus the present study aims to quantify the chemical combination of this drug. The samples included 18 specimen of Crack collected from different zones of Tehran, Iran. All specimens were in the form of inodorous cream solid powdery substance. TLC and HPLC methods were used to perform semi-quantitative and quantitative analysis of the components, respectively. The TLC analysis showed no cocaine compound in the specimens while they all revealed to contain heroin, codeine, morphine and caffeine. All but two specimens contained thebaine. None of the specimens contained amphetamine, benzodiazepines, tricyclic antidepressants, aspirin, barbiturates, tramadol and buprenorphine. Acetaminophen was found in four specimens. HPLC revealed heroin to be the foundation substance in all specimens and most of them contained a significant amount of acetylcodeine. The present analysis of the chemical combination of Crack showed that this substance is a heroin-based narcotic which is basically different from the cocaine-based crack used in Western countries. Studies like the present one at different time points, especially when abnormal clinical signs are detected, can reveal the chemical combination of the target substance and contribute to the clinical management of its acute or chronic poisoning.

Antinociceptive and antiallodynic effects of Momordica charantia L. in tibial and sural nerve transection-induced neuropathic pain in rats.

PubMed

Jain, Vivek; Pareek, Ashutosh; Paliwal, Nishant; Ratan, Yashumati; Jaggi, Amteshwar Singh; Singh, Nirmal

2014-02-01

This study was designed to investigate the ameliorative potential of Momordica charantia L. (MC) in tibial and sural nerve transection (TST)-induced neuropathic pain in rats. TST was performed by sectioning tibial and sural nerve portions (2 mm) of the sciatic nerve, and leaving the common peroneal nerve intact. Acetone drop, pin-prick, hot plate, paint-brush, and walking track tests were performed to assess cold allodynia, mechanical and heat hyperalgesia, and dynamic mechanical allodynia and tibial functional index, respectively. The levels of tumour necrosis factor (TNF)-alpha and thio-barbituric acid reactive substances (TBARS) were measured in the sciatic nerve as an index of inflammation and oxidative stress. MC (all doses, orally, once daily) was administered to the rats for 24 consecutive days. TST led to significant development of cold allodynia, mechanical and heat hyperalgesia, dynamic mechanical allodynia, and functional deficit in walking along with rise in the levels of TBARS and TNF-alpha. Administration of MC (200, 400, and 800 mg/kg) significantly attenuated TST-induced behavioural and biochemical changes. Furthermore, pretreatment of BADGE (120 mg/kg, intraperitoneally) abolished the protective effect of MC in TST-induced neuropathic pain. Collectively, it is speculated that PPAR-gamma agonistic activity, anti-inflammatory, and antioxidative potential is critical for antinociceptive effect of MC in neuropathic pain.

Interlaboratory studies with the Chinese hamster V79 cell metabolic cooperation assay to detect tumor-promoting agents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bohrman, J.S.; Burg, J.R.; Elmore, E.

1988-01-01

Three laboratories participated in an interlaboratory study to evaluate the usefulness of the Chinese hamster V79 cell metabolic cooperation assay to predict the tumor-promoting activity of selected chemical. Twenty-three chemicals of different chemical structures (phorbol esters, barbiturates, phenols, artificial sweeteners, alkanes, and peroxides) were chosen for testing based on in vivo promotion activities, as reported in the literature. Assay protocols and materials were standardized, and the chemicals were coded to facilitate unbiased evaluation. A chemical was tested only once in each laboratory, with one of the three laboratories testing only 15 out of 23 chemicals. Dunnett's test was used formore » statistical analysis. Chemicals were scored as positive (at least two concentration levels statistically different than control), equivocal (only one concentration statistically different), or negative. For 15 chemicals tested in all three laboratories, there was complete agreement among the laboratories for nine chemicals. For the 23 chemicals tested in only two laboratories, there was agreement on 16 chemicals. With the exception of the peroxides and alkanes, the metabolic cooperation data were in general agreement with in vivo data. However, an overall evaluation of the V79 cell system for predicting in vivo promotion activity was difficult because of the organ specificity of certain chemicals and/or the limited number of adequately tested nonpromoting chemicals.« less

Increase in migraine diagnoses and guideline-concordant treatment in veterans, 2004-2012.

PubMed

Altalib, H H; Fenton, B T; Sico, J; Goulet, J L; Bathulapalli, H; Mohammad, A; Kulas, J; Driscoll, M; Dziura, J; Mattocks, K; Kerns, R; Brandt, C; Haskell, S

2017-01-01

Background and aim Health administrators, policy makers, and educators have attempted to increase guideline adherence of migraine medications while reducing inappropriate use of opioid- and barbiturate-containing medications. We evaluated the burden of migraine and proportion of guideline-concordant care in a large, national health care system over time. Methods We conducted a time-series study using data from the Veterans Health Administration (VHA) electronic health record. Veterans with migraines were identified by ICD-9 code (346.X). Prescriptions and comorbid conditions were evaluated before and after migraine diagnosis. Chi-square tests and logistic regression were performed. Results A total of 57,064 veterans were diagnosed with migraine headache (5.3%), with women significantly more likely diagnosed (11.6% vs. 4.4%, p < 0.0001). The number of veterans diagnosed with migraine has significantly increased over the years. By 2012, triptans were prescribed to 43% of people with migraine, with no difference by gender. However, triptan prescriptions increased from 2004 to 2012 in men, but not women, veterans. Preventive medicines showed a significant increase with the year of migraine diagnosis, after controlling for age, sex, race, and for comorbidities treated with medications used for migraine prevention. Conclusions The burden of migraines is increasing within the VHA, with a corresponding increase in the delivery of guideline-concordant acute and prophylactic migraine-specific medication.

Overview of four prescription monitoring/review programs in Canada.

PubMed

Furlan, Andrea D; MacDougall, Peter; Pellerin, Denise; Shaw, Karen; Spitzig, Doug; Wilson, Galt; Wright, Janet

2014-01-01

Prescription monitoring or review programs collect information about prescription and dispensing of controlled substances for the purposes of monitoring, analysis and education. In Canada, it is the responsibility of the provincial institutions to organize, maintain and run such programs. To describe the characteristics of four provincial programs that have been in place for >6 years. The managers of the prescription monitoring⁄review programs of four provinces (British Columbia, Alberta, Saskatchewan and Nova Scotia) were invited to present at a symposium at the Canadian Pain Society in May 2012. In preparation for the symposium, one author collected and summarized the information. Three provinces have a mix of review and monitoring programs; the program in British Columbia is purely for review and education. All programs include controlled substances (narcotics, barbiturates and psychostimulants); however, other substances are differentially included among the programs: anabolic steroids are included in Saskatchewan and Nova Scotia; and cannabinoids are included in British Columbia and Nova Scotia. Access to the database is available to pharmacists in all provinces. Physicians need consent from patients in British Columbia, and only professionals registered with the program can access the database in Alberta. The definition of inappropriate prescribing and dispensing is not uniform. Double doctoring, double pharmacy and high-volume dispensing are considered to be red flags in all programs. There is variability among Canadian provinces in managing prescription monitoring⁄review programs.

Can anesthetic treatment worsen outcome in status epilepticus?

PubMed

Sutter, Raoul; Kaplan, Peter W

2015-08-01

Status epilepticus refractory to first-line and second-line antiepileptic treatments challenges neurologists and intensivists as mortality increases with treatment refractoriness and seizure duration. International guidelines advocate anesthetic drugs, such as continuously administered high-dose midazolam, propofol, and barbiturates, for the induction of therapeutic coma in patients with treatment-refractory status epilepticus. The seizure-suppressing effect of anesthetic drugs is believed to be so strong that some experts recommend using them after benzodiazepines have failed. Although the rationale for the use of anesthetic drugs in patients with treatment-refractory status epilepticus seems clear, the recommendation of their use in treating status epilepticus is based on expert opinions rather than on strong evidence. Randomized trials in this context are lacking, and recent studies provide disturbing results, as the administration of anesthetics was associated with poor outcome independent of possible confounders. This calls for caution in the straightforward use of anesthetics in treating status epilepticus. However, there are still more questions than answers, and current evidence for the adverse effects of anesthetic drugs in patients with status epilepticus remains too limited to advocate a change of treatment algorithms. In this overview, the rationale and the conflicting clinical implications of anesthetic drugs in patients with treatment-refractory status epilepticus are discussed, and remaining questions are elaborated. This article is part of a Special Issue entitled "Status Epilepticus". Copyright © 2015 Elsevier Inc. All rights reserved.

Preliminary results of the global audit of treatment of refractory status epilepticus.

PubMed

Ferlisi, M; Hocker, S; Grade, M; Trinka, E; Shorvon, S

2015-08-01

The treatment of refractory and super refractory status epilepticus is a "terra incognita" from the point of view of evidence-based medicine. As randomized or controlled studies that are sufficiently powered are not feasible in relation to the many therapies and treatment approaches available, we carried out an online multinational audit (registry) in which neurologists or intensivists caring for patients with status epilepticus may prospectively enter patients who required general anesthesia to control the status epilepticus (SE). To date, 488 cases from 44 different countries have been collected. Most of the patients had no history of epilepsy and had a cryptogenic etiology. First-line treatment was delayed and not in line with current guidelines. The most widely used anesthetic of first choice was midazolam (59%), followed by propofol and barbiturates. Ketamine was used in most severe cases. Other therapies were administered in 35% of the cases, mainly steroids and immunotherapy. Seizure control was achieved in 74% of the patients. Twenty-two percent of patients died during treatment, and four percent had treatment actively withdrawn because of an anticipated poor outcome. The neurological outcome was good in 36% and poor in 39.3% of cases, while 25% died during hospitalization. Factors that positively influenced outcome were younger age, history of epilepsy, and low number of different anesthetics tried. This article is part of a Special Issue entitled "Status Epilepticus". Copyright © 2015. Published by Elsevier Inc.

[The role of gamma-aminobutyric acid in the mechanism of action of anticonvulsant drugs].

PubMed

Chmielewska, B

2000-01-01

Decreased activity of gamma-aminobutyric acid, the major inhibitory neurotransmitter in CNS can be epileptogenic. Manipulation of the GABA system has been a target for development of antiepileptic drugs. The different ways for augmenting gabaergic inhibition by conventional and new AEDs are presented in this paper. Among the I generation, barbiturates and benzodiazepines are potent anticonvulsants that act as GABA modulators in postsynaptic GABA-A receptor complex but their usefulness is limited by dependence and tolerance to antiseizure activity. The II generation drugs vigabatrin and tiagabine, and to some extent gabapentin have been developed by a rationale strategy and none of them exert direct action in GABA receptors. Only two former drugs exhibit selective, strictly defined activity: vigabatrine is an irreversible inhibitor of GABA-aminotransferase and tiagabine acts as a GABA-uptake inhibitor from synaptic cleft into neurons and glia. Gabapentin binds to a novel receptors in epileptogenic areas in CNS and enhances GABA turnover. Drugs with multiple mechanisms of action, felbamate and topiramate not only potentiate gabaergic inhibition in several ways but also diminish the activity of excitatory amino acids at their NMDA or AMPA receptors; the later mechanism seems to be essential for their potential neuroprotective activity in epileptogenesis. None of gabamimetic drugs provide optimal seizure control but better tolerability of newer ones and well-established mechanisms of action provide possible harmless therapy.

Physiologic, Behavioral, and Histologic Responses to Various Euthanasia Methods in C57BL/6NTac Male Mice

PubMed Central

Boivin, Gregory P; Bottomley, Michael A; Schiml, Patricia A; Goss, Lori; Grobe, Nadja

2017-01-01

Rodent euthanasia using exposure to increasing concentrations of CO2 has come under scrutiny due to concerns of potential pain during the euthanasia process. Alternatives to CO2, such as isoflurane and barbiturates, have been proposed as more humane methods of euthanasia. In this study, we examined 3 commonly used euthanasia methods in mice: intraperitoneal injection of pentobarbital–phenytoin solution, CO2 inhalation, and isoflurane anesthesia followed by CO2 inhalation. We hypothesized that pentobarbital–phenytoin euthanasia would cause fewer alterations in cardiovascular response, result in less behavioral evidence of pain or stress, and produce lower elevations in ACTH than would the isoflurane and CO2 methods, which we hypothesized would not differ in regard to these parameters. ACTH data suggested that pentobarbital–phenytoin euthanasia may be less stressful to mice than are isoflurane and CO2 euthanasia. Cardiovascular, behavioral, and activity data did not consistently or significantly support isoflurane or pentobarbital–phenytoin euthanasia as less stressful methods than CO2. Euthanasia with CO2 was the fastest method of the 3 techniques. Therefore, we conclude that using CO2 with or without isoflurane is an acceptable euthanasia method. Pathologic alterations in the lungs were most severe with CO2 euthanasia, and alternative euthanasia techniques likely are better suited for studies that rely on analysis of the lungs. PMID:28905718

Epidemiology of acute drug poisoning in a tertiary center from Iasi County, Romania.

PubMed

Sorodoc, Victorita; Jaba, Irina M; Lionte, Catalina; Mungiu, Ostin C; Sorodoc, Laurentiu

2011-12-01

The aim of this retrospective epidemiological study was to investigate the demographical, etiological and clinical characteristics of acute drug poisonings in Iasi County, Romania. All patients were referred and admitted in the Toxicology Clinic of "Sf. Ioan" Emergency Clinic Hospital Iasi, Romania. Between 2003 and 2009, 811 cases of acute drug poisonings were recorded, counting for 28.43% from the total number of poisonings. The majority of these poisonings resulted in mild (51.94%) and medium (28.35%) clinical forms, while 19.71% were coma situations. In all, 63.51% of patients originated from urban areas, 39.94% were unemployed and the patients were predominantly women (66.46%). A high percentage (97.27%) were suicide attempts, using only one type of drug (65.88%) and the 21-30 years group (29.8%) records the highest incidence, for both women and men. The most frequently involved drugs were benzodiazepines 13.69%, anticonvulsive drugs 8.63%, barbiturates 8.51% and cardiovascular drugs 5.92%. Drugs combinations were recorded in 32.92% of cases and 1.2% were combinations between drugs and other substances. Mortality was the outcome in 0.3% of the total registered number of acute drug poisonings. This study underlines that in order to provide a proper management of these situations, a Regional Poison Information Center is absolutely necessary.

How phenobarbital revolutionized epilepsy therapy: the story of phenobarbital therapy in epilepsy in the last 100 years.

PubMed

Yasiry, Zeid; Shorvon, Simon D

2012-12-01

Phenobarbital (phenobarbitone) was first used as an antiepileptic drug 100 years ago, in 1912. This article tells the story of the discovery of its antiepileptic action, its early development, and the subsequent course of its clinical use over the 100-year period. The side effects, pharmacokinetics, and misuse of barbiturates are considered, along with the more recent clinical trials and the drug's current clinical utilization. The introduction of controlled drug regulations, the comparative cost of phenobarbital, and its inclusion on the World Health Organization (WHO) essential drug list are discussed. It is one of the few drugs on the formulary in 1912 that is still listed today, and remarkably its efficacy in epilepsy has not been significantly bettered. The current recommendation by the WHO is that phenobarbital should be offered as the first option for therapy for convulsive epilepsy in adults and children if availability can be ensured. This is rated as a strong recommendation because of the proven efficacy and low cost of phenobarbital, and despite its perceived side-effect profile and the practical problems of access. Whether this recommendation puts "a hierarchy on the brain," as has been suggested, is arguable. Much still needs to be learned about the drug's effects, and the issues raised by phenobarbital have lessons for all antiepileptic drug therapy. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

Propofol for ECT anesthesia a review of the literature.

PubMed

Rasmussen, Keith G

2014-09-01

Propofol is a commonly used anesthetic drug for electroconvulsive therapy (ECT), as evidenced by the frequency with which its use is reported in ECT literature. Concerns have been raised over its propensity to be associated with shortened seizure duration vis-à-vis other anesthetic drugs, thus limiting its use in some settings. However, in the surgical anesthesia literature, propofol has shown distinct advantages such as improved hemodynamics and postanesthesia recovery. Given the capricious availability of standard barbiturate anesthetics in some countries, propofol use has probably increased. Thus, a review of its profile for a number of outcome measures in ECT is appropriate. Herein, the author reviews the extensive literature for propofol in ECT, focusing on 5 outcome measures: seizure duration, hemodynamics, postanesthesia recovery, cognitive adverse effects, and therapeutic efficacy. Results indicate that propofol is indeed robustly associated with shorter seizures than other anesthetics but that antidepressant efficacy does not seem to be compromised. Heart rate and blood pressure changes are not as high with propofol, and postanesthesia recovery may be quicker with propofol as well. Not enough data are available regarding cognitive adverse effects to make definitive conclusions, but so far, there does not seem to be a worsened cognitive profile when it is used in ECT. Propofol seems to be an acceptable anesthetic for ECT with advantages for some situations. Using the lowest effective anesthetic dosage minimizes its effect on seizure elicitation and duration.

Medications and impaired driving.

PubMed

Hetland, Amanda; Carr, David B

2014-04-01

To describe the association of specific medication classes with driving outcomes and provide clinical recommendations. The MEDLINE and EMBASE databases were searched for articles published from January 1973 to June 2013 on classes of medications associated with driving impairment. The search included outcome terms such as automobile driving, motor vehicle crash, driving simulator, and road tests. Only English-language articles that contained findings from observational or interventional designs with ≥ 10 participants were included in this review. Cross-sectional studies, case series, and case reports were excluded. Driving is an important task and activity for the majority of adults. Some commonly prescribed medications have been associated with driving impairment measured by road performance, driving simulation, and/or motor vehicle crashes. This review of 30 studies identified findings with barbiturates, benzodiazepines, hypnotics, antidepressants, opioid and nonsteroidal analgesics, anticonvulsants, antipsychotics, antiparkinsonian agents, skeletal muscle relaxants, antihistamines, anticholinergic medications, and hypoglycemic agents. Additional studies of medication impact on sedation, sleep latency, and psychomotor function, as well as the role of alcohol, are also discussed. Psychotropic agents and those with central nervous system side effects were associated with measures of impaired driving performance. It is difficult to determine if such associations are actually a result of medication use or the medical diagnosis itself. Regardless, clinicians should be aware of the increased risk of impaired driving with specific classes of medications, educate their patients, and/or consider safer alternatives.

Total intravenous anesthesia as a target-controlled infusion. An evolutive analysis.

PubMed

Nora, Fernando Squeff

2008-01-01

Total intravenous anesthesia (TIVA) has seen several developments since it was first used. Since the synthesis of the first intravenous anesthetics, with the introduction of barbiturates (1921) and thiopental (1934), TIVA has evolved until the development of TIVA with target-controlled infusion pumps (TCI). The first pharmacokinetic model for the use of TCI was described by Schwilden in 1981. From that moment on, it was demonstrated that it is possible to maintain the desired plasma concentration of a drug using an infusion pump managed by a computer. The objective of this report was to describe the theoretical bases of TCI, propose the development of a common TCI vocabulary, which has not been done in Brazil and make a critical analysis of the current aspects of TCI in the world and in Brazil. The advent of new infusion pumps with pharmacokinetic models of remifentanil, sufentanil and propofol opens a new chapter in TIVA and aligns Brazil with the world tendency in TCI. Those systems will allow TCI of hypnotics and opioids concomitantly. However, the most important conclusion refers to the economy, since drugs used in those pumps will not be restricted to only one drug company, similar to what happened with propofol. Nowadays, TCI devices for the use of propofol and opioids, which accept any pharmaceutical presentation, with the advantage of changing the concentration of the drug in the syringe according to the dilution desired are available.

Fast targeted analysis of 132 acidic and neutral drugs and poisons in whole blood using LC-MS/MS.

PubMed

Di Rago, Matthew; Saar, Eva; Rodda, Luke N; Turfus, Sophie; Kotsos, Alex; Gerostamoulos, Dimitri; Drummer, Olaf H

2014-10-01

The aim of this study was to develop an LC-MS/MS based screening technique that covers a broad range of acidic and neutral drugs and poisons by combining a small sample volume and efficient extraction technique with simple automated data processing. After protein precipitation of 100μL of whole blood, 132 common acidic and neutral drugs and poisons including non-steroidal anti-inflammatory drugs, barbiturates, anticonvulsants, antidiabetics, muscle relaxants, diuretics and superwarfarin rodenticides (47 quantitated, 85 reported as detected) were separated using a Shimadzu Prominence HPLC system with a C18 separation column (Kinetex XB-C18, 4.6mm×150mm, 5μm), using gradient elution with a mobile phase of 25mM ammonium acetate buffer (pH 7.5)/acetonitrile. The drugs were detected using an ABSciex(®) API 2000 LC-MS/MS system (ESI+ and -, MRM mode, two transitions per analyte). The method was fully validated in accordance with international guidelines. Quantification data obtained using one-point calibration compared favorably to that using multiple calibrants. The presented LC-MS/MS assay has proven to be applicable for determination of the analytes in blood. The fast and reliable extraction method combined with automated processing gives the opportunity for high throughput and fast turnaround times for forensic and clinical toxicology. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

The historical significance of anaesthesia events at Pearl Harbor.

PubMed

Crowhurst, Ja

2014-07-01

Up to the end of World War II, less than 10% of the general anaesthetics administered was with intravenous barbiturates. The remaining 90% of anaesthetics given in the USA were with diethyl ether. In the United Kingdom and elsewhere, chloroform was also popular. Diethyl ether administration was a relatively safe and simple procedure, often delegated to nurses or junior doctors with little or no specific training in anaesthesia. During the Japanese attack on the US bases at Pearl Harbor, with reduced stocks of diethyl ether available, intravenous Sodium Pentothal(®), a most 'sophisticated and complex' drug, was used with devastating effects in many of those hypovolaemic, anaemic and septic patients. The hazards of spinal anaesthesia too were realised very quickly. These effects were compounded by the dearth of trained anaesthetists. This paper presents the significance of the anaesthesia tragedies at Pearl Harbor, and the discovery in the next few years of many other superior drugs that caused medical and other health professionals to realise that anaesthesia needed to be a specialist medical discipline in its own right. Specialist recognition, aided by the foundation of the National Health Service in the UK, the establishment of Faculties of Anaesthesia and appropriate training in pharmacology, physiology and other sciences soon followed. Modern anaesthesiology, as we understand it today, was born and a century or more of ether anaesthesia finally ceased.

Acute Human Self-Poisoning with the N-Phenylpyrazole Insecticide Fipronil –A GABAA-Gated Chloride Channel Blocker

PubMed Central

Mohamed, Fahim; Senarathna, Lalith; Percy, Adrian; Abeyewardene, Manel; Eaglesham, Geoffrey; Cheng, Ron; Azher, Shifa; Hittarage, Ariyasena; Dissanayake, Wasantha; Sheriff, MH Rezvi; Davies, Willie; Buckley, Nick; Eddleston, Michael

2005-01-01

Objective Fipronil, a broad spectrum N-phenylpyrazole insecticide that inhibits GABAA-gated chloride channels, has been in use since the mid-1990s. A high affinity for insect compared to mammalian GABA receptors results in lower animal toxicity than other insecticides blocking this channel. To date, only two accidental cases of fipronil poisoning in humans have been published. Case series We report seven patients with fipronil self-poisoning seen prospectively in Sri Lanka together with pharmacokinetics for four patients. Non-sustained generalized tonic-clonic seizures were seen in two patients (peak measured plasma fipronil concentrations 1600 and 3744 μg/L); both were managed with diazepam without complications. A patient with a peak measured plasma concentration of 1040 μg/L was asymptomatic throughout his stay. Plasma concentration was still high at discharge 3–4 days post-ingestion when the patients were well. Retrospective review of >1000 pesticide poisoning deaths since 1995 found only one death from fipronil-based products. In contrast to the good outcome of the above cases, this patient required intubation and ventilation and had continuous fits despite therapy with barbiturates and benzodiazepines. Conclusions Our experience with prospectively observed patients suggests that fipronil poisoning is characterized by vomiting, agitation, and seizures, and normally has a favorable outcome. Management should concentrate on supportive care and early treatment of seizures. However, further experience is needed to determine whether increased susceptibility to fipronil or larger doses can produce status epilepticus. PMID:15641641

Ultrabright and Fluorogenic Probes for Multicolor Imaging and Tracking of Lipid Droplets in Cells and Tissues.

PubMed

Collot, Mayeul; Fam, Tkhe Kyong; Ashokkumar, Pichandi; Faklaris, Orestis; Galli, Thierry; Danglot, Lydia; Klymchenko, Andrey S

2018-04-25

Lipid droplets (LDs) are intracellular lipid-rich organelles that regulate the storage of neutral lipids and were recently found to be involved in many physiological processes, metabolic disorders, and diseases including obesity, diabetes, and cancers. Herein we present a family of new fluorogenic merocyanine fluorophores based on an indolenine moiety and a dioxaborine barbiturate derivative. These so-called StatoMerocyanines (SMCy) fluoresce from yellow to the near-infrared (NIR) in oil with an impressive fluorescence enhancement compared to aqueous media. Additionally, SMCy display remarkably high molar extinction coefficients (up to 390 000 M -1 cm -1 ) and high quantum yield values (up to 100%). All the members of this new family specifically stain the LDs in live cells with very low background noise. Unlike Nile Red, a well-known lipid droplet marker, SMCy dyes possess narrow absorption and emission bands in the visible, thus allowing multicolor imaging. SMCy proved to be compatible with fixation and led to high-quality 3D images of lipid droplets in cells and tissues. Their high brightness allowed efficient tissue imaging of adipocytes and circulating LDs. Moreover their remarkably high two-photon absorption cross-section, especially SMCy5.5 (up to 13 300 GM), as well as their capacity to efficiently fluoresce in the NIR region led to two-photon multicolor tissue imaging (liver). Taking advantage of the available color palette, lipid droplet exchange between cells was tracked and imaged, thus demonstrating intercellular communication.

Recovery from dispositional and pharmacodynamic tolerance after chronic pentobarbital treatment.

PubMed

Okamoto, M; Rao, S N; Reyes, J; Rifkind, A B

1985-10-01

Recovery characteristics of dispositional and pharmacodynamic tolerances produced by chronic Na-pentobarbital treatment were studied. To study dispositional tolerance, the rate of disappearance of pentobarbital from blood was estimated by sequential blood sampling before and after chronic treatment and during 15 days of withdrawal after chronic treatment. Pentobarbital half-life values were compared with four representative cytochrome P-450-mediated hepatic microsomal mixed-function oxidase reactions: aminopyrine demethylase, benzo(a)pyrene hydroxylase, 7-ethoxycoumarin deethylase and 7-ethoxyresorufin deethylase and with the concentration of cytochrome P-450 in sequentially biopsied liver samples. Pharmacodynamic tolerance was evaluated by measuring the increase in pentobarbital blood concentration required to produce predetermined central nervous system functional depression ratings. The recovery from dispositional tolerance was more rapid than the recovery from pharmacodynamic tolerance. Thus, whereas cytochrome P-450 levels and pentobarbital elimination rates were increased to close to twice pretreatment values by chronic treatment, by about 2 week post-withdrawal the values had normalized. In contrast, pharmacodynamic tolerance persisted after no residual dispositional tolerance remained. The neuronal functions most sensitive to barbiturate (i.e., sedation and loss of fine motor coordination) exhibited a greater degree of pharmacodynamic tolerance than other functions; hence the recovery of these neuronal functions took a longer period of time for their recovery. However, the rates of recovery of pharmacodynamic tolerance at all levels of central nervous system function seemed relatively constant indicating that there are uniform readaptation mechanisms for all the central nervous systems functions.

The role of training dose in drug discrimination: a review

PubMed Central

Stolerman, Ian P; Childs, Emma; Ford, Matthew M; Grant, Kathleen A

2011-01-01

Drug discrimination has been an important technique in behavioural pharmacology for at least 40 years. The characteristics of drug-produced discriminative stimuli are influenced by behavioural and pharmacological variables, including the doses used to establish discriminations. This review covers studies on the effects of varying the training dose of a drug in a search for general principles that are applicable across different drug classes and methodological approaches. With respect to quantitative changes, relationships between training dose and rate of acquisition or magnitude of stimulus control were found for most drug classes. Acquisition accelerated with dose up to a point beyond which drug-induced impairments of performance had a deleterious impact. Sensitivity to the training drug as measured by ED50 values typically increased when the training dose was reduced. Qualitative changes were more complex and appeared to fall into three categories: (i) changes in profiles of generalisation between partial and full agonists; (ii) reduced specificity of some discriminations at small training doses and (iii) changes in the relative salience of actions mediated through different neurotransmitter systems or from central and peripheral sites. Three-lever discrimination procedures incorporating ‘drug versus drug’ or “dose versus dose” contingencies enabled detection of more subtle differences than the simple ‘drug versus no drug’ approach when applied to the opioid, hallucinogen and barbiturate classes of drugs. These conclusions have implications for the interpretation of data from studies that utilise either within- or between-subject designs for studying the discriminative stimulus effects of drugs. PMID:21808191

Catatonia: a syndrome appears, disappears, and is rediscovered.

PubMed

Fink, Max

2009-07-01

Catatonia is the psychiatric syndrome of disturbed motor functions amid disturbances in mood and thought first described in 1874. It was quickly found in 10% to 38% of psychiatric populations. After it was tied to schizophrenia as a type in the psychiatric classification, its recognition became increasingly limited and by the 1980s questions were asked as to where the catatonics had gone. The decline is largely owing to the change in venue for psychiatric practice from asylum to office, the rejection of physical examination, and the dependence on item rating scales for diagnosis. In the 1970s, broad surveys again showed that catatonia was as common as before among patients with mania and depression, and as a toxic response to neuroleptic drugs. The latter recognition, that the neuroleptic malignant syndrome is the same syndrome as malignant catatonia, and is effectively treated as such, sparked a renewed interest. Clinicians developed rating scales to identify the catatonia syndrome and applied the immediate relief afforded by a barbiturate or a benzodiazepine as a diagnostic test, the lorazepam test. Effective treatments were described as high doses of benzodiazepines and electroconvulsive therapy (ECT). Surveys using catatonia rating scales showed catatonia to have many faces. Catatonia is presently limited to a type of schizophrenia in the psychiatric classification. Its recognition as a disorder of its own, such as delirium and dementia, should now be recognized. This experience reinforced the utility of the medical model for diagnosis. An application for melancholia is described.

Extracorporeal elimination of butalbital in acute aspirin-butalbital-caffeine-codeine (Fiorinal with Codeine) poisoning.

PubMed

Poyant, Janelle O; Albright, Robert; Clain, Jeremy; Pandompatam, Govind; Barreto, Erin F

2017-11-10

Butalbital is a small molecule (approximately 220 Da), with 26% protein binding, a 0.8 L/kg volume of distribution, and is eliminated nearly 80% unchanged in the urine. Although hemodialysis has been used to treat overdoses of other barbiturates, the extracorporeal clearance of butalbital is unknown. The objective of this case is to describe the use of extracorporeal therapy to augment elimination of butalbital after an overdose of aspirin 325 mg-butalbital 50 mg-caffeine 40 mg with codeine 30 mg (Fiorinal with Codeine). This is a case report of a single patient. A 67-year-old female was admitted to the medical intensive care unit approximately 3 h after ingestion of 40 tablets of Fiorinal with Codeine. Her presentation was notable for a decline in mental status, preserved renal function and a relatively low peak salicylate concentration at 46.4 mg/dL (3.4 mmol/L). Approximately 8 h after ingestion of 2000 mg of butalbital, our patient's serum concentration was 26.9 mg/L (normal <10 mg/L). At the end of a four-hour hemodialysis session, the total body elimination of butalbital was approximately 60% which corresponded to an intradialytic clearance of 233-300 mL/min. The extracorporeal clearance of butalbital observed in this case demonstrates the utility of dialysis to augment drug elimination in a Fiorinal with Codeine overdose.

Fingerprinting groundwater pollution in catchments with contrasting contaminant sources using microorganic compounds.

PubMed

Stuart, Marianne E; Lapworth, Dan J; Thomas, Jenny; Edwards, Laura

2014-01-15

Evaluating the occurrence of microorganics helps to understand sources and processes which may be controlling the transport and fate of emerging contaminants (ECs). A study was carried out at the contrasting instrumented environmental observatory sites at Oxford, on the peri-urban floodplain gravel aquifer of the River Thames and Boxford, in the rural valley of the River Lambourn on the chalk aquifer, in Southern England to explore the use of ECs to fingerprint contaminant sources and flow pathways in groundwater. At Oxford compounds were typical of a local waste tip plume (not only plasticisers and solvents but also barbiturates and N,N-diethyl-m-toluamide (DEET)) and of the urban area (plasticisers and mood-enhancing drugs such as carbamazepine). At Boxford the results were different with widespread occurrence of agricultural pesticides, their metabolites and the solvent trichloroethene, as well as plasticisers, caffeine, butylated food additives, DEET, parabens and trace polyaromatic hydrocarbons (PAHs). Groups of compounds used in pharmaceuticals and personal care products of different provenance in the environment could be distinguished, i) historical household and medical waste, ii) long-term household usage persistent in groundwater and iii) current usage and contamination from surface water. Co-contaminant and degradation products can also indicate the likely source of contaminants. A cocktail of contaminants can be used as tracers to provide information on catchment pathways and groundwater/surface water interactions. A prominent feature in this study is the attenuation of many EC compounds in the hyporheic zone. © 2013.

Lack of cross-reactivity of Ambien (zolpidem) with drugs in standard urine drug screens.

PubMed

Piergies, A A; Sainati, S; Roth-Schechter, B

1997-04-01

To determine in healthy volunteers (men and women; 18 to 40 years old) the potential cross-reactivity of Ambien (zolpidem) and/or its metabolites with drugs that are screened by the Syva EMIT II and the Abbott ADx urine drug screens assays. Open-label, fixed-treatment sequence of 1 night each of treatment with zolpidem (10 mg) and temazepam (15 mg). Clinical Pharmacology Unit within a teaching hospital. Over a 24-hour period, presence or absence of positive results on the Syva EMIT II or the Abbott ADx urine drug assay system, each performed at two different laboratory assay sites. Following ingestion of zolpidem, no subject had any positive response in either laboratory to the Syva EMIT II or the Abbott ADx urine drug screen assays at 0, 4, 8, 12, and 24 hours postdose. During the same time period, all subjects had measurable zolpidem plasma concentrations at 1.5 and 8 hours postdose, with mean concentrations of 115.2 ng/mL and 30.1 ng/mL, respectively (in agreement with its half-life of 2.5 hours). The positive response rate at 10 hours after ingestion of Restoril (temazepam) among the four laboratory/assay combinations ranged from 36.8% to 73.7%, a range that is within the reported response rates for these tests. These data indicate that zolpidem will not cross-react in standard urine drug screens with benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines.

A second dihydroorotate dehydrogenase (Type A) of the human pathogen Enterococcus faecalis: expression, purification, and steady-state kinetic mechanism.

PubMed

Marcinkeviciene, J; Jiang, W; Locke, G; Kopcho, L M; Rogers, M J; Copeland, R A

2000-05-01

We report the identification, expression, and characterization of a second Dihydroorotate dehydrogenase (DHODase A) from the human pathogen Enterococcus faecalis. The enzyme consists of a polypeptide chain of 322 amino acids that shares 68% identity with the cognate type A enzyme from the bacterium Lactococcus lactis. E. faecalis DHODase A catalyzed the oxidation of l-dihydroorotate while reducing a number of substrates, including fumarate, coenzyme Q(0), and menadione. The steady-state kinetic mechanism has been determined with menadione as an oxidizing substrate at pH 7.5. Initial velocity and product inhibition data suggest that the enzyme follows a two-site nonclassical ping-pong kinetic mechanism. The absorbance of the active site FMN cofactor is quenched in a concentration-dependent manner by titration with orotate and barbituric acid, two competitive inhibitors with respect to dihydroorotate. In contrast, titration of the enzyme with menadione had no effect on FMN absorbance, consistent with nonoverlapping binding sites for dihyroorotate and menadione, as suggested from the kinetic mechanism. The reductive half-reaction has been shown to be only partially rate limiting, and an attempt to evaluate the slow step in the overall reaction has been made by simulating orotate production under steady-state conditions. Our data indicate that the oxidative half-reaction is a rate-limiting segment, while orotate, most likely, retains significant affinity for the reduced enzyme, as suggested by the product inhibition pattern. Copyright 2000 Academic Press.

Epilepsy and recommendations for breastfeeding.

PubMed

Veiby, Gyri; Bjørk, Marte; Engelsen, Bernt A; Gilhus, Nils Erik

2015-05-01

The objective of this paper is to provide a synopsis of benefits and potential harmful effects of exposure to antiepileptic drugs (AEDs) via breastmilk, and present recommendations for breastfeeding in women with epilepsy. The article is based on a discretionary selection of English language articles retrieved by a literature search in the PubMed database, the LactMed database, and the authors' clinical experience. Breastfeeding is associated with benefits for the infant, including nutrition, protection against infectious and immunological disease, and promotion of development and psychological attachment. Exposure to AEDs via breastmilk could potentially produce side effects or negatively affect development. Most studies on AED transfer through breastmilk report infant serum levels well below the limit of an expected pharmacological effect. Some drugs have the potential to reach significant serum levels in breastfed infants, such as barbiturates, benzodiazepines, lamotrigine, and ethosuximide. Thus, breastfed infants should be monitored for side effects. Still, adverse symptoms are rarely reported in breastfed infants of mothers taking AEDs, and prospective studies have failed to demonstrate any negative developmental effects in children that have been exposed to AEDs via breastmilk. The nursing infant's degree of drug exposure can be minimized by breastfeeding when drug concentrations in the milk are low, reducing maternal AED dosage to prepregnancy levels, and administering mixed nutrition. Most AEDs are considered safe or moderately safe during breastfeeding. Mothers with epilepsy should be encouraged to breastfeed, provided careful monitoring of the infant. Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Functional relationship between brainstem putative pain-facilitating neurons and spinal nociceptfive neurons during development of inflammation in rats.

PubMed

Salas, Rafael; Ramirez, Karla; Tortorici, Victor; Vanegas, Horacio; Vazquez, Enrique

2018-05-01

The so-called on- and off-cells of the rostral ventromedial medulla (RVM) send their axons to the spinal dorsal horn. Activation of on-cells precedes and coincides with a facilitation, and activation of off-cells coincides with an inhibition, of withdrawal reflexes elicited by noxious agents. Considerable evidence supports the notion that on- and off-cells modulate nocifensive reflexes during opioid and non-opioid action and also during normal circumstances and during peripheral neuropathy and inflammation. Yet it is unclear whether on- and off-cells act upon sensory spinal circuits that might lead to ascending projections and the experience of pain. Here, in deeply anesthetized rats we recorded single unit discharges from pairs of one on-like or off-like cell in RVM and a nociceptive neuron in the spinal dorsal horn with input from a hind paw. Both ongoing activity and responses to a calibrated noxious stimulus applied to the paw were documented during basal conditions and during development of paw inflammation. Probably due to the strong barbiturate anesthesia, off-like cells were depressed and did not yield interpretable results. However, we showed for the first time that during the increase in neuronal activity that results from paw inflammation the activity of spinal nociceptive neurons reflects the activity of their partner on-like cells in a highly correlated manner. This implies a tight relationship between spinal sensory and RVM modulatory functions that may underlie inflammation-induced hyperreflexia and clinically relevant hyperalgesia. Copyright © 2018 Elsevier B.V. All rights reserved.

Thiopental Inhibits Global Protein Synthesis by Repression of Eukaryotic Elongation Factor 2 and Protects from Hypoxic Neuronal Cell Death

PubMed Central

Schwer, Christian I.; Lehane, Cornelius; Guelzow, Timo; Zenker, Simone; Strosing, Karl M.; Spassov, Sashko; Erxleben, Anika; Heimrich, Bernd; Buerkle, Hartmut; Humar, Matjaz

2013-01-01

Ischemic and traumatic brain injury is associated with increased risk for death and disability. The inhibition of penumbral tissue damage has been recognized as a target for therapeutic intervention, because cellular injury evolves progressively upon ATP-depletion and loss of ion homeostasis. In patients, thiopental is used to treat refractory intracranial hypertension by reducing intracranial pressure and cerebral metabolic demands; however, therapeutic benefits of thiopental-treatment are controversially discussed. In the present study we identified fundamental neuroprotective molecular mechanisms mediated by thiopental. Here we show that thiopental inhibits global protein synthesis, which preserves the intracellular energy metabolite content in oxygen-deprived human neuronal SK-N-SH cells or primary mouse cortical neurons and thus ameliorates hypoxic cell damage. Sensitivity to hypoxic damage was restored by pharmacologic repression of eukaryotic elongation factor 2 kinase. Translational inhibition was mediated by calcium influx, activation of the AMP-activated protein kinase, and inhibitory phosphorylation of eukaryotic elongation factor 2. Our results explain the reduction of cerebral metabolic demands during thiopental treatment. Cycloheximide also protected neurons from hypoxic cell death, indicating that translational inhibitors may generally reduce secondary brain injury. In conclusion our study demonstrates that therapeutic inhibition of global protein synthesis protects neurons from hypoxic damage by preserving energy balance in oxygen-deprived cells. Molecular evidence for thiopental-mediated neuroprotection favours a positive clinical evaluation of barbiturate treatment. The chemical structure of thiopental could represent a pharmacologically relevant scaffold for the development of new organ-protective compounds to ameliorate tissue damage when oxygen availability is limited. PMID:24167567

A Small-Molecule Inhibitor of Human DNA Polymerase η Potentiates the Effects of Cisplatin in Tumor Cells.

PubMed

Zafar, Maroof K; Maddukuri, Leena; Ketkar, Amit; Penthala, Narsimha R; Reed, Megan R; Eddy, Sarah; Crooks, Peter A; Eoff, Robert L

2018-02-20

Translesion DNA synthesis (TLS) performed by human DNA polymerase eta (hpol η) allows tolerance of damage from cis-diamminedichloroplatinum(II) (CDDP or cisplatin). We have developed hpol η inhibitors derived from N-aryl-substituted indole barbituric acid (IBA), indole thiobarbituric acid (ITBA), and indole quinuclidine scaffolds and identified 5-((5-chloro-1-(naphthalen-2-ylmethyl)-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (PNR-7-02), an ITBA derivative that inhibited hpol η activity with an IC 50 value of 8 μM and exhibited 5-10-fold specificity for hpol η over replicative pols. We conclude from kinetic analyses, chemical footprinting assays, and molecular docking that PNR-7-02 binds to a site on the little finger domain and interferes with the proper orientation of template DNA to inhibit hpol η. A synergistic increase in CDDP toxicity was observed in hpol η-proficient cells co-treated with PNR-7-02 (combination index values = 0.4-0.6). Increased γH2AX formation accompanied treatment of hpol η-proficient cells with CDDP and PNR-7-02. Importantly, PNR-7-02 did not impact the effect of CDDP on cell viability or γH2AX in hpol η-deficient cells. In summary, we observed hpol η-dependent effects on DNA damage/replication stress and sensitivity to CDDP in cells treated with PNR-7-02. The ability to employ a small-molecule inhibitor of hpol η to improve the cytotoxic effect of CDDP may aid in the development of more effective chemotherapeutic strategies.

Study of orotidine 5'-monophosphate decarboxylase in complex with the top three OMP, BMP, and PMP ligands by molecular dynamics simulation.

PubMed

Jamshidi, Shirin; Jalili, Seifollah; Rafii-Tabar, Hashem

2015-01-01

Catalytic mechanism of orotidine 5'-monophosphate decarboxylase (OMPDC), one of the nature most proficient enzymes which provides large rate enhancement, has not been fully understood yet. A series of 30 ns molecular dynamics (MD) simulations were run on X-ray structure of the OMPDC from Saccharomyces cerevisiae in its free form as well as in complex with different ligands, namely 1-(5'-phospho-D-ribofuranosyl) barbituric acid (BMP), orotidine 5'-monophosphate (OMP), and 6-phosphonouridine 5'-monophosphate (PMP). The importance of this biological system is justified both by its high rate enhancement and its potential use as a target in chemotherapy. This work focuses on comparing two physicochemical states of the enzyme (protonated and deprotonated Asp91) and three ligands (substrate OMP, inhibitor, and transition state analog BMP and substrate analog PMP). Detailed analysis of the active site geometry and its interactions is properly put in context by extensive comparison with relevant experimental works. Our overall results show that in terms of hydrogen bond occupancy, electrostatic interactions, dihedral angles, active site configuration, and movement of loops, notable differences among different complexes are observed. Comparison of the results obtained from these simulations provides some detailed structural data for the complexes, the enzyme, and the ligands, as well as useful insights into the inhibition mechanism of the OMPDC enzyme. Furthermore, these simulations are applied to clarify the ambiguous mechanism of the OMPDC enzyme, and imply that the substrate destabilization and transition state stabilization contribute to the mechanism of action of the most proficient enzyme, OMPDC.

Oral drug self-administration: an overview of laboratory animal studies.

PubMed

Meisch, R A

2001-06-01

Many abused drugs can be established as orally delivered reinforcers for rhesus monkeys and other animals. Benzodiazepines, barbiturates, opioids, psychomotor stimulants, dissociative anesthetics, and ethanol can come to serve as reinforcers when taken by mouth. The principal problems in establishing drugs as reinforcers by the oral route of administration are (1) aversive taste, (2) delay in onset of central nervous system effects, and (3) consumption of low volumes of drug solution. Strategies have been devised to successfully overcome these problems, and orally delivered drugs can be established as effective reinforcers. Reinforcing actions are demonstrated by consumption of greater volumes of drug solution than volumes of the water vehicle, and supporting evidence for reinforcing effects consists of the maintenance of behavior under intermittent schedules of reinforcement and the generation of orderly dose-response functions. This article presents an overview of studies of behavior reinforced by oral drug reinforcement. Factors that control oral drug intake include dose, schedule of reinforcement, food restriction, and alternative reinforcers. Many drugs, administered by the experimenter, can alter oral drug reinforcement. Relative reinforcing effects can be assessed by choice procedures and by persistence of behavior across increases in schedule size. In general, reinforcing effects increase directly with dose. Rhesus monkeys prefer combinations of reinforcing drugs to the component drugs. The taste of drug solutions may act as a conditioned reinforcer and a discriminative stimulus. Consequences of drug intake include tolerance and physiological dependence. Findings with orally self-administered drugs are similar to many findings with other positive reinforcers, including intravenously self-administered drugs.

The impact of substance use disorders on clinical outcomes in older-adult psychiatric inpatients.

PubMed

Lane, Scott D; da Costa, Sabrina C; Teixeira, Antonio L; Reynolds, Charles F; Diniz, Breno S

2018-02-01

To examine associations among substance use disorder (SUD) and measures of length of stay (LOS) and non-psychiatric medical comorbidity (MEDCO) in older-adult inpatients with serious mental illness (SMI), hypothesizing SUD would be related to worse clinical outcomes. A cross-sectional study analyzed medical records from 2010 to 2016 of 7258 inpatients with SMI ≥ age 50, obtained from a 274-bed psychiatric hospital. Descriptive analyses examined prevalence rates for SUD status (+/-), individual drug classes, and total number of SUDs (polysubstance use disorders). Regression models examined the influence of 2 independent variables of interest: (1) SUD status (+/-) and (2) type of SUD (ie, specific drug), controlling for demographic factors and additional (non-SUD) psychiatric disorders. Two dependent (outcome) variables were examined: LOS and MEDCO. The overall SUD rate was 26%; cocaine was the most common SUD (≈ 10%). SUD status and additional (non-SUD) psychiatric diagnoses were significantly associated with longer LOS (both P < 0.001). For individual SUDs, cocaine, marijuana, opiates, and alcohol were all significantly associated with LOS (all P < 0.01). SUD status, age, sex, admission status, and race were significantly associated with MEDCO (all P < 0.002). For individual SUDs, barbiturates, opiates, and alcohol were all significantly associated with MEDCO (P < 0.01). The prevalence of SUD in this sample underscores concerns related to treating older adults presenting providers with comorbid SUD and SMI. This combination may increase the burden and complexity of care, warranting further investigation into mechanisms and long-term consequences. Copyright © 2017 John Wiley & Sons, Ltd.

[Exposure to solvents and tardy epilepsy: 2 clinical cases].

PubMed

Bernardini, P; Scoppetta, C

1992-01-01

Organic solvents (OS) are widely used in industry and craft work. The neurotoxic effects of OS are well known in occupational exposure occurring in poor industrial hygiene conditions. There has been interest recently in a possible epileptogenic effect of OS exposure. Two cases are reported of late onset epilepsy observed in workers heavily exposed to OS. Case 1 was a 27-year-old male painter employed in a car body repair workshop. Solvent exposure was high for a few months because after his regular work, the man continued working as a car body painter in his own private concern. After a period of weakness and headache, probably indicating an excessive solvent absorption, he suffered two generalized paroxysmal seizures during sleep which necessitated hospitalization and continuous treatment with barbiturates. Case 2 was a 44-year-old male painter in a road advertising billboard factory who was continuously exposed to OS. Ten years previously he had been exposed to accidental massive inhalation of solvent vapours while opening a drum of solvents for coloured paint. Acute solvent poisoning followed and seven weeks later he suffered several epileptic episodes associated with typical EEG alterations; for many years, however, treatment was ineffective. In both cases there was neither a history of neurologic disease nor any other neurologic dysfunctions and the results of comprehensive neuroradiological studies were normal. Evidence exists of a chronological connection between high exposure to paint solvents and clinical evidence of late onset epilepsy, but it is not possible to identify a definite causal relationship.(ABSTRACT TRUNCATED AT 250 WORDS)

Drugs Used for Parenteral Sedation in Dental Practice

PubMed Central

Dionne, Raymond A.; Gift, Helen C.

1988-01-01

The relative efficacy and safety of drugs and combinations used clinically in dentistry as premedicants to alleviate patient apprehension are largely unsubstantiated. To evaluate the efficacy and safety of agents used for parenteral sedation through controlled clinical trials, it is first necessary to identify which drugs, doses, and routes of administration are actually used in practice. A survey instrument was developed to characterize the drugs used clinically for anesthesia and sedation by dentists with advanced training in pain control. A random sample of 500 dentists who frequently use anesthesia and sedation in practice was selected from the Fellows of the American Dental Society of Anesthesiology. The first mailing was followed by a second mailing to nonrespondents after 30 days. The respondents report a variety of parenteral sedation techniques in combination with local anesthesia (the response categories are not mutually exclusive): nitrous oxide (64%), intravenous conscious sedation (59%), intravenous “deep” sedation (47%), and outpatient general anesthesia (27%). Drugs most commonly reported for intravenous sedation include diazepam, methohexital, midazolam, and combinations of these drugs with narcotics. A total of 82 distinct drugs and combinations was reported for intravenous sedation and anesthesia. Oral premedication and intramuscular sedation are rarely used by this group. Most general anesthesia reported is done on an outpatient basis in private practice. These results indicate that a wide variety of drugs is employed for parenteral sedation in dental practice, but the most common practice among dentists with advanced training in anesthesia is local anesthesia supplemented with intravenous sedation consisting of a benzodiazepine and an opioid or a barbiturate. PMID:3250279

The effect of central nervous system depressant, stimulant and hallucinogenic drugs on injury severity in patients admitted for trauma.

PubMed

Cordovilla-Guardia, Sergio; Lardelli-Claret, Pablo; Vilar-López, Raquel; López-Espuela, Fidel; Guerrero-López, Francisco; Fernández-Mondéjar, Enrique

2017-08-04

The effect of drugs other than alcohol on severity of trauma remains unclear. Pooled data analyses in previous studies that grouped substances with opposite effects on the central nervous system (CNS) may have masked the influence of substances on injury severity. The aim was to analyze the effect of stimulant, hallucinogenic and depressant drugs other than alcohol on injury severity in trauma patients. The presence of alcohol, stimulant drugs (cocaine, amphetamines and methamphetamines), depressant drugs (benzodiazepines, opiates, methadone and barbiturates) and hallucinogenic drugs (THC and PCP) was analyzed in 1187 patients between 16 and 70 years old admitted to a trauma hospital between November 2012 and June 2015. Injury severity was determined prospectively as the Injury Severity Score. A multivariate analysis was used to quantify the strength of association between exposure to substances and trauma severity, using the presence of alcohol as a stratification variable. Drugs other than alcohol were found in 371 patients (31.3%): 32 (2.7%) stimulants, 186 (15.3%) depressants, 78 (6.6%) hallucinogenics and 75 (5.6%) polydrug use. The presence of CNS depressant substances was associated with increased injury severity only in patients also exposed to alcohol, with an adjusted odds ratio of 4.63 (1.37-15.60) for moderate injuries and 7.83 (2.53-24.21) for severe. CNS depressant drugs had a strong influence on injury severity in patients who screened positive for alcohol consumption. Copyright © 2017 SESPAS. Publicado por Elsevier España, S.L.U. All rights reserved.

Associations between Community Attachments and Adolescent Substance Use in Nationally Representative Samples

PubMed Central

Wray-Lake, Laura; Maggs, Jennifer L.; Johnston, Lloyd D.; Bachman, Jerald G.; O’Malley, Patrick M.; Schulenberg, John E.

2012-01-01

Purpose Social capital and social attachment theories of substance use argue that positive bonds to society and the conventional values they promote deter adolescents from substance use. Using nationally representative samples of U.S. high school seniors, we hypothesized that adolescents’ community attachments, measured by social trust, social responsibility, and religiosity, would be negatively associated with lifetime and 30-day substance use. Method We used repeated cross-sectional nationally representative high school senior data from 1976–2008 Monitoring the Future Study cohorts (weighted N = 64,246; 51.6% female). Participation rate ranged from 77% to 86% across years. A series of multiple linear and logistic regressions examined unique associations of adolescents’ social trust, social responsibility, and religiosity with lifetime and 30-day use of cigarettes, alcohol, marijuana, hallucinogens, cocaine, amphetamines, barbiturates, tranquilizers, and narcotics. Models controlled for gender, race, college aspirations, high school grades, parents’ education, and survey year. Results Social trust, social responsibility, and religiosity showed independent negative associations with use of cigarettes, alcohol, marijuana, and six other types of drugs. After accounting for controls, community attachments related to lower lifetime and past 30-day use. Associations were consistent across measures, except social responsibility was not associated with binge drinking or lifetime illicit drugs besides marijuana. Conclusions Study strengths included the nationally representative sample, diverse substance use measures, and inclusion of controls. We extend theory by suggesting that distinct aspects of adolescents’ community attachments uniquely relate to lower substance use. Results suggest potential public health benefits of integrating promotion of community attachments with substance use prevention. PMID:22999832

Hypericum grandifolium Choisy: a species native to Macaronesian Region with antidepressant effect.

PubMed

Sánchez-Mateo, C C; Bonkanka, C X; Rabanal, R M

2009-01-21

Various species of Hypericum genus have been used in the Canary Islands as sedative, diuretic, vermifuge, wound healing, antihysteric and antidepressant agent. Studies have shown that methanol extract of Hypericum grandifolium Choisy is active in tetrabenazine-induced ptosis and forced swimming tests. In the current study, the aqueous, butanol and chloroform fractions obtained from the methanol extract as well as three sub-fractions derived from the chloroform fraction were evaluated for their central nervous effects in mice, particularly their antidepressant activity. The central nervous effect of different fractions and sub-fractions of Hypericum grandifolium was evaluated in mice using various behavioural models including locomotor and muscle relaxant activity, forced swimming test, effect on normal body temperature, barbiturate-induced sleep, tetrabenazine-induced syndrome and 5-hydroxytryptohan-induced head twitches and syndrome. We found that the butanol and chloroform fractions and all sub-fractions showed an antidepressant effect in the forced swimming test, the chloroform fraction being the most active. They produced no effects or only a slight depression of locomotor activity. Chloroform fraction significantly increased the pentobarbital-induced sleeping time, produced a slight but significant hypothermia and antagonized tetrabenazine-induced ptosis, whereas the butanol fraction produced a slight potentiation of 5-HTP-induced head twitches and syndrome. The present results, together with previous pharmacological and phytochemical data, indicated that Hypericum grandifolium possess antidepressant-like effects in mice and that different constituents, such as the flavonoids and the benzophenone derivatives, could be responsible at least in part for the antidepressant effects observed for this species.

The prevalence of alcohol and psychotropic drugs in fatalities of road-traffic accidents in Jordan during 2008-2014.

PubMed

Al-Abdallat, Imad M; Al Ali, Rayyan; Hudaib, Arwa A; Salameh, Ghada A M; Salameh, Rakiz J M; Idhair, Ahmed K F

2016-04-01

Several studies confirmed alcohol and psychotropic drug consumption as important risk factors underlying fatal accidents. This paper presents updated toxicological findings in the fatalities of road traffic accidents of Amman district, in order to have an overall picture of the occurrence of these substances in these victims in Jordan. Over a seven-year period (2008-2014), 2743, autopsies were conducted at Jordan University Hospital in which the sum of n = 311 (11.38%) were victims of road traffic accidents. Blood samples from these victims were collected. Toxicology screening for psychotropic drugs and alcohol was conducted on these samples, and the results were analyzed according to age, sex and victim's status. This study revealed that Alcohol and psychotropic drugs were positive in 36.5%, (n = 58) of the cases, and for alcohol alone (n = 13, 37.1%). The majority of the victims were pedestrians (n = 155, 49.8%). Additionally, 29.6% (n = 92) of the cases were of ages 19-29. Detected psychotropic drugs were benzodiazepines, barbiturates. None of the collected specimens were positive for illicit cocaine, amphetamines or cannabis. The results from this study proved the existence of alcohol and psychotropic drugs in the victims of road traffic accidents; Indicating an association between the uses of these substances in accident involvement. Though having some limitations, other conclusions require further data collection, cooperation with related parties in Jordan, and utilizing simple extended toxicological screens. Copyright © 2016 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

Chronic exposure to emissions from photocopiers in copy shops causes oxidative stress and systematic inflammation among photocopier operators in India.

PubMed

Elango, Nithya; Kasi, Vallikkannu; Vembhu, Bhuvaneswari; Poornima, Jeyanthi Govindasamy

2013-09-11

We assessed indoor air quality in photocopier centers and investigated whether occupational exposure to emissions from photocopiers is associated with decline in lung function or changes in haematological parameters, oxidative stress and inflammatory status. Indoor air quality was monitored in five photocopier centers. Pulmonary function was assessed by spirometry in 81 photocopier operators (64 male and 17 female) and 43 healthy control (31 male and 12 female) subjects. Hematological status, serum thio-barbituric acid reactive substances (TBARS), total ferric reducing antioxidant capacity (FRAC), leukotriene B4 (LTB4), 8-isoprostane, C reactive protein (CRP), interleukin 8 (IL-8), clara cell protein (CC-16), intercellular adhesion molecule 1 (ICAM-1) and eosinophilic cationic protein (ECP) were analyzed. Relationships between cumulative exposure, lung function and inflammatory markers were assessed. PM10 and PM2.5 were above the permissible levels in all the photocopier centers, whereas the levels of carbon monoxide, nitrogen oxides, ozone, sulphur dioxide, lead, arsenic, nickel, ammonia, benzene and benzo(a)pyrene were within Indian ambient air quality standards. Lung function was similar in the photocopier operators and control subjects. Serum TBARS was significantly higher and FRAC was lower among photocopier operators when compared to healthy controls. Plasma IL-8, LTB4, ICAM-1 and ECP were significantly higher in the photocopier exposed group. Photocopiers emit high levels of particulate matter. Long term exposure to emissions from photocopiers was not associated with decreased lung function, but resulted in high oxidative stress and systemic inflammation leading to high risk of cardiovascular diseases.

Impact of new-generation agents on antiepileptic drug prescribing patterns in a residential ICF-MR facility.

PubMed

Smith, Stacey Allison; McKee, Jerry R

2004-06-01

Describe the impact of newer antiepileptic drugs (AEDs) on prescribing practices in a large, residential intermediate-care facility for the mentally retarded (ICF-MR), with onsite clinical pharmacist support services, over a 15-year period. All residents at the facility receiving AEDs for management of seizure disorder were included in this retrospective assessment. Number and type of AEDs used per individual were recorded and analyzed over the 15-year interval. Current prescribing practices were evaluated regarding rational polytherapy prescribing trends. 400-bed residential ICF-MR for the severe to profoundly mentally retarded. All individuals residing at the ICF-MR facility receiving AED therapy for a seizure disorder. Residents were primarily in the severe to profound range of developmental disability, with multiple medical comorbidities. Clinical pharmacists actively participate in all treatment teams and monthly neurology clinic to promote and encourage rational pharmacotherapy. Prescribing trends related to AED therapy were followed over a 15-year period. Comparisons were made regarding monotherapy and polytherapy at multiple-year intervals, with specific emphasis on how the newer generation AEDs have affected use of older medications. Overall trend from 1988 suggests more monotherapy and less use of barbiturates. Introduction of a new generation of AEDs has not affected the overall trend toward one- or two-drug regimens over the period in review. The relative stability of the number of AEDs per resident during the introduction of a new generation of AEDs suggests that as new drugs are added, ineffective or problem-prone drugs are discontinued.

A controlled investigation of propofol, thiopentone and methohexitone.

PubMed

Gold, M I; Abraham, E C; Herrington, C

1987-09-01

This was a randomized study of 180 ASA physical status I and II patients, 60 in each group who received propofol (PROP), 2.5 mg . kg-1, thiopentone (THIO), 4 mg . kg-1, or methohexitone (METH), 1.5 mg . kg-1. Control values, followed by changes after induction and during a 3-min delay before intubation were recorded for the following parameters: heart rate (HR), systolic and diastolic blood pressures (SBP, DBP), respiratory rate (RR), end-tidal CO2 (PETCO2), and induction time (IT). In addition, the incidence of adverse reactions and time for recovery from anaesthesia were noted. The IT (mean +/- SE) was 35 +/- 1 sec for propofol, 35 +/- 1.2 sec for thiopentone and 34 +/- 1.4 sec for methohexitone. Ninety-three per cent of the PROP group fell asleep with one dose and required no additional doses. Fifty per cent of each of the THIO and METH groups required additional agents (p less than 0.05). METH was associated with the highest elevation in HR, PROP the least (p less than 0.05). PROP was associated with the most decrease in SBP and DBP and in addition respiratory depression (p less than 0.05). The incidence of injection pain or excitatory activity was equal in the three groups with the exception that 14 patients who received METH developed hiccoughs while none did in the other groups. PROP was associated with the most rapid recovery, particularly with respect to the orientation time. We conclude that PROP is an effective alternative to barbiturate induction and that the published recommended doses of THIO and METH are often ineffective.

Metabolic mechanisms of drug-nutrient interactions.

PubMed

Hathcock, J N

1985-01-01

Metabolic mechanisms of nutrition and drug interactions include 1) the effects of diet on drug metabolism and action and 2) the effects of drugs on nutritional processes. The type, amount, and timing of foods consumed influence drug dissolution, absorption, distribution, metabolism, and excretion. High-fat meals enhance the absorption of griseofulvin and some other drugs. Milk and other sources of calcium inhibit absorption of tetracycline. High-fat meals increase plasma concentrations of free fatty acids and thereby displace many drugs from binding sites on plasma albumin. High-protein diets increase the activity of the mixed-function oxidase system and enhance the metabolism of numerous drugs. High-electrolyte intakes increase excretion of lithium and also diminish the action of diuretic agents. Bile acid sequestrants and some laxatives decrease lipid digestion and absorption, as well as absorption of the fat-soluble vitamins. Numerous drugs, including tetracycline and cholestyramine, bind iron and decrease its absorption. Coumarins inhibit the function of vitamin K. Phenobarbital and other anticonvulsants are inducers of cytochrome P-450 and the mixed-function oxidase system. Long-term treatment with these inducers can cause excessive metabolism and deficiency of vitamin D. Prooxidant drugs such as chloroquine, drugs detoxified by conjugation with glutathione, and alcohol can deplete reduced glutathione with consequent effects on amino acid transport and the redox status of cells. Acid-forming foods acidify the urine and increase the loss of alkaline drugs such as the amphetamines. Base-forming drugs increase the loss of acidic drugs such as barbiturates. The range of metabolic interactions of drugs and nutrients includes the full scope of physiological processes to which drugs and nutrients are subject.

Structural Basis of Cerebellar Microcircuits in the Rat

PubMed Central

Cerminara, Nadia L.; Aoki, Hanako; Loft, Michaela; Apps, Richard

2013-01-01

The topography of the cerebellar cortex is described by at least three different maps, with the basic units of each map termed “microzones,” “patches,” and “bands.” These are defined, respectively, by different patterns of climbing fiber input, mossy fiber input, and Purkinje cell (PC) phenotype. Based on embryological development, the “one-map” hypothesis proposes that the basic units of each map align in the adult animal and the aim of the present study was to test this possibility. In barbiturate anesthetized adult rats, nanoinjections of bidirectional tracer (Retrobeads and biotinylated dextran amine) were made into somatotopically identified regions within the hindlimb C1 zone in copula pyramidis. Injection sites were mapped relative to PC bands defined by the molecular marker zebrin II and were correlated with the pattern of retrograde cell labeling within the inferior olive and in the basilar pontine nuclei to determine connectivity of microzones and patches, respectively, and also with the distributions of biotinylated dextran amine-labeled PC terminals in the cerebellar nuclei. Zebrin bands were found to be related to both climbing fiber and mossy fiber inputs and also to cortical representation of different parts of the ipsilateral hindpaw, indicating a precise spatial organization within cerebellar microcircuitry. This precise connectivity extends to PC terminal fields in the cerebellar nuclei and olivonuclear projections. These findings strongly support the one-map hypothesis and suggest that, at the microcircuit level of resolution, the cerebellar cortex has a common plan of spatial organization for major inputs, outputs, and PC phenotype. PMID:24133249

Early drug discovery and the rise of pharmaceutical chemistry.

PubMed

Jones, Alan Wayne

2011-06-01

Studies in the field of forensic pharmacology and toxicology would not be complete without some knowledge of the history of drug discovery, the various personalities involved, and the events leading to the development and introduction of new therapeutic agents. The first medicinal drugs came from natural sources and existed in the form of herbs, plants, roots, vines and fungi. Until the mid-nineteenth century nature's pharmaceuticals were all that were available to relieve man's pain and suffering. The first synthetic drug, chloral hydrate, was discovered in 1869 and introduced as a sedative-hypnotic; it is still available today in some countries. The first pharmaceutical companies were spin-offs from the textiles and synthetic dye industry and owe much to the rich source of organic chemicals derived from the distillation of coal (coal-tar). The first analgesics and antipyretics, exemplified by phenacetin and acetanilide, were simple chemical derivatives of aniline and p-nitrophenol, both of which were byproducts from coal-tar. An extract from the bark of the white willow tree had been used for centuries to treat various fevers and inflammation. The active principle in white willow, salicin or salicylic acid, had a bitter taste and irritated the gastric mucosa, but a simple chemical modification was much more palatable. This was acetylsalicylic acid, better known as Aspirin®, the first blockbuster drug. At the start of the twentieth century, the first of the barbiturate family of drugs entered the pharmacopoeia and the rest, as they say, is history. Copyright © 2011 John Wiley & Sons, Ltd.

Chronic exposure to emissions from photocopiers in copy shops causes oxidative stress and systematic inflammation among photocopier operators in India

PubMed Central

2013-01-01

Background We assessed indoor air quality in photocopier centers and investigated whether occupational exposure to emissions from photocopiers is associated with decline in lung function or changes in haematological parameters, oxidative stress and inflammatory status. Methods Indoor air quality was monitored in five photocopier centers. Pulmonary function was assessed by spirometry in 81 photocopier operators (64 male and 17 female) and 43 healthy control (31 male and 12 female) subjects. Hematological status, serum thio-barbituric acid reactive substances (TBARS), total ferric reducing antioxidant capacity (FRAC), leukotriene B4 (LTB4), 8-isoprostane, C reactive protein (CRP), interleukin 8 (IL-8), clara cell protein (CC-16), intercellular adhesion molecule 1 (ICAM-1) and eosinophilic cationic protein (ECP) were analyzed. Relationships between cumulative exposure, lung function and inflammatory markers were assessed. Results PM10 and PM2.5 were above the permissible levels in all the photocopier centers, whereas the levels of carbon monoxide, nitrogen oxides, ozone, sulphur dioxide, lead, arsenic, nickel, ammonia, benzene and benzo(a)pyrene were within Indian ambient air quality standards. Lung function was similar in the photocopier operators and control subjects. Serum TBARS was significantly higher and FRAC was lower among photocopier operators when compared to healthy controls. Plasma IL-8, LTB4, ICAM-1 and ECP were significantly higher in the photocopier exposed group. Conclusions Photocopiers emit high levels of particulate matter. Long term exposure to emissions from photocopiers was not associated with decreased lung function, but resulted in high oxidative stress and systemic inflammation leading to high risk of cardiovascular diseases. PMID:24025094

Severe Carisoprodol Withdrawal After a 14-Year Addiction and Acute Overdose.

PubMed

Vo, Kathy T; Horng, Howard; Smollin, Craig G; Benowitz, Neal L

2017-05-01

Carisoprodol, a centrally acting muscle relaxant with a high abuse potential, has barbiturate-like properties at the GABA-A receptor, leading to central nervous system depression and desired effects. Its tolerance and dependence has been previously demonstrated in an animal model, and withdrawal has been described in several recent case reports. Many cases can be effectively managed with a short course of benzodiazepines or antipsychotic agents. However, abrupt cessation in a patient with a history of long-term and high-dose carisoprodol abuse may result in symptoms that are more difficult for providers to treat. We present a case of a 34-year-old man with a long history of carisoprodol abuse who was found unresponsive after having ingested 7.5 grams of carisoprodol. He was intubated and admitted to the intensive care unit. He was given propofol, dexmedetomidine, fentanyl, ketamine, lorazepam, midazolam, quetiapine, and haloperidol, some at high-dose infusions, before his agitation and ventilator asynchrony could be controlled. His improvement coincided with the addition of carisoprodol and phenobarbital to his treatment regimen. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Trends show increasing emergency department presentations for drug-related disorders and treatment. This case highlights an uncommon case of carisoprodol withdrawal that may be encountered by emergency physicians, and demonstrates that benzodiazepines may not be sufficient to suppress severe withdrawal symptoms. Treatment with carisoprodol and phenobarbital provided additional benefit and can be considered in cases of severe carisoprodol withdrawal. Copyright © 2016 Elsevier Inc. All rights reserved.

Sniffer patch laser uncaging response (SPLURgE): an assay of regional differences in allosteric receptor modulation and neurotransmitter clearance

PubMed Central

Christian, Catherine A.

2013-01-01

Allosteric modulators exert actions on neurotransmitter receptors by positively or negatively altering the effective response of these receptors to their respective neurotransmitter. γ-Aminobutyric acid (GABA) type A ionotropic receptors (GABAARs) are major targets for allosteric modulators such as benzodiazepines, neurosteroids, and barbiturates. Analysis of substances that produce similar effects has been hampered by the lack of techniques to assess the localization and function of such agents in brain slices. Here we describe measurement of the sniffer patch laser uncaging response (SPLURgE), which combines the sniffer patch recording configuration with laser photolysis of caged GABA. This methodology enables the detection of allosteric GABAAR modulators endogenously present in discrete areas of the brain slice and allows for the application of exogenous GABA with spatiotemporal control without altering the release and localization of endogenous modulators within the slice. Here we demonstrate the development and use of this technique for the measurement of allosteric modulation in different areas of the thalamus. Application of this technique will be useful in determining whether a lack of modulatory effect on a particular category of neurons or receptors is due to insensitivity to allosteric modulation or a lack of local release of endogenous ligand. We also demonstrate that this technique can be used to investigate GABA diffusion and uptake. This method thus provides a biosensor assay for rapid detection of endogenous GABAAR modulators and has the potential to aid studies of allosteric modulators that exert effects on other classes of neurotransmitter receptors, such as glutamate, acetylcholine, or glycine receptors. PMID:23843428

Sniffer patch laser uncaging response (SPLURgE): an assay of regional differences in allosteric receptor modulation and neurotransmitter clearance.

PubMed

Christian, Catherine A; Huguenard, John R

2013-10-01

Allosteric modulators exert actions on neurotransmitter receptors by positively or negatively altering the effective response of these receptors to their respective neurotransmitter. γ-Aminobutyric acid (GABA) type A ionotropic receptors (GABAARs) are major targets for allosteric modulators such as benzodiazepines, neurosteroids, and barbiturates. Analysis of substances that produce similar effects has been hampered by the lack of techniques to assess the localization and function of such agents in brain slices. Here we describe measurement of the sniffer patch laser uncaging response (SPLURgE), which combines the sniffer patch recording configuration with laser photolysis of caged GABA. This methodology enables the detection of allosteric GABAAR modulators endogenously present in discrete areas of the brain slice and allows for the application of exogenous GABA with spatiotemporal control without altering the release and localization of endogenous modulators within the slice. Here we demonstrate the development and use of this technique for the measurement of allosteric modulation in different areas of the thalamus. Application of this technique will be useful in determining whether a lack of modulatory effect on a particular category of neurons or receptors is due to insensitivity to allosteric modulation or a lack of local release of endogenous ligand. We also demonstrate that this technique can be used to investigate GABA diffusion and uptake. This method thus provides a biosensor assay for rapid detection of endogenous GABAAR modulators and has the potential to aid studies of allosteric modulators that exert effects on other classes of neurotransmitter receptors, such as glutamate, acetylcholine, or glycine receptors.

Delayed posthypoxic leukoencephalopathy: a case series and review of the literature

PubMed Central

Zamora, Carlos A; Nauen, David; Hynecek, Robert; Ilica, Ahmet T; Izbudak, Izlem; Sair, Haris I; Gujar, Sachin K; Pillai, Jay J

2015-01-01

Background Delayed posthypoxic leukoencephalopathy (DPHL) is a rare and underrecognized entity where patients manifest a neurological relapse after initial recovery from an acute hypoxic episode. We sought to describe the magnetic resonance imaging (MRI) findings in a group of patients with DPHL and review the available literature. Methods Retrospective case series including patients who presented with neurological and/or psychiatric symptoms after recovery from an acute hypoxic episode. The history and clinical presentation were reviewed from the electronic medical records. MRI scans were evaluated from the picture archiving and communication system. We performed a comprehensive review of the English medical literature for prior published cases of DPHL and describe the key imaging findings that have been reported related to this condition. Results A total of five patients were identified, including four patients with respiratory failure due to drug overdoses from benzodiazepines, opioids, and/or barbiturates, and one patient who presented after cardiopulmonary arrest due to pulmonary embolism. All patients showed diffuse, extensive, and confluent white matter signal abnormalities including prominent restricted diffusion, extending to the subcortical white matter and respecting the U-fibers. There was no gyral edema or contrast enhancement. In one case histopathology was available, which highlighted patchy subcortical myelin loss with sparing of U-fibers and demonstrated prominent macrophage/microglial inflammation with extensive axonal damage. Of the other four patients, two were at their neurological baselines and two had persistent neurological deficits at the time of discharge. Conclusions The described constellation of MRI findings is highly suggestive of DPHL in the appropriate clinical setting. PMID:26357591

Piracetam and other structurally related nootropics.

PubMed

Gouliaev, A H; Senning, A

1994-05-01

Nearly three decades have now passed since the discovery of the piracetam-like nootropics, compounds which exhibit cognition-enhancing properties, but for which no commonly accepted mechanism of action has been established. This review covers clinical, pharmacokinetic, biochemical and behavioural results presented in the literature from 1965 through 1992 (407 references) of piracetam, oxiracetam, pramiracetam, etiracetam, nefiracetam, aniracetam and rolziracetam and their structural analogues. The piracetam-like nootropics are capable of achieving reversal of amnesia induced by, e.g., scopolamine, electroconvulsive shock and hypoxia. Protection against barbiturate intoxication is observed and some benefit in clinical studies with patients suffering from mild to moderate degrees of dementia has been demonstrated. No affinity for the alpha 1-, alpha 2-, beta-, muscarinic, 5-hydroxytryptamine-, dopamine, adenosine-A1-, mu-opiate, gamma-aminobutyric acid (GABA) (except for nefiracetam (GABAA)), benzodiazepine and glutamate receptors has been found. The racetams possess a very low toxicity and lack serious side effects. Increased turnover of different neurotransmitters has been observed as well as other biochemical findings, e.g., inhibition of enzymes such as prolylendopeptidase. So far, no generally accepted mechanism of action has, however, emerged. We believe that the effect of the racetams is due to a potentiation of already present neurotransmission and that much evidence points in the direction of a modulated ion flux by, e.g., potentiated calcium influx through non-L-type voltage-dependent calcium channels, potentiated sodium influx through alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor gated channels or voltage-dependent channels or decreases in potassium efflux. Effects on carrier mediated ion transport are also possible.

Protein tethering enables rapid and label-free SERS platform for screening drugs of abuse (Conference Presentation)

NASA Astrophysics Data System (ADS)

Siddhanta, Soumik; Wróbel, Maciej S.; Barman, Ishan

2017-02-01

A quick, cost-effective method for detection of drugs of abuse in biological fluids would be of great value in healthcare, law enforcement, and home testing applications. The alarming rise in narcotics abuse has led to considerable focus on developing potent and versatile analytical tools that can address this societal problem. While laboratory testing plays a key role in the current detection of drug misuse and the evaluation of patients with drug induced intoxication, these typically require expensive reagents and trained personnel, and may take hours to complete. Thus, a significant unmet need is to engineer a facile method that can rapidly detect drugs with little sample preparation, especially the bound fraction that is typically dominant in the blood stream. Here we report an approach that combines the exquisite sensitivity of surface enhanced Raman spectroscopy (SERS) and a facile protein tethering mechanism to reliably detect four different classes of drugs, barbiturate, benzodiazepine, amphetamine and benzoylecgonine. The proposed approach harnesses the reliable and specific attachment of proteins to both drugs and nanoparticle to facilitate the enhancement of spectral markers that are sensitive to the presence of the drugs. In conjunction with chemometric tools, we have shown the ability to quantify these drugs lower than levels achievable by existing clinical immunoassays. Through molecular docking simulations, we also probe the mechanistic underpinnings of the protein tethering approach, opening the door to detection of a broad class of narcotics in biological fluids within a few minutes as well as for groundwater analysis and toxin detection.

Importance of Urinary Drug Screening in the Multiple Sleep Latency Test and Maintenance of Wakefulness Test.

PubMed

Anniss, Angela M; Young, Alan; O'Driscoll, Denise M

2016-12-15

Multiple sleep latency testing (MSLT) and the maintenance of wakefulness test (MWT) are gold-standard objective tests of daytime sleepiness and alertness; however, there is marked variability in their interpretation and practice. This study aimed to determine the incidence of positive drug screens and their influence on MSLT, MWT, and polysomnographic variables. All patients attending Eastern Health Sleep Laboratory for MSLT or MWT over a 21-mo period were included in the study. Urinary drug screening for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, methadone, and opiates was performed following overnight polysomnography (PSG). Demographics and PSG variables were compared. Of 69 studies, MSLT (43) and MWT (26), 16% of patients had positive urinary drug screening (7 MSLT; 4 MWT). Drugs detected included amphetamines, cannabinoids, opiates, and benzodiazepines. No patient self-reported use of these medications prior to testing. No demographic, MSLT or MWT PSG data or overnight PSG data showed any statistical differences between positive and negative drug screen groups. Of seven MSLT patients testing positive for drug use, one met criteria for the diagnosis of narcolepsy and five for idiopathic hypersomnia. On MWT, three of the four drug-positive patients had a history of a motor vehicle accident and two patients were occupational drivers. These findings indicate drug use is present in patients attending for daytime testing of objective sleepiness and wakefulness. These data support routine urinary drug screening in all patients undergoing MSLT or MWT studies to ensure accurate interpretation in the context of illicit and prescription drug use. © 2016 American Academy of Sleep Medicine

Demographic profile and extent of healthcare resource utilisation of patients with severe traumatic brain injury: still a major public health problem.

PubMed

Wee, Jing Zhong; Yang, Yun Rui Jasmine; Lee, Qian Yi Ruth; Cao, Kelly; Chong, Chin Ted

2016-09-01

Trauma is the fifth principal cause of death in Singapore, with traumatic brain injury (TBI) being the leading specific subordinate cause. This study was an eight-year retrospective review of the demographic profiles of patients with severe TBI who were admitted to the neurointensive care unit (NICU) of the National Neuroscience Institute at Tan Tock Seng Hospital, Singapore, between 2004 and 2011. A total of 780 TBI patients were admitted during the study period; 365 (46.8%) patients sustained severe TBI (i.e. Glasgow Coma Scale score ≤ 8), with the majority (75.3%) being male. The ages of patients with severe TBI ranged from 14-93 years, with a bimodal preponderance in young adults (i.e. 21-40 years) and elderly persons (i.e. > 60 years). Motor vehicle accidents (48.8%) and falls (42.5%) were the main mechanisms of injury. Invasive line monitoring was frequently employed; invasive arterial blood pressure monitoring and central venous pressure monitoring were used in 81.6% and 60.0% of the patients, respectively, while intracranial pressure (ICP) measurement was required in 47.4% of the patients. The use of tiered therapy to control ICP (e.g. sedation, osmotherapy, cerebrospinal fluid drainage, moderate hyperventilation and barbiturate-induced coma) converged with international practices. The high-risk groups for severe TBI were young adults and elderly persons involved in motor vehicle accidents and falls, respectively. In the NICU, the care of patients with severe TBI requires heavy utilisation of resources. The healthcare burden of these patients extends beyond the acute critical care phase.

[Ketamine as anesthetic agent in electroconvulsion therapy].

PubMed

Janke, C; Bumb, J M; Aksay, S S; Thiel, M; Kranaster, L; Sartorius, A

2015-05-01

Electroconvulsive therapy (ECT) is a well-established, safe and effective treatment for severe psychiatric disorders. Ketamine is known as a core medication in anesthesiology and has recently gained interest in ECT practice as there are three potential advantages: (1) ketamine has no anticonvulsive actions, (2) according to recent studies ketamine could possess a unique intrinsic antidepressive potential and (3) ketamine may exhibit neuroprotective properties, which again might reduce the risk of cognitive side effects associated with ECT. The use of ketamine in psychiatric patients has been controversially discussed due to its dose-dependent psychotropic and psychotomimetic effects. This study was carried out to test if the occurrence of side effects is comparable and if seizure quality is better with ketamine when compared to thiopental. This retrospective study analyzed a total of 199 patients who received ketamine anesthesia for a total of 2178 ECT sessions. This cohort was compared to patients who were treated with thiopental for 1004 ECT sessions. A repeated measurement multiple logistic regression analysis revealed significant advantages in the ketamine group for seizure concordance and postictal suppression (both are surrogates for central inhibition). S-ketamin also necessitated the use of a higher dose of urapidil and a higher maximum postictal heart frequency. Clinically relevant psychiatric side effects were rare in both groups. No psychiatric side effects occurred in the subgroup of patients with schizophrenia (ketamine: n = 30). The mean dose of S-ketamine used increased in the first years but stabilized at 63 mg per patient in 2014. From these experiences it can be concluded that S-ketamine can be recommended at least as a safe alternative to barbiturates.

Stereoselective modulatory actions of oleamide on GABAA receptors and voltage-gated Na+ channels in vitro: a putative endogenous ligand for depressant drug sites in CNS

PubMed Central

Verdon, Bernard; Zheng, Jian; Nicholson, Russell A; Ganelli, C Robin; Lees, George

2000-01-01

cis-9,10-octadecenoamide (‘oleamide') accumulates in CSF on sleep deprivation. It induces sleep in animals (the trans form is inactive) but its cellular actions are poorly characterized. We have used electrophysiology in cultures from embryonic rat cortex and biochemical studies in mouse nerve preparations to address these issues. Twenty μM cis-oleamide (but not trans) reversibly enhanced GABAA currents and depressed the frequency of spontaneous excitatory and inhibitory synaptic activity in cultured networks. cis-oleamide stereoselectively blocked veratridine-induced (but not K+-induced) depolarisation of mouse synaptoneurosomes (IC50, 13.9 μM). The cis isomer stereoselectively blocked veratridine-induced (but not K+-induced) [3H]-GABA release from mouse synaptosomes (IC50, 4.6 μM). At 20 μM cis-oleamide, but not trans, produced a marked inhibition of Na+ channel-dependent rises in intrasynaptosomal Ca2+. The physiological significance of these observations was examined by isolating Na+ spikes in cultured pyramidal neurones. Sixty-four μM cis-oleamide did not significantly alter the amplitude, rate of rise or duration of unitary action potentials (1 Hz). cis-Oleamide stereoselectively suppressed sustained repetitive firing (SRF) in these cells with an EC50 of 4.1 μM suggesting a frequency- or state-dependent block of voltage-gated Na+ channels. Oleamide is a stereoselective modulator of both postsynaptic GABAA receptors and presynaptic or somatic voltage-gated Na+ channels which are crucial for synaptic inhibition and conduction. The modulatory actions are strikingly similar to those displayed by sedative or anticonvulsant barbiturates and a variety of general anaesthetics. Oleamide may represent an endogenous modulator for drug receptors and an important regulator of arousal. PMID:10694234

No association between intraoperative hypothermia or supplemental protective drug and neurologic outcomes in patients undergoing temporary clipping during cerebral aneurysm surgery: findings from the Intraoperative Hypothermia for Aneurysm Surgery Trial.

PubMed

Hindman, Bradley J; Bayman, Emine O; Pfisterer, Wolfgang K; Torner, James C; Todd, Michael M

2010-01-01

Although hypothermia and barbiturates improve neurologic outcomes in animal temporary focal ischemia models, the clinical efficacy of these interventions during temporary occlusion of the cerebral vasculature during intracranial aneurysm surgery (temporary clipping) is not established. A post hoc analysis of patients from the Intraoperative Hypothermia for Aneurysm Surgery Trial who underwent temporary clipping was performed. Univariate and multivariate logistic regression methods were used to test for associations between hypothermia, supplemental protective drug, and short- (24-h) and long-term (3-month) neurologic outcomes. An odds ratio more than 1 denotes better outcome. Patients undergoing temporary clipping (n = 441) were assigned to intraoperative hypothermia (33.3 degrees +/- 0.8 degrees C, n = 208) or normothermia (36.7 degrees +/- 0.5 degrees C, n = 233), with 178 patients also receiving supplemental protective drug (thiopental or etomidate) during temporary clipping. Three months after surgery, 278 patients (63%) had good outcome (Glasgow Outcome Score = 1). Neither hypothermia (P = 0.847; odds ratio = 1.043, 95% CI = 0.678-1.606) nor supplemental protective drug (P = 0.835; odds ratio = 1.048, 95% CI = 0.674-1.631) were associated with 3-month Glasgow Outcome Score. The effect of supplemental protective drug did not significantly vary with temperature. The effects of hypothermia and protective drug did not significantly vary with temporary clip duration. Similar findings were made for 24-h neurologic status and 3-month Neuropsychological Composite Score. In the Intraoperative Hypothermia for Aneurysm Surgery Trial, neither systemic hypothermia nor supplemental protective drug affected short- or long-term neurologic outcomes of patients undergoing temporary clipping.

The influence of the nasal mucosa and the carotid rete upon hypothalamic temperature in sheep

PubMed Central

Baker, Mary Ann; Hayward, James N.

1968-01-01

1. In chronically-prepared sheep, intracranial temperatures were measured in the cavernous sinus among the vessels of the carotid rete and at the circle of Willis extravascularly, and in the preoptic area and in other brain stem regions. Extracranial temperatures were measured intravascularly in the carotid or internal maxillary arteries and on the nasal mucosa and the skin of the ear. 2. At 20° C ambient temperature, shifts in temperature of the hypothalamus and of other brain sites paralleled temperature shifts in the cerebral arterial blood which was cooler than central arterial blood. During periods of arousal and of paradoxical sleep, vasoconstriction of the nasal mucosa and the ear skin occurred and temperatures at the cerebral arteries and in the brain rose without a comparable rise in central arterial blood temperature. 3. Anaesthetic doses of barbiturate abolished the temperature oscillations in the cerebral arterial blood and the brain. When air was blown rapidly over the nasal mucosa in anaesthetized animals, temperatures dropped precipitously in the cavernous sinus, at the cerebral arteries, and in the brain, while central arterial temperature fell only slightly. Injections of latex into the facial venous system demonstrated a venous pathway from the nasal mucosa to the cavernous sinus. 4. When sheep were exposed to 45-50° C ambient temperature, respiratory rate increased 5-10 times and the temperature gradient between central and cerebral arterial blood widened. 5. It is concluded that venous blood returning from the nasal mucosa and the skin of the head to the cavernous sinus cools the central arterial blood in the carotid rete. This is an important factor in the maintenance of hypothalamic temperature in the wool-covered, long-nosed, panting sheep and undoubtedly affects hypothalamic thermoreceptors and temperature regulation in artiodactyls. PMID:5685288

Developmental nicotine exposure adversely effects respiratory patterning in the barbiturate anesthetized neonatal rat.

PubMed

Barreda, Santiago; Kidder, Ian J; Mudery, Jordan A; Bailey, E Fiona

2015-03-01

Neonates at risk for sudden infant death syndrome (SIDS) are hospitalized for cardiorespiratory monitoring however, monitoring is costly and generates large quantities of averaged data that serve as poor predictors of infant risk. In this study we used a traditional autocorrelation function (ACF) testing its suitability as a tool to detect subtle alterations in respiratory patterning in vivo. We applied the ACF to chest wall motion tracings obtained from rat pups in the period corresponding to the mid-to-end of the third trimester of human pregnancy. Pups were drawn from two groups: nicotine-exposed and saline-exposed at each age (i.e., P7, P8, P9, and P10). Respiratory-related motions of the chest wall were recorded in room air and in response to an arousal stimulus (FIO2 14%). The autocorrelation function was used to determine measures of breathing rate and respiratory patterning. Unlike alternative tools such as Poincare plots that depict an averaged difference in a measure breath to breath, the ACF when applied to a digitized chest wall trace yields an instantaneous sample of data points that can be used to compare (data) points at the same time in the next breath or in any subsequent number of breaths. The moment-to-moment evaluation of chest wall motion detected subtle differences in respiratory pattern in rat pups exposed to nicotine in utero and aged matched saline-exposed peers. The ACF can be applied online as well as to existing data sets and requires comparatively short sampling windows (∼2 min). As shown here, the ACF could be used to identify factors that precipitate or minimize instability and thus, offers a quantitative measure of risk in vulnerable populations. Copyright © 2015 Elsevier B.V. All rights reserved.

Neural Correlates and Mechanisms of Spatial Release From Masking: Single-Unit and Population Responses in the Inferior Colliculus

PubMed Central

Lane, Courtney C.; Delgutte, Bertrand

2007-01-01

Spatial release from masking (SRM), a factor in listening in noisy environments, is the improvement in auditory signal detection obtained when a signal is separated in space from a masker. To study the neural mechanisms of SRM, we recorded from single units in the inferior colliculus (IC) of barbiturate-anesthetized cats, focusing on low-frequency neurons sensitive to interaural time differences. The stimulus was a broadband chirp train with a 40-Hz repetition rate in continuous broadband noise, and the unit responses were measured for several signal and masker (virtual) locations. Masked thresholds (the lowest signal-to-noise ratio, SNR, for which the signal could be detected for 75% of the stimulus presentations) changed systematically with signal and masker location. Single-unit thresholds did not necessarily improve with signal and masker separation; instead, they tended to reflect the units’ azimuth preference. Both how the signal was detected (through a rate increase or decrease) and how the noise masked the signal response (suppressive or excitatory masking) changed with signal and masker azimuth, consistent with a cross-correlator model of binaural processing. However, additional processing, perhaps related to the signal’s amplitude modulation rate, appeared to influence the units’ responses. The population masked thresholds (the most sensitive unit’s threshold at each signal and masker location) did improve with signal and masker separation as a result of the variety of azimuth preferences in our unit sample. The population thresholds were similar to human behavioral thresholds in both SNR value and shape, indicating that these units may provide a neural substrate for low-frequency SRM. PMID:15857966

[Etiology of initially unexplained confusion of excitability in deadly nightshade poisoning with suicidal intent. Symptoms, differential diagnosis, toxicology and physostigmine therapy of anticholinergic syndrome].

PubMed

Heindl, S; Binder, C; Desel, H; Matthies, U; Lojewski, I; Bandelow, B; Kahl, G F; Chemnitius, J M

2000-11-10

After a walk in a wood a 55-year-old teacher was admitted to the emergency unit of a university hospital because of somnolence and excitability. Her rectal temperature was 37.8 degrees C, she had sinus tachycardia (rate of 130/min) but no other significant findings. With the exception of C-reactive protein (10 mg/dl), MCV (101 fl), MCH (34 pg) and arterial blood gases (pH 7.483, pCO2 35.5 mmHg, base excess 5.1 mmp/l) laboratory tests were within normal limits. Qualitative screening of serum for benzodiazepines, barbiturates and antidepressives was negative. Neurological examination, including lumbar puncture and cranial computed tomography were noncontributory. 10 hours after admission the patient developed signs of an anticholinergic syndrome with mydriasis, dry mouth, tachycardia, hot skin and an atonic bladder. Physostigmine 2 mg completely reversed the neurological and mental symptoms. After gas chromatography, mass-spectrometry of a urine sample showed an atropine molecular fragment with a molecular weight of 271. At intervals of 3 to 5 hours the recurrence of confusion and excitability required 4 further i.v. injection of physostigmine. The patient subsequently became accessible to psychiatric examination and reported that during the walk she had swallowed 8-10 berries of deadly nightshade with suicidal intent. In case of excitability and confusion as well as somnolence or coma of uncertain aetiology an anticholinergic syndrome caused by ingestion of atropine-containing plants or psychoactive drugs (phenothiazines, butyrophenones, tri- or tetracyclic antidepressants) should be included in the differential diagnosis. If there are suggestive clinical findings (tachycardia, somnolence, coma or threatened respiratory arrest, physostigmine should be given if there are no contraindications.

Anaesthetic and other treatments of shell shock: World War I and beyond.

PubMed

McKenzie, A G

2012-03-01

Post-traumatic stress disorder (PTSD) is an important health risk factor for military personnel deployed in modern warfare. In World War I this condition (then known as shell shock or 'neurasthenia') was such a problem that 'forward psychiatry' was begun by French doctors in 1915. Some British doctors tried general anaesthesia as a treatment (ether and chloroform), while others preferred application of electricity. Four British 'forward psychiatric units' were set up in 1917. Hospitals for shell shocked soldiers were also established in Britain, including (for officers) Craiglockhart War Hospital in Edinburgh; patients diagnosed to have more serious psychiatric conditions were transferred to the Royal Edinburgh Asylum. Towards the end of 1918 anaesthetic and electrical treatments of shell shock were gradually displaced by modified Freudian methods psychodynamic intervention. The efficacy of 'forward psychiatry' was controversial. In 1922 the War Office produced a report on shell shock with recommendations for prevention of war neurosis. However, when World War II broke out in 1939, this seemed to have been ignored. The term 'combat fatigue' was introduced as breakdown rates became alarming, and then the value of pre-selection was recognised. At the Maudsley Hospital in London in 1940 barbiturate abreaction was advocated for quick relief from severe anxiety and hysteria, using i.v. anaesthetics: Somnifaine, paraldehyde, Sodium Amytal. 'Pentothal narcosis' and 'narco-analysis' were adopted by British and American military psychiatrists. However, by 1945 medical thinking gradually settled on the same approaches that had seemed to be effective in 1918. The term PTSD was introduced in 1980. In the UK the National Institute for Health and Clinical Excellence (NICE) guidelines for management (2005) recommend trauma-focussed Cognitive Behavioural Therapy and consideration of antidepressants.

The HIV antiretroviral drug efavirenz has LSD-like properties.

PubMed

Gatch, Michael B; Kozlenkov, Alexey; Huang, Ren-Qi; Yang, Wenjuan; Nguyen, Jacques D; González-Maeso, Javier; Rice, Kenner C; France, Charles P; Dillon, Glenn H; Forster, Michael J; Schetz, John A

2013-11-01

Anecdotal reports have surfaced concerning misuse of the HIV antiretroviral medication efavirenz ((4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one) by HIV patients and non-infected teens who crush the pills and smoke the powder for its psychoactive effects. Molecular profiling of the receptor pharmacology of efavirenz pinpointed interactions with multiple established sites of action for other known drugs of abuse including catecholamine and indolamine transporters, and GABAA and 5-HT(2A) receptors. In rodents, interaction with the 5-HT(2A) receptor, a primary site of action of lysergic acid diethylamine (LSD), appears to dominate efavirenz's behavioral profile. Both LSD and efavirenz reduce ambulation in a novel open-field environment. Efavirenz occasions drug-lever responding in rats discriminating LSD from saline, and this effect is abolished by selective blockade of the 5-HT(2A) receptor. Similar to LSD, efavirenz induces head-twitch responses in wild-type, but not in 5-HT(2A)-knockout, mice. Despite having GABAA-potentiating effects (like benzodiazepines and barbiturates), and interactions with dopamine transporter, serotonin transporter, and vesicular monoamine transporter 2 (like cocaine and methamphetamine), efavirenz fails to maintain responding in rats that self-administer cocaine, and it fails to produce a conditioned place preference. Although its molecular pharmacology is multifarious, efavirenz's prevailing behavioral effect in rodents is consistent with LSD-like activity mediated via the 5-HT(2A) receptor. This finding correlates, in part, with the subjective experiences in humans who abuse efavirenz and with specific dose-dependent adverse neuropsychiatric events, such as hallucinations and night terrors, reported by HIV patients taking it as a medication.

The HIV Antiretroviral Drug Efavirenz has LSD-Like Properties

PubMed Central

Gatch, Michael B; Kozlenkov, Alexey; Huang, Ren-Qi; Yang, Wenjuan; Nguyen, Jacques D; González-Maeso, Javier; Rice, Kenner C; France, Charles P; Dillon, Glenn H; Forster, Michael J; Schetz, John A

2013-01-01

Anecdotal reports have surfaced concerning misuse of the HIV antiretroviral medication efavirenz ((4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one) by HIV patients and non-infected teens who crush the pills and smoke the powder for its psychoactive effects. Molecular profiling of the receptor pharmacology of efavirenz pinpointed interactions with multiple established sites of action for other known drugs of abuse including catecholamine and indolamine transporters, and GABAA and 5-HT2A receptors. In rodents, interaction with the 5-HT2A receptor, a primary site of action of lysergic acid diethylamine (LSD), appears to dominate efavirenz's behavioral profile. Both LSD and efavirenz reduce ambulation in a novel open-field environment. Efavirenz occasions drug-lever responding in rats discriminating LSD from saline, and this effect is abolished by selective blockade of the 5-HT2A receptor. Similar to LSD, efavirenz induces head-twitch responses in wild-type, but not in 5-HT2A-knockout, mice. Despite having GABAA-potentiating effects (like benzodiazepines and barbiturates), and interactions with dopamine transporter, serotonin transporter, and vesicular monoamine transporter 2 (like cocaine and methamphetamine), efavirenz fails to maintain responding in rats that self-administer cocaine, and it fails to produce a conditioned place preference. Although its molecular pharmacology is multifarious, efavirenz's prevailing behavioral effect in rodents is consistent with LSD-like activity mediated via the 5-HT2A receptor. This finding correlates, in part, with the subjective experiences in humans who abuse efavirenz and with specific dose-dependent adverse neuropsychiatric events, such as hallucinations and night terrors, reported by HIV patients taking it as a medication. PMID:23702798

Epidemiology of alcohol and other drug use among motor vehicle crash victims admitted to a trauma center.

PubMed

Walsh, J Michael; Flegel, Ron; Cangianelli, Leo A; Atkins, Randolph; Soderstrom, Carl A; Kerns, Timothy J

2004-09-01

The objectives of this research were to (1) determine the incidence and prevalence of alcohol and other drug use among motor vehicle crash (MVC) victims admitted to a regional Level-I trauma center, and (2) to examine the utility of using a rapid point-of-collection (POC) drug-testing device to identify MVC patients with drug involvement. Blood and urine specimens were routinely collected per clinical protocol for each MVC victim at the time of admission. Blood alcohol concentration (BAC) levels were determined per standard clinical protocol. Clinical urine specimens were routinely split so that a POC drug-testing device for the detection of commonly abused drugs (Marijuana, Cocaine, Amphetamines, Methamphetamines, and Opiates) could be compared to that of the standard hospital laboratory analysis of each urine specimen (which also included Barbiturates and Benzodiazepines). In the six-month period of this study, nearly two-thirds of trauma center admissions were victims of motor vehicle crashes. During this time, blood and urine was collected from 322 MVC victims. Toxicology results indicated that 59.3% of MVC victims tested positive for either commonly abused drugs or alcohol. More patients tested positive for drug use than tested positive for alcohol, with 33.5% testing positive for drug use only, 15.8% testing positive for alcohol use only, and 9.9% testing positive for both drugs and alcohol. Less than half (45.2%) of the substance-abusing patients in this study would have been identified by an alcohol test alone. After alcohol, marijuana and benzodiazepines were the most frequently detected drugs. Point of collection (POC) test results correlated well with laboratory results and provide important information to initiate rapid intervention/treatment for substance use problems among injured patients.

A Method of Managing Severe Traumatic Brain Injury in the Absence of Intracranial Pressure Monitoring: The Imaging and Clinical Examination Protocol.

PubMed

Chesnut, Randall M; Temkin, Nancy; Dikmen, Sureyya; Rondina, Carlos; Videtta, Walter; Petroni, Gustavo; Lujan, Silvia; Alanis, Victor; Falcao, Antonio; de la Fuenta, Gustavo; Gonzalez, Luis; Jibaja, Manuel; Lavarden, Arturo; Sandi, Freddy; Mérida, Roberto; Romero, Ricardo; Pridgeon, Jim; Barber, Jason; Machamer, Joan; Chaddock, Kelley

2018-01-01

The imaging and clinical examination (ICE) algorithm used in the Benchmark Evidence from South American Trials: Treatment of Intracranial Pressure (BEST TRIP) randomized controlled trial is the only prospectively investigated clinical protocol for traumatic brain injury management without intracranial pressure (ICP) monitoring. As the default literature standard, it warrants careful evaluation. We present the ICE protocol in detail and analyze the demographics, outcome, treatment intensity, frequency of intervention usage, and related adverse events in the ICE-protocol cohort. The 167 ICE protocol patients were young (median 29 years) with a median Glasgow Coma Scale motor score of 4 but with anisocoria or abnormal pupillary reactivity in 40%. This protocol produced outcomes not significantly different from those randomized to the monitor-based protocol (favorable 6-month extended Glasgow Outcome Score in 39%; 41% mortality rate). Agents commonly employed to treat suspected intracranial hypertension included low-/moderate-dose hypertonic saline (72%) and mannitol (57%), mild hyperventilation (adjusted partial pressure of carbon dioxide 30-35 mm Hg in 73%), and pressors to maintain cerebral perfusion (62%). High-dose hyperosmotics or barbiturates were uncommonly used. Adverse event incidence was low and comparable to the BEST TRIP monitored group. Although this protocol should produce similar/acceptable results under circumstances comparable to those in the trial, influences such as longer pre-hospital times and non-specialist transport personnel, plus an intensive care unit model of aggressive physician-intensive care by small groups of neurotrauma-focused intensivists, which differs from most high-resource models, support caution in expecting the same results in dissimilar settings. Finally, this protocol's ICP-titration approach to suspected intracranial hypertension (vs. crisis management for monitored ICP) warrants further study.

Role of Intracranial Pressure Monitoring in Management of Patients with Severe Traumatic Brain Injury: Results of a Large Level I Trauma Center in Southern Iran.

PubMed

Khalili, Hosseinali; Sadraei, Nazanin; Niakan, Amin; Ghaffarpasand, Fariborz; Sadraei, Amin

2016-10-01

To determine the role of intracranial pressure (ICP) monitoring in management of patients with severe traumatic brain injury (TBI) admitted to a large level I trauma center in Southern Iran. This was a cohort study performed during a 2-year period in a level I trauma center in Southern Iran including all adult patients (>16 years) with severe TBI (Glasgow Coma Scale [GCS] score, 3-8) who underwent ICP monitoring through ventriculostomy. The management was based on the recorded ICP values with threshold of 20 mm Hg. Decompressive craniectomy was performed in patients with intractable intracranial hypertension (persistent ICP ≥25 mm Hg). In unresponsive patients, barbiturate coma was induced. Patients were followed for 6 months and Glasgow Outcome Scale Extended was recorded. The determinants of favorable and unfavorable outcome were also determined. Overall, we included 248 patients with mean age of 34.6 ± 16.6 years, among whom there were 216 men (87.1%) and 32 women (12.9%). Eighty-five patients (34.2%) had favorable and 163 (65.8%) unfavorable outcomes. Those with favorable outcome had significantly lower age (P = 0.004), higher GCS score on admission (P < 0.001), lower Rotterdam score (P = 0.035), fewer episodes of intracranial hypertension (P < 0.001), and lower maximum recorded ICP (P = 0.041). These factors remained statistically significant after elimination of confounders by multivariate logistic regression model. Age, GCS score on admission, Rotterdam score, intracranial hypertension, and maximum recorded ICP are important determinants of outcome in patients with severe TBI. ICP monitoring assisted us in targeted therapy and management of patients with severe TBI. Copyright © 2016 Elsevier Inc. All rights reserved.

Intracranial pressure monitoring after primary decompressive craniectomy in traumatic brain injury: a clinical study.

PubMed

Picetti, Edoardo; Caspani, Maria Luisa; Iaccarino, Corrado; Pastorello, Giulia; Salsi, Pierpaolo; Viaroli, Edoardo; Servadei, Franco

2017-04-01

Intracranial pressure (ICP) monitoring represents an important tool in the management of traumatic brain injury (TBI). Although current information exists regarding ICP monitoring in secondary decompressive craniectomy (DC), little is known after primary DC following emergency hematoma evacuation. Retrospective analysis of prospectively collected data. Inclusion criteria were age ≥18 years and admission to the intensive care unit (ICU) for TBI and ICP monitoring after primary DC. Exclusion criteria were ICU length of stay (LOS) <1 day and pregnancy. Major objectives were: (1) to analyze changes in ICP/cerebral perfusion pressure (CPP) after primary DC, (2) to evaluate the relationship between ICP/CPP and neurological outcome and (3) to characterize and evaluate ICP-driven therapies after DC. A total of 34 patients were enrolled. Over 308 days of ICP/CPP monitoring, 130 days with at least one episode of intracranial hypertension (26 patients, 76.5%) and 57 days with at least one episode of CPP <60 mmHg (22 patients, 64.7%) were recorded. A statistically significant relationship was discovered between the Glasgow Outcome Scale (GOS) scores and mean post-decompression ICP (p < 0.04) and between GOS and CPP minimum (CPPmin) (p < 0.04). After DC, persisting intracranial hypertension was treated with: barbiturate coma (n = 7, 20.6%), external ventricular drain (EVD) (n = 4, 11.8%), DC diameter widening (n = 1, 2.9%) and removal of newly formed hematomas (n = 3, 8.8%). Intracranial hypertension and/or low CPP occurs frequently after primary DC; their occurence is associated with an unfavorable neurological outcome. ICP monitoring appears useful in guiding therapy after primary DC.

Effect of GABA agonists and GABA-A receptor modulators on cocaine- and food-maintained responding and cocaine discrimination in rats.

PubMed

Barrett, Andrew C; Negus, S Stevens; Mello, Nancy K; Caine, S Barak

2005-11-01

Recent studies indicate that GABAergic ligands modulate abuse-related effects of cocaine. The goal of this study was to evaluate the effects of a mechanistically diverse group of GABAergic ligands on the discriminative stimulus and reinforcing effects of cocaine in rats. One group of rats was trained to discriminate 5.6 mg/kg cocaine from saline in a two-lever, food-reinforced, drug discrimination procedure. In two other groups, responding was maintained by cocaine (0-3.2 mg/kg/injection) or liquid food (0-100%) under a fixed ratio 5 schedule. Six GABA agonists were tested: the GABA-A receptor agonist muscimol, the GABA-B receptor agonist baclofen, the GABA transaminase inhibitor gamma-vinyl-GABA (GVG), and three GABA-A receptor modulators (the barbiturate pentobarbital, the high-efficacy benzodiazepine midazolam, and the low-efficacy benzodiazepine enazenil). When tested alone, none of the compounds substituted fully for the discriminative stimulus effects of cocaine. As acute pretreatments, select doses of midazolam and pentobarbital produced 2.2- to 3.6-fold rightward shifts in the cocaine dose-effect function. In contrast, muscimol, baclofen, GVG, and enazenil failed to alter the discriminative stimulus effects of cocaine. In assays of cocaine- and food-maintained responding, midazolam and pentobarbital decreased cocaine self-administration at doses 9.6- and 3.3-fold lower, respectively, than those that decreased food-maintained responding. In contrast, muscimol, baclofen, and GVG decreased cocaine self-administration at doses that also decreased food-maintained responding. Enazenil failed to alter cocaine self-administration. Together with previous studies, these data suggest that among mechanistically diverse GABA agonists, high-efficacy GABA-A modulators may be the most effective for modifying the abuse-related effects of cocaine.

Immunohistochemical expression of insulin, glucagon, and somatostatin in pancreatic islets of horses with and without insulin resistance.

PubMed

Newkirk, Kim M; Ehrensing, Gordon; Odoi, Agricola; Boston, Raymond C; Frank, Nicholas

2018-02-01

OBJECTIVE To assess insulin, glucagon, and somatostatin expression within pancreatic islets of horses with and without insulin resistance. ANIMALS 10 insulin-resistant horses and 13 insulin-sensitive horses. PROCEDURES For each horse, food was withheld for at least 10 hours before a blood sample was collected for determination of serum insulin concentration. Horses with a serum insulin concentration < 20 μU/mL were assigned to the insulin-sensitive group, whereas horses with a serum insulin concentration > 20 μU/mL underwent a frequently sampled IV glucose tolerance test to determine sensitivity to insulin by minimal model analysis. Horses with a sensitivity to insulin < 1.0 × 10 -4 L•min -1 •mU -1 were assigned to the insulin-resistant group. All horses were euthanized with a barbiturate overdose, and pancreatic specimens were harvested and immunohistochemically stained for determination of insulin, glucagon, and somatostatin expression in pancreatic islets. Islet hormone expression was compared between insulin-resistant and insulin-sensitive horses. RESULTS Cells expressing insulin, glucagon, and somatostatin made up approximately 62%, 12%, and 7%, respectively, of pancreatic islet cells in insulin-resistant horses and 64%, 18%, and 9%, respectively, of pancreatic islet cells in insulin-sensitive horses. Expression of insulin and somatostatin did not differ between insulin-resistant and insulin-sensitive horses, but the median percentage of glucagon-expressing cells in the islets of insulin-resistant horses was significantly less than that in insulin-sensitive horses. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that, in insulin-resistant horses, insulin secretion was not increased but glucagon production might be downregulated as a compensatory response to hyperinsulinemia.

Phenobarbital Induction and Chemical Synergism Demonstrate the Role of UDP-Glucuronosyltransferases in Detoxification of Naphthalophos by Haemonchus contortus Larvae

PubMed Central

Ruffell, Angela P.; Ingham, Aaron B.

2014-01-01

We used an enzyme induction approach to study the role of detoxification enzymes in the interaction of the anthelmintic compound naphthalophos with Haemonchus contortus larvae. Larvae were treated with the barbiturate phenobarbital, which is known to induce the activity of a number of detoxification enzymes in mammals and insects, including cytochromes P450 (CYPs), UDP-glucuronosyltransferases (UDPGTs), and glutathione (GSH) S-transferases (GSTs). Cotreatment of larvae with phenobarbital and naphthalophos resulted in a significant increase in the naphthalophos 50% inhibitory concentration (IC50) compared to treatment of larvae with the anthelmintic alone (up to a 28-fold increase). The phenobarbital-induced drug tolerance was reversed by cotreatment with the UDPGT inhibitors 5-nitrouracil, 4,6-dihydroxy-5-nitropyrimidine, probenecid, and sulfinpyrazone. Isobologram analysis of the interaction of 5-nitrouracil with naphthalophos in phenobarbital-treated larvae clearly showed the presence of strong synergism. The UDPGT inhibitors 5-nitrouracil, 4,6-dihydroxy-5-nitropyrimidine, and probenecid also showed synergistic effects with non-phenobarbital-treated worms (synergism ratio up to 3.2-fold). This study indicates that H. contortus larvae possess one or more UDPGT enzymes able to detoxify naphthalophos. In highlighting the protective role of this enzyme group, this study reveals the potential for UDPGT enzymes to act as a resistance mechanism that may develop under drug selection pressure in field isolates of this species. In addition, the data indicate the potential for a chemotherapeutic approach utilizing inhibitors of UDPGT enzymes as synergists to increase the activity of naphthalophos against parasitic worms and to combat detoxification-mediated drug resistance if it arises in the field. PMID:25288079

Phenobarbital induction and chemical synergism demonstrate the role of UDP-glucuronosyltransferases in detoxification of naphthalophos by Haemonchus contortus larvae.

PubMed

Kotze, Andrew C; Ruffell, Angela P; Ingham, Aaron B

2014-12-01

We used an enzyme induction approach to study the role of detoxification enzymes in the interaction of the anthelmintic compound naphthalophos with Haemonchus contortus larvae. Larvae were treated with the barbiturate phenobarbital, which is known to induce the activity of a number of detoxification enzymes in mammals and insects, including cytochromes P450 (CYPs), UDP-glucuronosyltransferases (UDPGTs), and glutathione (GSH) S-transferases (GSTs). Cotreatment of larvae with phenobarbital and naphthalophos resulted in a significant increase in the naphthalophos 50% inhibitory concentration (IC50) compared to treatment of larvae with the anthelmintic alone (up to a 28-fold increase). The phenobarbital-induced drug tolerance was reversed by cotreatment with the UDPGT inhibitors 5-nitrouracil, 4,6-dihydroxy-5-nitropyrimidine, probenecid, and sulfinpyrazone. Isobologram analysis of the interaction of 5-nitrouracil with naphthalophos in phenobarbital-treated larvae clearly showed the presence of strong synergism. The UDPGT inhibitors 5-nitrouracil, 4,6-dihydroxy-5-nitropyrimidine, and probenecid also showed synergistic effects with non-phenobarbital-treated worms (synergism ratio up to 3.2-fold). This study indicates that H. contortus larvae possess one or more UDPGT enzymes able to detoxify naphthalophos. In highlighting the protective role of this enzyme group, this study reveals the potential for UDPGT enzymes to act as a resistance mechanism that may develop under drug selection pressure in field isolates of this species. In addition, the data indicate the potential for a chemotherapeutic approach utilizing inhibitors of UDPGT enzymes as synergists to increase the activity of naphthalophos against parasitic worms and to combat detoxification-mediated drug resistance if it arises in the field. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Effects of three hypnotics on the sleep-wakefulness cycle in sleep-disturbed rats.

PubMed

Shinomiya, Kazuaki; Shigemoto, Yuki; Omichi, Junji; Utsu, Yoshiaki; Mio, Mitsunobu; Kamei, Chiaki

2004-04-01

New sleep disturbance model in rats is useful for estimating the characteristics of some hypnotics. The present study was undertaken to investigate the utility of a sleep disturbance model by placing rats on a grid suspended over water using three kinds of hypnotics, that is, short-acting benzodiazepine (triazolam), intermediate-acting benzodiazepine (flunitrazepam) and long-acting barbiturate (phenobarbital). Electrodes for measurement of EEG and EMG were implanted into the frontal cortex and the dorsal neck muscle of rats. EEG and EMG were recorded with an electroencephalogram. SleepSign ver.2.0 was used for EEG and EMG analysis. Total times of wakefulness, non-REM and REM sleep were measured from 0900 to 1500 hours. In rats placed on the grid suspended over water up to 1 cm under the grid surface, not only triazolam but also flunitrazepam and phenobarbital caused a shortening of sleep latency. Both flunitrazepam and phenobarbital were effective in increasing of total non-REM sleep time in rats placed on sawdust or the grid, and the effects of both drugs in rats placed on the grid were larger than those in rats placed on sawdust. Measurement of the hourly non-REM sleep time was useful for investigating the peak time and duration of effect of the three hypnotics. Phenobarbital showed a decrease in total REM sleep time in rats placed on the grid, although both triazolam and flunitrazepam were without effect. The present insomnia model can be used as a sleep disturbance model for testing not only the sleep-inducing effects but also the sleep-maintaining effects including non-REM sleep and REM sleep of hypnotics.

High-temperature solid-phase microextraction procedure for the detection of drugs by gas chromatography-mass spectrometry.

PubMed

Staerk, U; Külpmann, W R

2000-08-18

High-temperature headspace solid-phase microextraction (SPME) with simultaneous ("in situ") derivatisation (acetylation or silylation) is a new sample preparation technique for the screening of illicit drugs in urine and for the confirmation analysis in serum by GC-MS. After extraction of urine with a small portion of an organic solvent mixture (e.g., 2 ml of hexane-ethyl acetate) at pH 9, the organic layer is separated and evaporated to dryness in a small headspace vial. A SPME-fiber (e.g., polyacrylate) doped with acetic anhydride-pyridine (for acetylation) is exposed to the vapour phase for 10 min at 200 degrees C in a blockheater. The SPME fiber is then injected into the GC-MS for thermal desorption and analysis. After addition of perchloric acid and extraction with n-hexane to remove lipids, the serum can be analysed after adjusting to pH 9 as described for urine. Very clean extracts are obtained. The various drugs investigated could be detected and identified in urine by the total ion current technique at the following concentrations: amphetamines (200 microg/l), barbiturates (500 microg/l), benzodiazepines (100 microg/l), benzoylecgonine (150 microg/l), methadone (100 microg/l) and opiates (200 microg/l). In serum all drugs could be detected by the selected ion monitoring technique within their therapeutic range. As compared to liquid-liquid extraction only small amounts of organic solvent are needed and larger amounts of the pertinent analytes could be transferred to the GC column. In contrast to solid-phase extraction (SPE), the SPME-fiber is reusable several times (as there is no contamination by endogenous compounds). The method is time-saving and can be mechanised by the use of a dedicated autosampler.

Single-molecule force-conductance spectroscopy of hydrogen-bonded complexes

NASA Astrophysics Data System (ADS)

Pirrotta, Alessandro; De Vico, Luca; Solomon, Gemma C.; Franco, Ignacio

2017-03-01

The emerging ability to study physical properties at the single-molecule limit highlights the disparity between what is observable in an ensemble of molecules and the heterogeneous contributions of its constituent parts. A particularly convenient platform for single-molecule studies are molecular junctions where forces and voltages can be applied to individual molecules, giving access to a series of electromechanical observables that can form the basis of highly discriminating multidimensional single-molecule spectroscopies. Here, we computationally examine the ability of force and conductance to inform about molecular recognition events at the single-molecule limit. For this, we consider the force-conductance characteristics of a prototypical class of hydrogen bonded bimolecular complexes sandwiched between gold electrodes. The complexes consist of derivatives of a barbituric acid and a Hamilton receptor that can form up to six simultaneous hydrogen bonds. The simulations combine classical molecular dynamics of the mechanical deformation of the junction with non-equilibrium Green's function computations of the electronic transport. As shown, in these complexes hydrogen bonds mediate transport either by directly participating as a possible transport pathway or by stabilizing molecular conformations with enhanced conductance properties. Further, we observe that force-conductance correlations can be very sensitive to small changes in the chemical structure of the complexes and provide detailed information about the behavior of single molecules that cannot be gleaned from either measurement alone. In fact, there are regions during the elongation that are only mechanically active, others that are only conductance active, and regions where both force and conductance changes as the complex is mechanically manipulated. The implication is that force and conductance provide complementary information about the evolution of molecules in junctions that can be used to interrogate basic structure-transport relations at the single-molecule limit.

How does active substance use at psychiatric admission impact suicide risk and hospital length-of-stay?

PubMed

Miller, Keith A; Hitschfeld, Mario J; Lineberry, Timothy W; Palmer, Brian A

2016-01-01

Despite their high prevalence, little is known about the effects of substance use disorders and active substance use on the suicide risk or length-of-stay of psychiatric inpatients. This study examines the relationship between active substance use at the time of psychiatric hospitalization and changes in suicide risk measures and length-of-stay. Admission and discharge ratings on the Suicide Status Form-II-R, diagnoses, and toxicology data from 2,333 unique psychiatric inpatients were examined. Data for patients using alcohol, tetrahydrocannabinol, methamphetamines, cocaine, benzodiazepines, opiates, barbiturates, phencyclidine, and multiple substances on admission were compared with data from 1,426 admissions without substance use. Patients with substance use by toxicology on admission had a 0.9 day shorter length-of-stay compared to toxicology-negative patients. During initial nurse evaluation on the inpatient unit, these patients reported lower suicide measures (i.e., suicidal ideation frequency, overall suicide risk, and wish-to-die). No significant between-group differences were seen at discharge. Patients admitted with a substance use disorder diagnosis had a 1.0 day shorter length-of-stay than those without, while those with a substance use disorder diagnosis and positive toxicology reported the lowest measures of suicidality on admission. These results remained independent of psychiatric diagnosis. For acute psychiatric inpatients, suicide risk is higher and length-of-stay is longer in patients with substance use disorders who are NOT acutely intoxicated compared with patients without a substance use disorder. Toxicology-positive patients are less suicidal on admission and improve faster than their toxicology-negative counterparts. This study gives support to the clinical observation that acutely intoxicated patients may stabilize quickly with regard to suicidal urges and need for inpatient care.

The pharmaceutical industry and the German National Socialist Regime: I.G. Farben and pharmacological research.

PubMed

López-Muñoz, F; García-García, P; Alamo, C

2009-02-01

Before the National Socialist party came to power, the German pharmaceutical industry constituted an international reference as far as the development of new medicines was concerned, having been responsible for synthetic analgesics (phenacetin, phenazones, acetylsalicylic acid), arsphenamine, barbiturates and sulfonamides. The year 1925 saw the founding of I.G. Farben (Interessen-Gemeinschaft Farbenindustrie AG), a conglomerate of companies that would monopolize the country's chemical production and come to own all its major pharmaceutical industries. During the World War II, I.G. Farben participated in numerous operations associated with the criminal activities of the Nazi executive, including the use of slave labour in plants built close to concentration camps, such as that at Auschwitz. With regard to medical and pharmacological research projects, I.G. Farben became involved in experimental programmes using patients from the Nazi regime's euthanasia programmes and healthy subjects recruited without their consent from concentration camps, on whom various pharmacological substances were tested, including sulfamide and arsenical derivatives and other preparations whose composition is not precisely known (B-1012, B-1034, 3382 or Rutenol, 3582 or Acridine), generally in relation to the treatment of infectious diseases, such as typhus, erysipelas, scarlet fever or paratyphoid diarrhoea. Furthermore, I.G. Farben played a decisive role in the German army's chemical warfare programme, contributing to the development of the first two neurotoxic substances, later known as 'nerve agents', tabun and sarin. Some of these activities came to light as a result of the one the famous Nuremberg Trials in 1947, which saw 24 executives and scientists from I.G. Farben brought to justice for, among other offences, the use of slave labour in the concentration camps and forced experimentation with drugs on prisoners.

A Survey of Hospice and Palliative Care Clinicians' Experiences and Attitudes Regarding the Use of Palliative Sedation.

PubMed

Maiser, Samuel; Estrada-Stephen, Karen; Sahr, Natasha; Gully, Jonathan; Marks, Sean

2017-09-01

A variety of terms and attitudes surround palliative sedation (PS) with little research devoted to hospice and palliative care (HPC) clinicians' perceptions and experiences with PS. These factors may contribute to the wide variability in the reported prevalence of PS. This study was designed to better identify hospice and palliative care (HPC) clinician attitudes toward, and clinical experiences with palliative sedation (PS). A 32-question survey was distributed to members of the American Academy of Hospice and Palliative Medicine (n = 4678). The questions explored the language clinicians use for PS, and their experiences with PS. Nine hundred thirty-six (20% response rate) responded to the survey. About 83.21% preferred the terminology of PS compared with other terms. A majority felt that PS is a bioethically appropriate treatment for refractory physical and nonphysical symptoms in dying patients. Most felt PS was not an appropriate term in clinical scenarios when sedation occurred as an unintended side effect from standard treatments. Hospice clinicians use PS more consistently and with less distress than nonhospice clinician respondents. Benzodiazepines (63.1%) and barbiturates (18.9%) are most commonly prescribed for PS. PS is the preferred term among HPC clinicians for the proportionate use of pharmacotherapies to intentionally lower awareness for refractory symptoms in dying patients. PS is a bioethically appropriate treatment for refractory symptoms in dying patients. However, there is a lack of clear agreement about what is included in PS and how the practice of PS should be best delivered in different clinical scenarios. Future efforts to investigate PS should focus on describing the clinical scenarios in which PS is utilized and on the level of intended sedation necessary, in an effort to better unify the practice of PS.

Increase in Self-Injury as a Method of Self-Harm in Ghent, Belgium: 1987-2013

PubMed Central

Vancayseele, Nikita; Portzky, Gwendolyn; van Heeringen, Kees

2016-01-01

Background Self-harm is a major health care problem and changes in its prevalence and characteristics can have important implications for suicide prevention. The objective was to describe trends in the epidemiology of self-harm based on emergency department (A&E departments) visits over a 26-year period in Ghent, Belgium. Methods We analyzed data on all self-harm presentations from the three large general hospitals in Ghent between 1987 and 2013. We investigated trends in prevalence (events by year per 100.000), methods and alcohol use. Results Rates of self-harm steadily decreased during the 26-year study period. In general female rates of self-harm were higher than male rates. The mean patient age was 35 years. The most commonly used method of self-harm was self-poisoning by means of an overdose of medication (80.8%), followed by cutting (10.2%) and hanging (4.2%). Psychotropics (including antidepressants, benzodiazepines, barbiturates and other tranquilizers) were the most frequently used drugs (74.5%). A proportional increase in the use of self-injurious methods in self-harm was highly significant, more specifically in the use of hanging, jumping from heights and the use of other violent methods such as the use of firearms, jumping before a moving object or other traffic related injury. Conclusion This epidemiological study showed an increase in the use of high-lethality methods in self-harm which has important implications for suicide prevention. As restrictions in the availability of these methods are difficult or impossible to achieve, prevention programmes will have to emphasize the role of thorough psychosocial assessment and adequate follow-up care of self-harm patients. PMID:27249421

Post-electroconvulsive therapy recovery and reorientation time with methohexital and ketamine: a randomized, longitudinal cross-over design trial

PubMed Central

Yen, Tony; Khafaja, Mohamad; Lam, Nicholas; Crumbacher, James; Schrader, Ronald; Rask, John; Billstrand, Mary; Rothfork, Jacob; Abbott, Christopher C.

2014-01-01

Objectives Methohexital, a barbiturate anesthetic commonly used for electroconvulsive therapy (ECT), possesses dose-dependent anticonvulsant properties, and its use can interfere with effective seizure therapy in patients with high seizure thresholds. Ketamine, a NMDA-antagonist with epileptogenic properties not broadly used for ECT inductions, is a commonly used induction agent for general anesthesia. Recent studies suggest that the use of ketamine is effective in allowing successful ECT treatment in patients with high seizure thresholds without an increase in side-effects. In this preliminary study, we directly compared the recovery and re-orientation times of subjects receiving ketamine and methohexital for ECTs. Methods Twenty patients were randomized in a cross-over design to receive methohexital and ketamine for ECT inductions in alternating fashion for six trials. Primary outcome measures were recovery time (voluntary movement, respiratory effort, blood pressure, consciousness, and O2 saturation) and re-orientation time. Secondary outcome measures were individual recovery variables, side-effect occurrence, and seizure duration. Results: Overall recovery time was not significantly different between the two treatment arms (F(1,17) = 0.72, P = 0.41). Re-orientation time was faster in the methohexital arm (F(1,17) = 9.23, P = 0.007). Conclusion Ketamine inductions resulted in higher number of side-effects, higher subject dropout rates, and a longer reorientation time with respect to methohexital inductions. No significant difference in post-anesthesia recovery time was found between the ketamine and methohexital arms. Intolerability to ketamine affected a significant proportion of subjects, and suggests that ketamine should remain as an alternative or adjunctive agent for patients with high seizure thresholds. PMID:24755722

A novel positive allosteric modulator of the GABAA receptor: the action of (+)-ROD188

PubMed Central

Thomet, Urs; Baur, Roland; Razet, Rodolphe; Dodd, Robert H; Furtmüller, Roman; Sieghart, Werner; Sigel, Erwin

2000-01-01

(+)-ROD188 was synthesized in the search for novel ligands of the GABA binding site. It shares some structural similarity with bicuculline. (+)-ROD188 failed to displace [3H]-muscimol in binding studies and failed to induce channel opening in recombinant rat α1β2γ2 GABAA receptors functionally expressed in Xenopus oocytes. (+)-ROD188 allosterically stimulated GABA induced currents. Displacement of [3H]-Ro15-1788 indicated a low affinity action at the benzodiazepine binding site. In functional studies, stimulation by (+)-ROD188 was little sensitive to the presence of 1 μM of the benzodiazepine antagonist Ro 15-1788, and (+)-ROD188 also stimulated currents mediated by α1β2, indicating a major mechanism of action different from that of benzodiazepines. Allosteric stimulation by (+)-ROD188 was similar in α1β2N265S as in unmutated α1β2, while that by loreclezole was strongly reduced. (+)-ROD188 also strongly stimulated currents elicited by either pentobarbital or 5α-pregnan-3α-ol-20-one (3α-OH-DHP), in line with a mode of action different from that of barbiturates or neurosteroids as channel agonists. Stimulation by (+)-ROD188 was largest in α6β2γ2 (α6β2γ2>>α1β2γ2=α5β2γ2>α2β2γ2= α3β2γ2), indicating a unique subunit isoform specificity. Miniature inhibitory postsynaptic currents (mIPSC) in cultures of rat hippocampal neurons, caused by spontaneous release of GABA showed a prolonged decay time in the presence of 30 μM (+)-ROD188, indicating an enhanced synaptic inhibitory transmission. PMID:11030736

Medications and Impaired Driving: A Review of the Literature

PubMed Central

Hetland, Amanda; Carr, David B

2013-01-01

Objective To describe the association of specific medication classes with driving outcomes and provide clinical recommendations. Data sources The MEDLINE and EMBASE databases were searched for articles published from January 1973 to June 2013 on specific classes of medications known to be associated with driving impairment. The search included outcome terms such as automobile driving, motor vehicle crash, driving simulator, and road tests. Study selection and data extraction Only English-language articles that contained findings from observational or interventional designs were included. Cross-sectional studies, case series, and case reports were excluded. Studies of ≥ 10 subjects were included in this review. Data synthesis Driving is an important task and activity for the majority of adults. Unfortunately, some specific classes of commonly prescribed medications have been associated with driving impairment as measured by road performance, driving simulation, and/or motor vehicle crashes. This review of 30 studies identified findings with barbiturates, benzodiazepines, certain non-benzodiazepine hypnotics, various antidepressants, opioid and non-steroidal analgesics, anticonvulsants, antipsychotics, antiparkinsonian agents, skeletal muscle relaxants, antihistamines, anticholinergic medications, and hypoglycemic agents. Additional studies identifying medication impacts on sedation, sleep latency, and psychomotor function – as well as the role of alcohol – are also discussed. Conclusions Psychotropic agents and those with CNS side effects were associated with various measures of impaired driving performance. It is difficult to determine if such associations are actually a result of medication use or perhaps the medical diagnosis itself. Regardless, clinicians should be aware of the increased risk of impaired driving with specific populations and classes of medications when prescribing these agents, educate their patients, and/or consider safer alternatives. PMID:24473486

Lethal Injection for Execution: Chemical Asphyxiation?

PubMed Central

Zimmers, Teresa A; Sheldon, Jonathan; Lubarsky, David A; López-Muñoz, Francisco; Waterman, Linda; Weisman, Richard; Koniaris, Leonidas G

2007-01-01

Background Lethal injection for execution was conceived as a comparatively humane alternative to electrocution or cyanide gas. The current protocols are based on one improvised by a medical examiner and an anesthesiologist in Oklahoma and are practiced on an ad hoc basis at the discretion of prison personnel. Each drug used, the ultrashort-acting barbiturate thiopental, the neuromuscular blocker pancuronium bromide, and the electrolyte potassium chloride, was expected to be lethal alone, while the combination was intended to produce anesthesia then death due to respiratory and cardiac arrest. We sought to determine whether the current drug regimen results in death in the manner intended. Methods and Findings We analyzed data from two US states that release information on executions, North Carolina and California, as well as the published clinical, laboratory, and veterinary animal experience. Execution outcomes from North Carolina and California together with interspecies dosage scaling of thiopental effects suggest that in the current practice of lethal injection, thiopental might not be fatal and might be insufficient to induce surgical anesthesia for the duration of the execution. Furthermore, evidence from North Carolina, California, and Virginia indicates that potassium chloride in lethal injection does not reliably induce cardiac arrest. Conclusions We were able to analyze only a limited number of executions. However, our findings suggest that current lethal injection protocols may not reliably effect death through the mechanisms intended, indicating a failure of design and implementation. If thiopental and potassium chloride fail to cause anesthesia and cardiac arrest, potentially aware inmates could die through pancuronium-induced asphyxiation. Thus the conventional view of lethal injection leading to an invariably peaceful and painless death is questionable. PMID:17455994

Intravenous anaesthetics inhibit nicotinic acetylcholine receptor-mediated currents and Ca2+ transients in rat intracardiac ganglion neurons

PubMed Central

Weber, Martin; Motin, Leonid; Gaul, Simon; Beker, Friederike; Fink, Rainer H A; Adams, David J

2004-01-01

The effects of intravenous (i.v.) anaesthetics on nicotinic acetylcholine receptor (nAChR)-induced transients in intracellular free Ca2+ concentration ([Ca2+]i) and membrane currents were investigated in neonatal rat intracardiac neurons. In fura-2-loaded neurons, nAChR activation evoked a transient increase in [Ca2+]I, which was inhibited reversibly and selectively by clinically relevant concentrations of thiopental. The half-maximal concentration for thiopental inhibition of nAChR-induced [Ca2+]i transients was 28 μM, close to the estimated clinical EC50 (clinically relevant (half-maximal) effective concentration) of thiopental. In fura-2-loaded neurons, voltage clamped at −60 mV to eliminate any contribution of voltage-gated Ca2+ channels, thiopental (25 μM) simultaneously inhibited nAChR-induced increases in [Ca2+]i and peak current amplitudes. Thiopental inhibited nAChR-induced peak current amplitudes in dialysed whole-cell recordings by ∼ 40% at −120, −80 and −40 mV holding potential, indicating that the inhibition is voltage independent. The barbiturate, pentobarbital and the dissociative anaesthetic, ketamine, used at clinical EC50 were also shown to inhibit nAChR-induced increases in [Ca2+]i by ∼40%. Thiopental (25 μM) did not inhibit caffeine-, muscarine- or ATP-evoked increases in [Ca2+]i, indicating that inhibition of Ca2+ release from internal stores via either ryanodine receptor or inositol-1,4,5-trisphosphate receptor channels is unlikely. Depolarization-activated Ca2+ channel currents were unaffected in the presence of thiopental (25 μM), pentobarbital (50 μM) and ketamine (10 μM). In conclusion, i.v. anaesthetics inhibit nAChR-induced currents and [Ca2+]i transients in intracardiac neurons by binding to nAChRs and thereby may contribute to changes in heart rate and cardiac output under clinical conditions. PMID:15644873

Effects of induction anesthetic agents on outcome of assisted reproductive technology: a comparison of propofol and thiopental sodium.

PubMed

Huang, H W; Huang, F J; Kung, F T; Tsai, M Y; Lin, H; Chang, S Y; Hsu, Y H; Chang, H W

2000-09-01

The use of propofol, as compared to barbiturates (e.g. thiopental), for short surgical procedures has been associated with more rapid recovery from the procedure. Propofol, an intravenous anesthetic drug, is frequently used as an adjunct to transvaginal oocyte retrieval but little is known about its effects upon fertilization, embryo development, and pregnancy rate when used drug the for induction of general anesthesia. This study was conducted to compare the outcome of assisted reproductive technology (ART) with the use of propofol versus thiopental sodium for the induction of general anesthesia during oocyte retrieval. In this retrospective study, 92 cases of infertile patients who underwent oocyte retrieval under the induction of general anesthesia with, respectively, either propofol (Group I, 72 cases) or thiopental sodium (Group II, 20 cases) were compared for fertilization rate, cleavage rate, and pregnancy rate. The fertilization rate was 68.9% for Group I and 66.7% for group II (p = 0.614). The cleavage rate was 96.5% for Group I and 94.8% for Group II (p = 0.294). The rate of good embryo grading and poor embryo grading was, respectively, 85.1% and 14.9% for Group I, versus 85.7% and 14.3% for Group II (p = 0.887). The pregnancy rate was 30.5% for Group I and 20.0% for Group II (p = 0.354). The implantation rate and abortion rate was, respectively, 9.1% and 18.2% for Group I versus 7.2% and 25.0% for Group II (implantation rate, p = 0.590; abortion rate, p = 0.600). There were no significant differences between these two groups for fertilization rate, cleavage rate, pregnancy rate, implantation rate and abortion rate. We suggest cautious use of propofol for the procedure of oocyte retrieval despite its associated more rapid post-operative recovery including less nausea/vomiting.

Preclinical evidence of the anxiolytic and sedative-like activities of Tagetes erecta L. reinforces its ethnobotanical approach.

PubMed

Pérez-Ortega, Gimena; Angeles-López, Guadalupe Esther; Argueta-Villamar, Arturo; González-Trujano, María Eva

2017-09-01

Morelos State is one of the regions of Mexico where several plant species are used in traditional medicine. Species from Tagetes genus (Asteraceae) are reported as useful in infusion to treat stomachache and intestinal diseases, but also as tranquilizers. In this study, medicinal uses of T. erecta including its depressant effect on the central nervous system (CNS) were explored by interviewing healers and merchants of local markets of Morelos State, and by investigation of the phytochemical and pharmacological tranquilizing properties. Specific anxiolytic and/or sedative-like responses of different doses of T. erecta (10, 30 and 100 or 300mg/kg, i.p.) were investigated using experimental models in mice such as: open-field, exploration cylinder, hole-board, and the barbituric-induced hypnosis potentiation. The possible anxiolytic mechanism of action was assessed in the presence of WAY100635 (0.32mg/kg, i.p.) and flumazenil (10mg/kg, i.p.), antagonists of 5-HT 1A and GABA/BDZs receptors, respectively. Individual flavonoids reported in this species were also evaluated in these experimental models. As a result of this study, healers and merchants from ten local regions of Morelos State recommended T. erecta flowers as an infusion or as a tincture for several culture-bound syndromes associated with CNS, among others. Anxiolytic and sedative-like activities of the T. erecta aqueous and organic polar extracts were corroborated in these models associated to a participation of rutin, kaempferol, quercetin, kaempferitrin, and β-sitosterol constituents; where 5-HT 1A , but not BDZs, receptors were involved as anxiolytic mechanism of action. These data support the anxiolytic and sedative-like properties of T. erecta in traditional medicine by involving mainly serotonergic neurotransmission because of the presence in part of flavonoids and the terpenoid β-sitosterol. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Synthesis and pharmacological evaluation of neurosteroid photoaffinity ligands

DOE Office of Scientific and Technical Information (OSTI.GOV)

Savechenkov, Pavel Y.; Chiara, David C.; Desai, Rooma

2017-08-01

Neuroactive steroids are potent positive allosteric modulators of GABAA receptors (GABAAR), but the locations of their GABAAR binding sites remain poorly defined. To discover these sites, we synthesized two photoreactive analogs of alphaxalone, an anesthetic neurosteroid targeting GABAAR, 11β-(4-azido-2,3,5,6-tetrafluorobenzoyloxy)allopregnanolone, (F4N3Bzoxy-AP) and 11-aziallopregnanolone (11-AziAP). Both photoprobes acted with equal or higher potency than alphaxalone as general anesthetics and potentiators of GABAAR responses, left-shifting the GABA concentration – response curve for human α1β3γ2 GABAARs expressed in Xenopus oocytes, and enhancing [3H]muscimol binding to α1β3γ2 GABAARs expressed in HEK293 cells. With EC50 of 110 nM, 11-AziAP is one the most potent general anestheticsmore » reported. [3H]F4N3Bzoxy-AP and [3H]11-AziAP, at anesthetic concentrations, photoincorporated into α- and β-subunits of purified α1β3γ2 GABAARs, but labeling at the subunit level was not inhibited by alphaxalone (30 μM). The enhancement of photolabeling by 3H-azietomidate and 3H-mTFD-MPAB in the presence of either of the two steroid photoprobes indicates the neurosteroid binding site is different from, but allosterically related to, the etomidate and barbiturate sites. Our observations are consistent with two hypotheses. First, F4N3Bzoxy-AP and 11-aziAP bind to a high affinity site in such a pose that the 11-photoactivatable moiety, that is rigidly attached to the steroid backbone, points away from the protein. Second, F4N3Bzoxy-AP, 11-aziAP and other steroid anesthetics, which are present at very high concentration at the lipid-protein interface due to their high lipophilicity, act via low affinity sites, as proposed by Akk et al. (Psychoneuroendocrinology 2009, 34S1, S59-S66).« less

A Multifaceted GABAA Receptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude).

PubMed

Hammer, Harriet; Bader, Benjamin M; Ehnert, Corina; Bundgaard, Christoffer; Bunch, Lennart; Hoestgaard-Jensen, Kirsten; Schroeder, Olaf H-U; Bastlund, Jesper F; Gramowski-Voß, Alexandra; Jensen, Anders A

2015-08-01

In the present study, we have elucidated the functional characteristics and mechanism of action of methaqualone (2-methyl-3-o-tolyl-4(3H)-quinazolinone, Quaalude), an infamous sedative-hypnotic and recreational drug from the 1960s-1970s. Methaqualone was demonstrated to be a positive allosteric modulator at human α1,2,3,5β2,3γ2S GABAA receptors (GABAARs) expressed in Xenopus oocytes, whereas it displayed highly diverse functionalities at the α4,6β1,2,3δ GABAAR subtypes, ranging from inactivity (α4β1δ), through negative (α6β1δ) or positive allosteric modulation (α4β2δ, α6β2,3δ), to superagonism (α4β3δ). Methaqualone did not interact with the benzodiazepine, barbiturate, or neurosteroid binding sites in the GABAAR. Instead, the compound is proposed to act through the transmembrane β((+))/α((-)) subunit interface of the receptor, possibly targeting a site overlapping with that of the general anesthetic etomidate. The negligible activities displayed by methaqualone at numerous neurotransmitter receptors and transporters in an elaborate screening for additional putative central nervous system (CNS) targets suggest that it is a selective GABAAR modulator. The mode of action of methaqualone was further investigated in multichannel recordings from primary frontal cortex networks, where the overall activity changes induced by the compound at 1-100 μM concentrations were quite similar to those mediated by other CNS depressants. Finally, the free methaqualone concentrations in the mouse brain arising from doses producing significant in vivo effects in assays for locomotion and anticonvulsant activity correlated fairly well with its potencies as a modulator at the recombinant GABAARs. Hence, we propose that the multifaceted functional properties exhibited by methaqualone at GABAARs give rise to its effects as a therapeutic and recreational drug. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Decompressive craniectomy or medical management for refractory intracranial hypertension: an AAST-MIT propensity score analysis.

PubMed

Nirula, Ram; Millar, D; Greene, Tom; McFadden, Molly; Shah, Lubdha; Scalea, Thomas M; Stein, Deborah M; Magnotti, Louis J; Jurkovich, Gregory J; Vercruysse, Gary; Demetriades, Demetrios; Scherer, Lynette A; Peitzman, Andrew; Sperry, Jason; Beauchamp, Kathryn; Bell, Scott; Feiz-Erfan, Iman; O'Neill, Patrick; Coimbra, Raul

2014-04-01

Moderate/severe traumatic brain injury (TBI) management involves minimizing cerebral edema to maintain brain oxygen delivery. While medical therapy (MT) consisting of diuresis, hyperosmolar therapy, ventriculostomy, and barbiturate coma is the standard of care, decompressive craniectomy (DC) for refractory intracranial hypertension (ICH) has gained renewed interest. Since TBI treatment guidelines consider DC a second-tier intervention after MT failure, we sought to determine if early DC (<48 hours) was associated with improved survival in patients with refractory ICH. Eleven Level 1 trauma centers provided clinical data and head computed tomographic scans for patients with a Glasgow Coma Scale (GCS) score of 13 or less and radiographic evidence of TBI excluding deaths within 48 hours. Computed tomographic scans were graded according to the Marshall classification. A propensity score to receive DC (regardless of whether DC was performed) was calculated for each patient based on patient characteristics, physiology, injury severity, GCS, severity of intracranial injury, and treatment center. Patients who actually received a DC were matched to patients with similar propensity scores who received MT for analysis. Outcomes were compared between early (<48 hours of injury) primary or secondary DC and matched controls and then between early primary DC only and matched controls. There were 2,602 patients who met the inclusion criteria ,of whom 264 (10.1%) received DC (either primary or secondary to another cranial procedure) and 109 (5%) had a DC that was primary. Variables associated with performing a DC included sex, race, intracranial pressure monitor placement, in-house trauma attending, traumatic subarachnoid hemorrhage, midline shift, and basal cistern compression. There was no survival benefit with early primary DC compared with the controls (relative risk, 1.07; 95% confidence interval, 0.67-1.73; p = 0.77), and resource use was higher. Early DC does not seem to significantly improve mortality in patients with refractory ICH compared with MT. Neurosurgeons should pause before entertaining this resource-demanding form of therapy. Therapeutic care/management, level III.

Capsaicin-sensitive sensory neurons are involved in the plasma catecholamine response of rats to selective stressors.

PubMed Central

Zhou, X F; Livett, B G

1991-01-01

1. The effect of capsaicin pre-treatment on adrenal catecholamine (CA) secretion in response to stress is controversial. In earlier experiments performed under pentobarbitone anaesthesia, the release of CA in response to stress was complicated by the effects of the barbiturate anaesthesia. 2. In the present study we have used conscious freely moving rats with indwelling cannulae to study the effect of neonatal capsaicin pre-treatment on the plasma CA response to different types of stressors (swimming stress, hypovolaemic stress, immobilization stress and cold stress). 3. After swimming for 20 min, plasma noradrenaline (NA) levels increased by 8-fold and adrenaline by 2-fold in control rats. The increase in plasma NA levels in the capsaicin group was attenuated at 10 min of swimming compared with the vehicle group (P < 0.05). 4. With hypovolaemic stress, there were no differences in plasma CA levels, blood pressure and heart rate between the capsaicin group and the vehicle group. There were also no differences in plasma CA levels after immobilization stress between the two groups. 5. With cold stress, plasma NA levels increased 5-fold and adrenaline levels by 3-fold over basal at 45 min in the vehicle pre-treated rats. This increase was not observed in the capsaicin group. 6. Immunoreactive substance P was depleted by only 68% in the splanchnic nerve following capsaicin pre-treatment. If the remaining 32% was biologically active substance P then it could account for the maintenance of the response to hypovolaemic and immobilization stress. However, it might be possible that the responses to hypovolaemic and immobilization stresses could be attenuated if a more complete depletion were achieved. 7. These results in conscious rats indicate that capsaicin-sensitive sensory neurons are required for plasma CA response to selective stressors. They are required for CA output in response to cold stress and to the early phase of swimming stress, but not to hypovolaemic stress and immobilization stress. PMID:1841948

Computer-assisted three-dimensional reconstructions of ( sup 14 C)-2-deoxy-D-glucose metabolism in cat lumbosacral spinal cord following cutaneous stimulation of the hindfoot

DOE Office of Scientific and Technical Information (OSTI.GOV)

Crockett, D.P.; Smith, W.K.; Proshansky, E.

1989-10-08

We report on computer-assisted three-dimensional reconstruction of spinal cord activity associated with stimulation of the plantar cushion (PC) as revealed by (14C)-2-deoxy-D-glucose (2-DG) serial autoradiographs. Moderate PC stimulation in cats elicits a reflex phasic plantar flexion of the toes. Four cats were chronically spinalized at about T6 under barbiturate anesthesia. Four to 11 days later, the cats were injected (i.v.) with 2-DG (100 microCi/kg) and the PC was electrically stimulated with needle electrodes at 2-5 times threshold for eliciting a reflex. Following stimulation, the spinal cord was processed for autoradiography. Subsequently, autoradiographs, representing approximately 8-18 mm from spinal segments L6-S1,more » were digitized for computer analysis and 3-D reconstruction. Several strategies of analysis were employed: (1) Three-dimensional volume images were color-coded to represent different levels of functional activity. (2) On the reconstructed volumes, virtual sections were made in the horizontal, sagittal, and transverse planes to view regions of 2-DG activity. (3) In addition, we were able to sample different regions within the grey and white matter semi-quantitatively (i.e., pixel intensity) from section to section to reveal differences between ipsi- and contralateral activity, as well as possible variation between sections. These analyses revealed 2-DG activity associated with moderate PC stimulation, not only in the ipsilateral dorsal horn as we had previously demonstrated, but also in both the ipsilateral and contralateral ventral horns, as well as in the intermediate grey matter. The use of novel computer analysis techniques--combined with an unanesthetized preparation--enabled us to demonstrate that the increased metabolic activity in the lumbosacral spinal cord associated with PC stimulation was much more extensive than had heretofore been observed.« less

Scale-up of organic reactions in ball mills: process intensification with regard to energy efficiency and economy of scale.

PubMed

Stolle, Achim; Schmidt, Robert; Jacob, Katharina

2014-01-01

The scale-up of the Knoevenagel-condensation between vanillin and barbituric acid carried out in planetary ball mills is investigated from an engineering perspective. Generally, the reaction proceeded in the solid state without intermediate melting and afforded selectively only one product. The reaction has been used as a model to analyze the influence and relationship of different parameters related to operation in planetary ball mills. From the viewpoint of technological parameters the milling ball diameter, dMB, the filling degree with respect to the milling balls' packing, ΦMB,packing, and the filling degree of the substrates with respect to the void volume of the milling balls' packing, ΦGS, have been investigated at different reaction scales. It was found that milling balls with small dMB lead to higher yields within shorter reaction time, treaction, or lower rotation frequency, rpm. Thus, the lower limit is set considering the technology which is available for the separation of the milling balls from the product after the reaction. Regarding ΦMB,packing, results indicate that the optimal value is roughly 50% of the total milling beakers' volume, VB,total, independent of the reaction scale or reaction conditions. Thus, 30% of VB,total are taken by the milling balls. Increase of the initial batch sizes changes ΦGS significantly. However, within the investigated parameter range no negative influence on the yield was observed. Up to 50% of VB,total can be taken over by the substrates in addition to 30% for the total milling ball volume. Scale-up factors of 15 and 11 were realized considering the amount of substrates and the reactor volume, respectively. Beside technological parameters, variables which influence the process itself, treaction and rpm, were investigated also. Variation of those allowed to fine-tune the reaction conditions in order to maximize the yield and minimize the energy intensity.

Recurrent erosion of the cornea.

PubMed Central

Brown, N.; Bron, A.

1976-01-01

Altogether, 80 patients aged between 24 and 73 years with recurrent erosion of the cornea have been studied and compared with a control group of 200. The patients' erosions were divisible into macroform and microform types. The macroform occurred in 10%, the microform in 56%, and both types in the same patients in 31%. The macroform was more commonly related to trauma than the microform. However, many (40%) were spontaneous in origin. The most common cause of the initial trauma was a finger nail. The recurrences occurred at around the time of waking, either just before or just after. Difficulty in opening the eye occurred in 10%. There was little evidence of precipitating factors, but eye rubbing was admitted by 10% and barbiturates were implicated in 3%. The corneae were examined in the healed state, when a high incidence (59%) were found to have superficial corneal dystrophies of the fingerprint lines, bleb, and Bietti's lacunar (map-like) types. These are considered individually, particular attention being paid to the distinction between the various types of line resembling the fingerprint line. Epithelial microcysts were also a common finding (59%) and were sometimes of the Cogan type. In only 11% of patients were there no corneal signs in the healed state. The need for careful examination of the cornea by retroillumination, using both the iris and the fundus, is stressed. The control group, in contrast, showed a very low incidence of dystrophies and cysts. Treatment was given initially with either drops or ointment and no differences in healing were found. Debridement was performed in 12 eyes as an initial treatment and also in four eyes which were not healing on medical treatment. Debridement assisted healing, but did not prevent recurrence. One eye was treated with debridement and scarification and seven with carbolization. These procedures appeared to reduce the recurrence rate. Sodium chloride ointment 5% was found useful as a prophylactic taken at bedtime, and the recurrence rate increased when it was withdrawn. Images PMID:1083744

[Ethanol and other psychoactive substances in fatal road traffic accidents in the Czech Republic in 2008].

PubMed

Mravcík, Viktor; Zábranský, Tomás; Vorel, Frantisek

2010-01-01

To map the recent prevalence of alcohol and other psychoactive substances in deceased victims of traffic accidents in the Czech Republic. The studied sample consisted of individuals autopsied in the departments of forensic medicine who died during traffic accidents in 2008 and were toxicologically tested for one or more of the following substances: ethanol, volatile substances, cannabis, opiates, stimulants, cocaine, benzodiazepines, and barbiturates. Case definition involved alcohol cases with blood alcohol concentration (BAC) 0.2 g/kg and higher; with cannabis, detections of active THC metabolites only were taken into account; from cases where volatile substances (solvents) were detected we included into the positive cases only those where substances were not produced post mortem or in some physiological or pathological statuses. The sample consisted of 1,040 persons deceased in traffic accidents, of whom 582 (56.0%) were toxicologically tested for one or more of the substances listed above. The sample has been divided into two subsamples--one of 778 (74.8%) active participants of road traffic accidents (pedestrians, bicyclists, and drivers) and other subsample consisting of 262 (25.4%) non-active participants. Ethanol was found in 38.3% of 381 tested and at least one of other psychoactive substances was found in 11.7% of 384 tested active participants--of those, stimulants (mostly methamphetamine) were found most frequently (6.5% of 337 tested), cannabis (5.9% of 203 tested) and benzodiazepines (3.9% of 363 tested active participants). Drivers were positive for ethanol in 29.2% cases, for one or more of other psychoactive substances except ethanol in 12.7% cases, most frequently for stimulants (9.2%) and cannabis (6.2%). Professional drivers were found negative for ethanol and other psychoactive substance except of one case of methamphetamine (6.7%). The study confirms high prevalence of alcohol and other psychoactive substances, especially stimulants (methamphetamine), cannabis and benzodiazepines, among deceased participants of road traffic accidents including drivers in the Czech Republic.

Pharmacodynamic response profiles of anxiolytic and sedative drugs.

PubMed

Chen, Xia; Broeyer, Freerk; de Kam, Marieke; Baas, Joke; Cohen, Adam; van Gerven, Joop

2017-05-01

Centrally-acting acutely anxiolytic drugs, such as benzodiazepines, barbiturates and gabapentinoids, affect various central nervous system (CNS) functions, which reflects not only their anxiolytic effects but also neuropsychological side-effects. To validate the pharmacodynamic biomarkers for GABA-ergic anxiolytics, this study determined the pharmacodynamics of two anxiolytics and a nonanxiolytic control, and linked them to their anxiolytic and sedative effects, during an anxiety-challenge study day. Twenty healthy volunteers were randomized in this placebo-controlled, double-blind, four-way cross-over study with single-dose alprazolam (1 mg), diphenhydramine (50 mg), pregabalin (200 mg) or placebo. The Neurocart was used between repeated fear-potentiated startle assessments. Thus, the potential influence of anxiety on CNS pharmacodynamic markers could be examined. Compared to placebo, VAS calmness increased with alprazolam (2.0 mm) and pregabalin (2.5 mm) but not with diphenhydramine. Saccadic peak velocity (SPV) declined after alprazolam (-57 ° s -1 ) and pregabalin (-28 ° s -1 ), more than with diphenhydramine (-14 ° s -1 ); so did smooth pursuit. The average responses of SPV and smooth pursuit were significantly correlated with the drug-induced increases in VAS calmness . The SPV-relative responses of VAS alertness , body-sway and adaptive-tracking also differed among alprazolam, pregabalin and diphenhydramine. Compared with the antihistaminergic sedative diphenhydramine, alprazolam and pregabalin caused larger SPV reduction, which was correlated with simultaneous improvement of subjective calmness, during a study day in which anxiety was stimulated repeatedly. The different effect profiles of the three drugs are in line with their pharmacological distinctions. These findings corroborate the profiling of CNS effects to demonstrate pharmacological selectivity, and further support SPV as biomarker for anxiolysis involving GABA-ergic neurons. The study also supports the use of prolonged mild threat to demonstrate anxiolytic effects in healthy volunteers. © 2016 The British Pharmacological Society.

Pentobarbital versus thiopental in the treatment of refractory intracranial hypertension in patients with traumatic brain injury: a randomized controlled trial

PubMed Central

Pérez-Bárcena, Jon; Llompart-Pou, Juan A; Homar, Javier; Abadal, Josep M; Raurich, Joan M; Frontera, Guillem; Brell, Marta; Ibáñez, Javier; Ibáñez, Jordi

2008-01-01

Introduction Experimental research has demonstrated that the level of neuroprotection conferred by the various barbiturates is not equal. Until now no controlled studies have been conducted to compare their effectiveness, even though the Brain Trauma Foundation Guidelines recommend that such studies be undertaken. The objectives of the present study were to assess the effectiveness of pentobarbital and thiopental in terms of controlling refractory intracranial hypertension in patients with severe traumatic brain injury, and to evaluate the adverse effects of treatment. Methods This was a prospective, randomized, cohort study comparing two treatments: pentobarbital and thiopental. Patients who had suffered a severe traumatic brain injury (Glasgow Coma Scale score after resuscitation ≤ 8 points or neurological deterioration during the first week after trauma) and with refractory intracranial hypertension (intracranial pressure > 20 mmHg) first-tier measures, in accordance with the Brain Trauma Foundation Guidelines. Results A total of 44 patients (22 in each group) were included over a 5-year period. There were no statistically significant differences in ' baseline characteristics, except for admission computed cranial tomography characteristics, using the Traumatic Coma Data Bank classification. Uncontrollable intracranial pressure occurred in 11 patients (50%) in the thiopental treatment group and in 18 patients (82%) in the pentobarbital group (P = 0.03). Under logistic regression analysis – undertaken in an effort to adjust for the cranial tomography characteristics, which were unfavourable for pentobarbital – thiopental was more effective than pentobarbital in terms of controlling intracranial pressure (odds ratio = 5.1, 95% confidence interval 1.2 to 21.9; P = 0.027). There were no significant differences between the two groups with respect to the incidence of arterial hypotension or infection. Conclusions Thiopental appeared to be more effective than pentobarbital in controlling intracranial hypertension refractory to first-tier measures. These findings should be interpreted with caution because of the imbalance in cranial tomography characteristics and the different dosages employed in the two arms of the study. The incidence of adverse effects was similar in both groups. Trial Registration (Trial registration: US Clinical Trials registry NCT00622570.) PMID:18759980

Hypothermia for Intracranial Hypertension after Traumatic Brain Injury.

PubMed

Andrews, Peter J D; Sinclair, H Louise; Rodriguez, Aryelly; Harris, Bridget A; Battison, Claire G; Rhodes, Jonathan K J; Murray, Gordon D

2015-12-17

In patients with traumatic brain injury, hypothermia can reduce intracranial hypertension. The benefit of hypothermia on functional outcome is unclear. We randomly assigned adults with an intracranial pressure of more than 20 mm Hg despite stage 1 treatments (including mechanical ventilation and sedation management) to standard care (control group) or hypothermia (32 to 35°C) plus standard care. In the control group, stage 2 treatments (e.g., osmotherapy) were added as needed to control intracranial pressure. In the hypothermia group, stage 2 treatments were added only if hypothermia failed to control intracranial pressure. In both groups, stage 3 treatments (barbiturates and decompressive craniectomy) were used if all stage 2 treatments failed to control intracranial pressure. The primary outcome was the score on the Extended Glasgow Outcome Scale (GOS-E; range, 1 to 8, with lower scores indicating a worse functional outcome) at 6 months. The treatment effect was estimated with ordinal logistic regression adjusted for prespecified prognostic factors and expressed as a common odds ratio (with an odds ratio <1.0 favoring hypothermia). We enrolled 387 patients at 47 centers in 18 countries from November 2009 through October 2014, at which time recruitment was suspended owing to safety concerns. Stage 3 treatments were required to control intracranial pressure in 54% of the patients in the control group and in 44% of the patients in the hypothermia group. The adjusted common odds ratio for the GOS-E score was 1.53 (95% confidence interval, 1.02 to 2.30; P=0.04), indicating a worse outcome in the hypothermia group than in the control group. A favorable outcome (GOS-E score of 5 to 8, indicating moderate disability or good recovery) occurred in 26% of the patients in the hypothermia group and in 37% of the patients in the control group (P=0.03). In patients with an intracranial pressure of more than 20 mm Hg after traumatic brain injury, therapeutic hypothermia plus standard care to reduce intracranial pressure did not result in outcomes better than those with standard care alone. (Funded by the National Institute for Health Research Health Technology Assessment program; Current Controlled Trials number, ISRCTN34555414.).

Gonococcal Endocarditis: The Gift That Stops Giving! An Uncommon Presentation of a Common Disease.

PubMed

Olayemi, G; Oferczak, M; Elagizi, A; El-Abbassi, I; Eschete, M; Crowe, J

2017-01-01

Gonorrhea is the 2nd most common sexually transmitted disease in the US with 800,000 cases of gonorrhea each year. Disseminated gonorrhea infection occurs in 0.5 percent - 3 percent of these patients and is more frequent in woman younger than 40 years of age. A 36 year old woman with a history of polysubstance abuse presented with 10 day history of feeling generally unwell. At presentation, vitals were remarkable for tachycardia and hypotension. Physical exam was remarkable for conjunctival pallor, bibasilar crackles, and tachycardia with grade III/VI systolic murmur loudest over the 2nd inter-costal space and loudest with expiration. No skin lesions were noted. Labs demonstrated leukocytosis (WBC 20,200 with 84 percent neutrophils);, anemia (Hb 6.7);, thrombocytosis (platelets 423 k/uL);, abnormal liver function tests (alkaline phosphatase 239 IU, AST 151 IU ALT 71 IU, albumin 2.5g/dL);, PT/INR 17.1/1.5. Troponin 0.42, BNP 823, D-dimer 619, and a urine drug screen that was positive for benzodiazepines, opiates, barbiturates, amphetamine, and THC. Hep panel and HIV were negative. Chest radiograph showed mild cardiomegaly and early interstitial edema. The patient was placed on broad spectrum antibiotics and given adequate fluid resuscitation and blood products. Blood cultures grew Neisseria gonorrhoeae. 2D ECHO showed a large pedunculated/mobile echo density adherent to the non-coronary and lefts cusps of the aortic valve. Proximal aortic root and aorto-mitral continuity were thickened, consistent with aortitis and/or abscess formation. Initial EKG on arrival showed junctional tachycardia which progressed into complete heart block. Cardiology was consulted and a pacemaker was placed emergently. However despite all aggressive measures the patient died of cardiac complications. Endocarditis is a rare complication of disseminated gonorrhea, occurring in only 1-2 percent of patients with gonoccocemia. The aortic valve is most commonly affected. Valve replacement is warranted in cases with severe dysfunction. Mortality remains around 19-20. Neisseria gonorrhoeae endocarditis should be included in the differential diagnosis in sexually active patients with endocarditis.

[Anesthesia in bronchial asthma].

PubMed

Bremerich, D H

2000-09-01

Asthma is defined as a chronic inflammatory airway disease in response to a wide variety of provoking stimuli. Characteristic clinical symptoms of asthma are bronchial hyperreactivity, reversible airway obstruction, wheezing and dyspnea. Asthma presents a major public health problem with increasing prevalence rates and severity worldwide. Despite major advances in our understanding of the clinical management of asthmatic patients, it remains a challenging population for anesthesiologists in clinical practice. The anesthesiologist's responsibility starts with the preoperative assessment and evaluation of the pulmonary function. For patients with asthma who currently have no symptoms, the risk of perioperative respiratory complications is extremely low. Therefore, pulmonary function should be optimized preoperatively and airway obstruction should be controlled by using steroids and bronchodilators. Preoperative spirometry is a simple means of assessing presence and severity of airway obstruction as well as the degree of reversibility in response to bronchodilator therapy. An increase of 15% in FEV1 is considered clinically significant. Most asymptomatic persons with asthma can safely undergo general anesthesia with and without endotracheal intubation. Volatile anesthetics are still recommended for general anesthetic techniques. As compared to barbiturates and even ketamine, propofol is considered to be the agent of choice for induction of anesthesia in asthmatics. The use of regional anesthesia does not reduce perioperative respiratory complications in asymptomatic asthmatics, whereas it is advantageous in symptomatic patients. Pregnant asthmatic and parturients undergoing anesthesia are at increased risk, especially if regional anesthetic techniques are not suitable and prostaglandin and its derivates are administered for abortion or operative delivery. Bronchial hyperreactivity associated with asthma is an important risk factor of perioperative bronchospasm. The occurrence of this potentially life-threatening condition in anesthesia practice varies from 0.17 to 4.2%. The anesthesiologists' goal should be to minimize the risk of inciting bronchospasm and to avoid triggering stimuli. As increases in airway resistance are noticed, therapy should be directed towards optimizing oxygenation and proper diagnosis needs to be established. With deepening anesthesia level and aggressive pharmacological management utilizing both, beta-agonists and steroids, respiratory failure may be properly controlled.

A review of suspected cases of driving under the influence of drugs (DUID) involved in traffic accidents in Istanbul (Turkey).

PubMed

Acar, Fatih; Asirdizer, Mahmut; Aker, Rezzan Gulhan; Kucukibrahimoglu, E Esra; Ates, Ismail; Erol, Yeter; Sahin, Aysegul

2013-08-01

Nowadays traffic accidents, which have high mortality and morbidity, are an important public health problem. The association between the use of alcohol and/or drugs by drivers and the increased risk of traffic accidents with a high risk of death and injury has been well described in the literature. This study aimed to review the incidence of cases of driving under the influence of drugs (DUID) among all cases of driving under the influence (DUI) of alcohol and/or other drugs involved in traffic accidents and to evaluate the type of the psychoactive drugs (with or without alcohol) detected in blood samples in Istanbul and its surrounding area. This study is the first investigation on the subject of DUID cases in Turkey. The reports of the Istanbul Toxicology Department of the Council of Forensic Medicine (Turkey) on suspected DUID cases involved in traffic accidents between 1 July 2010 and 30 June 2011 were retrospectively reviewed for alcohol and/or drug use. Alcohol analysis was requested in 4274 suspected DUI cases, whereas drug along with alcohol analysis was requested in only 91. The rate of suspected DUID cases (n = 91) among the suspected DUI cases (n = 4274) was only 2.1% and in this study, we evaluated only the DUID cases in detail. Alcohol was present in 44% of suspected DUID cases. Psychoactive drugs were present in 15.4% of cases. The incidence among 46 confirmed DUID cases was found to be 17.4% for cannabis, 8.7% for benzodiazepines, 4.3% for barbiturates, 4.3% for antidepressants, 2.2% for cocaine and 2.2% for amphetamines. Although there is a zero-tolerance approach for DUID in the Turkish regulations, it is not well recognised and not inspected by police and legal authorities who are responsible for taking measures in traffic accidents and for routine traffic controls in Turkey. It is concluded that psychoactive drugs should be checked as well as alcohol in all traffic accident cases and roadside controls. Copyright © 2013 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

Sensitive screening of abused drugs in dried blood samples using ultra-high-performance liquid chromatography-ion booster-quadrupole time-of-flight mass spectrometry.

PubMed

Chepyala, Divyabharathi; Tsai, I-Lin; Liao, Hsiao-Wei; Chen, Guan-Yuan; Chao, Hsi-Chun; Kuo, Ching-Hua

2017-03-31

An increased rate of drug abuse is a major social problem worldwide. The dried blood spot (DBS) sampling technique offers many advantages over using urine or whole blood sampling techniques. This study developed a simple and efficient ultra-high-performance liquid chromatography-ion booster-quadrupole time-of-flight mass spectrometry (UHPLC-IB-QTOF-MS) method for the analysis of abused drugs and their metabolites using DBS. Fifty-seven compounds covering the most commonly abused drugs, including amphetamines, opioids, cocaine, benzodiazepines, barbiturates, and many other new and emerging abused drugs, were selected as the target analytes of this study. An 80% acetonitrile solvent with a 5-min extraction by Geno grinder was used for sample extraction. A Poroshell column was used to provide efficient separation, and under optimal conditions, the analytical times were 15 and 5min in positive and negative ionization modes, respectively. Ionization parameters of both electrospray ionization source and ion booster (IB) source containing an extra heated zone were optimized to achieve the best ionization efficiency of the investigated abused drugs. In spite of their structural diversity, most of the abused drugs showed an enhanced mass response with the high temperature ionization from an extra heated zone of IB source. Compared to electrospray ionization, the ion booster (IB) greatly improved the detection sensitivity for 86% of the analytes by 1.5-14-fold and allowed the developed method to detect trace amounts of compounds on the DBS cards. The validation results showed that the coefficients of variation of intra-day and inter-day precision in terms of the signal intensity were lower than 19.65%. The extraction recovery of all analytes was between 67.21 and 115.14%. The limits of detection of all analytes were between 0.2 and 35.7ngmL -1 . The stability study indicated that 7% of compounds showed poor stability (below 50%) on the DBS cards after 6 months of storage at room temperature and -80°C. The reported method provides a new direction for abused drug screening using DBS. Copyright © 2017 Elsevier B.V. All rights reserved.

Interaction of biogenic amines with ethanol.

PubMed

Smith, A A

1975-01-01

Ethanol through its primary catabolite, acetaldehyde, competitively inhibits oxidation of aldehyde dehydrogenase substrates. As a consequence biogenic amines form increased quantities of alcohols rather than the corresponding acids. During this biotransformation, condensation reactions between deaminated and intact amines may occur which can yield tetrahydropapaverolines. These compounds are closely related to precursors of opioids which is cause to link ethanol abuse to morphine addiction. There is, however, no pharmacological or clinical evidence suggesting similarities between ethanol dependence or opiod addiction. Acetaldehyde plays an additional role in alkaloidal formation in vitro. Biogenic amines may react with acetaldehyde to form isoquinoline or carboline compounds. Some of these substances have significant pharmacological activity. Furthermore, they may enter neural stores and displace the natural neurotransmitter. Thus, they can act as false neurotransmitters. Some investigators believe that chronic ethanol ingestion leads to significant formation of such aberrant compounds which may then upset autonomic nervous system balance. This disturbance may explain the abnormal sympathetic activity seen in withdrawal. While these ideas about the etiology of alcohol abuse have a definite appeal, they are naturally based on in vitro preliminary work. Much study of the quantitative pharmacology of these compounds in animals is required before judgement can be made as to the merits of the proposed hypotheses. In the meantime, pharmacological studies on the ability of ethanol to depress respiration in the mouse has revealed that unlike opioids or barbituates, respiratory depression induced by ethanol requires the presence in brain of serotonin. This neurotransmitter also mediates the respiratory effects of several other alcohols but curiously, not chloral hydrate, yet this compound is purported to alter biogenic amine metabolism much like ethanol. Thus, the response to ethanol can be pharmacologically separated from other major narcotic classes such as opioids and barbiturates by respiratory depression effects. The specific requirement for serotonin mediation exhibited by ethanol and several other alcohols opens the door for a rational therapeutic approach to the treatment of alcohol abuse. At the same time, this finding tends to lessen the probability that alcoholism is in some way connected with the formation of addictive alkaloids.

Simultaneous analysis method for GHB, ketamine, norketamine, phenobarbital, thiopental, zolpidem, zopiclone and phenytoin in urine, using C18 poroshell column.

PubMed

Anilanmert, Beril; Çavuş, Fatma; Narin, Ibrahim; Cengiz, Salih; Sertler, Şefika; Özdemir, Ali Acar; Açikkol, Münevver

2016-06-01

Date-rape drugs have the potential to be used in drug-facilitated sexual assault, organ theft and property theft. Since they are colorless, tasteless and odorless, victims can drink without noticing, when added to the beverages. These drugs must be detected in time, before they are cleared up from the biofluids. A simultaneous extraction and determination method in urine for GHB, ketamine, norketamine, phenobarbital, thiopental, zolpidem, zopiclone and phenytoin (an anticonvulsant and antiepileptic drug) with LC-MS/MS was developed for the first time with analytically acceptable recoveries and validated. A 4 steps liquid-liquid extraction was applied, using only 1.000mL urine. A new age commercial C18 poroshell column with high column efficiency was used for LC-MS/MS analysis with a fast isocratic elution as 5.5min. A new MS transition were introduced for barbital. 222.7>179.8 with the effect of acetonitrile. Recoveries (%) were between 80.98-99.27 for all analytes, except for GHB which was 71.46. LOD and LOQ values were found in the ranges of 0.59-49.50 and 9.20-80.80ngmL(-1) for all the analytes (except for GHB:3.44 and 6.00μgmL(-1)). HorRat values calculated (between 0.25-1.21), revealed that the inter-day and interanalist precisions (RSD%≤14.54%) acceptable. The simultaneous extraction and determination of these 8 analytes in urine is challenging because of the difficulty arising from the different chemical properties of some. Since the procedure can extract drugs from a wide range of polarity and pKa, it increases the window of detection. Group representatives from barbiturates, z-drugs, ketamine, phenytoin and polar acidic drugs (GHB) have been successfully analyzed in this study with low detection limits. The method is important from the point of determining the combined or single use of these drugs in crimes and finding out the reasons of deaths related to these drugs. Copyright © 2016 Elsevier B.V. All rights reserved.

Patterns of Drugs and Drug Metabolites Observed in Meconium: What Do They Mean?

PubMed

McMillin, Gwendolyn A; Wood, Kelly E; Strathmann, Frederick G; Krasowski, Matthew D

2015-10-01

Meconium drug testing is performed to detect potentially harmful drug exposures in a newborn. Interpretation of meconium drug testing results can be complicated based on the patterns and proportional concentrations of the drug(s) and/or drug metabolite(s) detected. The objective of this study was to analyze meconium drug testing patterns in a de-identified dataset from a national reference laboratory (n = 76,631) and in a subset of the data, wherein specimens originated at a single academic medical center for which detailed chart review was possible (n = 3635). Meconium testing was performed using 11 immunoassay-based drug screens. Specimens that were positive for one or more drug screens were reflexed to corresponding confirmation tests performed by gas chromatography or liquid chromatography with mass spectrometric detection, targeted to identify and quantitate specific parent drug(s) and metabolite(s). The positivity rate was the highest for the cannabis metabolite 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (25.2%, n = 18,643), followed by opiates/oxycodone (23.2%, n = 17,778), amphetamine/methamphetamine (6.7%, n = 5134), cocaine metabolites (5.5%, n = 4205), methadone (5.3%, n = 4093), benzodiazepines (3.4%, n = 2603), barbiturates (1.1%, n = 834), propoxyphene (1.0%, n = 749), and phencyclidine (0.1%, n = 44). Based on documented pharmacy history, drugs administered to either the mother or newborn during the birth hospitalization were detected in meconium, providing evidence that drugs can be incorporated into meconium rapidly. Drugs administered directly to the newborn after birth were recovered in meconium as both parent drug and metabolites, providing evidence of neonatal metabolism. Overall, patterns observed in meconium exhibited many similarities to those patterns commonly reported with urine drug testing. Interpretation of meconium drug testing results requires comparison of results with clinical and analytical expectations, including maternal admissions to drug use, pharmacy history, recognized metabolic patterns for drugs of interest, cutoff concentrations, and other performance characteristics of the test. Concentrations of drug(s) and drug metabolites(s) may not reliably predict timing of drug use, extent of drug use, or frequency of drug exposures.

A brief history of epilepsy and its therapy in the Western Hemisphere.

PubMed

Gross, R A

1992-07-01

The history of epilepsy and its treatment in the western world dates back at least 4 millennia to the ancient civilization of the middle east. Past and present treatments have been empirical, usually reflecting the prevailing views of epilepsy, be they medical, theological or superstitious. Ancient physicians relied on clinical observation to distinguish between epileptic syndromes and infer their cause. Early pathophysiological theories of epilepsy correctly identified the brain as the site of the problem, but emphasized incorrect causes such as an excess of phlegm in the brain. Treatments consisted of prescribed diets or living conditions, occasional surgery such as bloodletting or skull trephination and medicinal herbs. These treatments, often ineffective, had the intellectual advantage of being based on pathophysiological principles, unlike current, more empirical, therapies. The unfortunate but widely held view of epilepsy as being due to occult or evil influences gained adherents even in the medical world during ancient times, and the later acceptance of Christianity allowed theological interpretations of seizures as well. Magical or religious treatments were more frequently prescribed as a result, practices which persist to this day. In the Renaissance an attempt was made to view epilepsy as a manifestation of physical illness rather than a moral or occult affliction, but it was during the Enlightenment that epilepsy was viewed along more modern lines, helped by advances in anatomy and pathology and the development of chemistry, pharmacy and physiology. The idea that focal irritation may cause seizures came about from clinical and experimental work, and was supported by the successful control of seizures by the (sedative) bromides and barbiturates in the late 19th century. The introduction of phenytoin showed that non-sedative drugs could be effective in controlling seizures as well, and the development of in vivo seizure models widened the scope of pharmaceutical agents tested for their efficacy against epilepsy. Increasing knowledge of the cellular mechanisms of epilepsy will, hopefully, allow the development and introduction of drugs with increasing specificity against seizure activity and the development of epilepsy.

Human liver microsomal cytochrome P-450 enzymes involved in the bioactivation of procarcinogens detected by umu gene response in Salmonella typhimurium TA 1535/pSK1002.

PubMed

Shimada, T; Iwasaki, M; Martin, M V; Guengerich, F P

1989-06-15

A total of 57 procarcinogens was examined for induction of umu gene response in the chimeric plasmid pSK1002, carried in Salmonella typhimurium TA 1535, after incubation with a series of human liver microsomal preparations which had been selected on the basis of characteristic levels of individual cytochrome P-450 (P-450) enzymes. The 18 most active compounds were selected and further analyzed using the umu gene response and correlative studies with a larger number of microsomal preparations, enzyme reconstitution studies involving purified enzymes, immunochemical inhibition, and patterns of stimulation and inhibition of catalytic activity by 7,8-benzoflavone. The results collectively indicate that 16 of these 18 most potent genotoxins examined are activated primarily either by P-450NF (the nifedipine oxidase) or P-450PA (the phenacetin O-deethylase). P-450NF appears to be the major enzyme involved in the bioactivation of aflatoxin B1, aflatoxin G1, sterigmatocystin, trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene, 6-aminochrysene, and tris-(2,3-dibromopropyl)phosphate in human liver. P-450PA appears to be the major enzyme involved in the bioactivation of 2-amino-3-methylimidazo[4,5-f]quinoline, 2-amino-3,5-dimethylimidazo[4, 5-f]quinoline, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, 2-aminoanthracene, 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole, 2-aminofluorene, 2-acetylaminofluorene, 4-aminobiphenyl, 3-amino-1-methyl-5H-pyrido[4,3-b] indole, and 2-aminodipyrido[1,2-a:3',2'-d]imidazole. More than one enzyme appears to contribute significantly to the bioactivation of the other two compounds examined, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b] indole and 6-nitrochrysene. The literature suggests that the two human liver P-450s involved in activation of these 16 procarcinogens are highly inducible by barbiturates, macrolide antibodies, and certain steroids (P-450NF) and by smoking and ingestion of charcoal-containing food (P-450PA); noninvasive assays are available to monitor the function of both P-450NF and P-450PA.

Substance Use in Pregnant Women Using the Emergency Department: Undertested And Overlooked?

PubMed Central

Moyer, C. Leigh; Johnson, Sean; Klug, Marilyn G.

2018-01-01

Introduction The objective was to determine if pregnant women visiting the emergency department (ED) are tested for substance use as frequently as non-pregnant women. Methods We captured all ED visits over a six-year period (2010–2016) from a single community hospital and identified women of childbearing age, defined for our study as 11–50 years old. We collected demographic data including age in years, ethnicity, body mass index, marital status, disposition, last encounter department, method of arrival, and day of week. An independent binary variable was created based on whether the woman was tested for alcohol or drugs (amphetamines, barbiturates, benzodiazepines, cannabis, cocaine, opioids) during her visit. We then compared rates of testing for substance use by pregnancy status. Results We identified 61,222 ED visits by women of childbearing age (range 11–50, mean 30.5, standard deviation 9.6) over a six-year period from 2010–2016. Of the 57,360 non-pregnant women, 4.14% were tested compared to 1.04% of the 3,862 pregnant women tested with a relative risk of 0.25 (p<0.001, 95% confidence interval [CI] [0.183–0.341]). The most highly tested chief complaints for all women – psychiatric or substance use concerns – showed pregnant women were still 37% and 54% less likely to be tested, respectively (risk ratio [RR] 0.46, 95% CI [0.19–1.13]; RR 0.63, 95% CI [0.41–0.96]). Beyond pregnancy status, we found no significant interaction between patient demographics and substance use testing. Conclusion Pregnant women presenting to the ED were 75% less likely to be tested for drug or alcohol use than non-pregnant women. Our study showed only pregnancy status as a statistically significant variable in drug- and alcohol-screening rates when pregnant and non-pregnant patient chief complaints and demographics were compared. Increased attention to the screening of pregnant women for substance use may be necessary to provide adequate care and intervention to this population. PMID:29760859

Antiurolithiatic Effect of Sirupeelai Samoola Kudineer: A Polyherbal Siddha Decoction on Ethylene Glycol-induced Renal Calculus in Experimental Rats

PubMed Central

Vasanthi, A. Hannah Rachel; Muthulakshmi, V.; Gayathri, V.; Manikandan, R.; Ananthi, S.; Kuruvilla, Sarah

2017-01-01

Background: Sirupeelai Samoola Kudineer (SK), a polyherbal decoction containing four medicinal plants has been used in Siddha system of medicine, practiced in Southern parts of India for the management of urolithiasis. Objective: The present study is carried out to scientifically validate the traditional claim and to study the mechanism of action of the drug. Materials and Methods: In the present study, anti-urolithiatic effect of SK was evaluated in Sprague-Dawley rats using ethylene glycol through drinking water and intraperitoneal injection of sodium oxalate. Renal damage was confirmed by the increased production of thiobarbituric acid reactive substance (TBARS). Results: Co-treatment with SK to urolithiatic rats for 21 days significantly prevented the elevation of renal and urinary stone biomarkers in plasma and renal tissue thereby preventing renal damage and the formation of renal calculi. Administration of SK at all doses and cystone restored the antioxidant (glutathione) levels by preventing the elevation of TBARS in the kidney tissue, which was further confirmed by histological sections. Conclusions: SK treatment promotes diuresis which leads to flushing of the renal stones and maintains the alkaline environment in the urinary system which probably mediates the antilithiatic activity. SK provides structural and functional protection to the kidneys by enhancing its physiological function against stone formation and validates its clinical use. SUMMARY SK exhibited antilithiatic and diuretic potential in ethylene glycol and sodium oxalate induced urolithiasis in ratsElevated urinary stone markers (Calcium, oxalate, uric acid, magnesium and phosphates) in plasma and renal tubular enzymes (LDH, GGT, ALP, AST ALT) in urolithiatic rats were reversed by SK treatmentSK administration significantly reduced the level of renal stress markers like Urea, Creatinine, LPO and elevated SOD, GPx, GSH levels aiding in nephroprotectionSK also provides structural and functional protection against ethylene glycol- induced renal calculus in rats as evidenced by histopathological studies. Abbreviations used: SK: Sirupeelai Samoola Kudineer; TBARS: ThioBarbituric Acid Reactive Substances; SOD: SuperOxide Dismutase; GPx: Gluthathione peroxidase; GSH- Glutathione; LPO: Lipid peroxidation as measured as TBARS; AST: Aspartate AminoTransferase; ALT: Alanine Amino transferase; GGT: Gamma Glutamyl Transferase; LDH: Lactate Dehydrogenase. PMID:28808392

High-dose benzodiazepine dependence: a qualitative study of patients' perception on cessation and withdrawal.

PubMed

Liebrenz, Michael; Gehring, Marie-Therese; Buadze, Anna; Caflisch, Carlo

2015-05-13

Benzodiazepine withdrawal syndrome has been reported following attempts to withdraw even from low or therapeutic doses and has been compared to barbiturate and alcohol withdrawal. This experience is known to deter patients from future cessation attempts. Research on other psychotropic substances shows that the reasons and motivations for withdrawal attempts - as well as the experiences surrounding those attempts - at least partially predict future efforts at discontinuation as well as relapse. We therefore aimed to qualitatively explore what motivates patients to discontinue this medication as well as to examine their experiences surrounding previous and current withdrawal attempts and treatment interventions in order to positively influence future help-seeking behavior and compliance. To understand these patients better, we conducted a series of 41 unstructured, narrative, in-depth interviews among adult Swiss patients with a long-term dependent use of benzodiazepines in doses equivalent to more than 40 mg diazepam per day and/or otherwise problematic use (mixing benzodiazepines, escalating dosage, recreational use or illegal purchase). Mayring's qualitative content analysis was used to evaluate findings. These high-dose benzodiazepine-dependent patients decision to change consumption patterns were affected by health concerns, the feeling of being addicted and social factors. Discontinuation attempts were frequent and not very successful with fast relapse. Withdrawal was perceived to be a difficult, complicated, and highly unpredictable process. The first attempt at withdrawal occurred at home and typically felt better than at the clinic. Inpatient treatment was believed to be more effective with long term treatment (approaches) than short term. Patients preferred gradual reduction of usage to abrupt cessation (and had experienced both). While no clear preferences for withdrawal were found for benzodiazepines with specific pharmacokinetic properties, participants frequently based their decision to participate in treatment on the availability of their preferred brand name and furthermore discarding equivalent dosage rationales. Our findings provide greater understanding of the factors that motivate high-dose benzodiazepine-dependent individuals to stop taking these medications, and how they experience withdrawal and treatment strategies. They underscore how patients' perceptions of treatment approaches contribute to compliant or non-compliant behavior.

Vesicular glutamate transporter DNPI/VGLUT2 is expressed by both C1 adrenergic and nonaminergic presympathetic vasomotor neurons of the rat medulla.

PubMed

Stornetta, Ruth L; Sevigny, Charles P; Schreihofer, Ann M; Rosin, Diane L; Guyenet, Patrice G

2002-03-12

The main source of excitatory drive to the sympathetic preganglionic neurons that control blood pressure is from neurons located in the rostral ventrolateral medulla (RVLM). This monosynaptic input includes adrenergic (C1), peptidergic, and noncatecholaminergic neurons. Some of the cells in this pathway are suspected to be glutamatergic, but conclusive evidence is lacking. In the present study we sought to determine whether these presympathetic neurons express the vesicular glutamate transporter BNPI/VGLUT1 or the closely related gene DNPI, the rat homolog of the mouse vesicular glutamate transporter VGLUT2. Both BNPI/VGLUT1 and DNPI/VGLUT2 mRNAs were detected in the medulla oblongata by in situ hybridization, but only DNPI/VGLUT2 mRNA was present in the RVLM. Moreover, BNPI immunoreactivity was absent from the thoracic spinal cord lateral horn. DNPI/VGLUT2 mRNA was present in many medullary cells retrogradely labeled with Fluoro-Gold from the spinal cord (T2; four rats). Within the RVLM, 79% of the bulbospinal C1 cells contained DNPI/VGLUT2 mRNA. Bulbospinal noradrenergic A5 neurons did not contain DNPI/VGLUT2 mRNA. The RVLM of six unanesthetized rats subjected to 2 hours of hydralazine-induced hypotension contained tenfold more c-Fos-ir DNPI/VGLUT2 neurons than that of six saline-treated controls. c-Fos-ir DNPI/VGLUT2 neurons included C1 and non-C1 neurons (3:2 ratio). In seven barbiturate-anesthetized rats, 16 vasomotor presympathetic neurons were filled with biotinamide and analyzed for the presence of tyrosine hydroxylase immunoreactivity and/or DNPI/VGLUT2 mRNA. Biotinamide-labeled neurons included C1 and non-C1 cells. Most non-C1 (9/10) and C1 presympathetic cells (5/6) contained DNPI/VGLUT2 mRNA. In conclusion, DNPI/VGLUT2 is expressed by most blood pressure-regulating presympathetic cells of the RVLM. The data suggest that these neurons may be glutamatergic and that the C1 adrenergic phenotype is one of several secondary phenotypes that are differentially expressed by subgroups of these cells. Copyright 2002 Wiley-Liss, Inc.

CYP3A5 mRNA degradation by nonsense-mediated mRNA decay.

PubMed

Busi, Florent; Cresteil, Thierry

2005-09-01

The total CYP3A5 mRNA level is significantly greater in carriers of the CYP3A5*1 allele than in CYP3A5*3 homozygotes. Most of the CYP3A5*3 mRNA includes an intronic sequence (exon 3B) containing premature termination codons (PTCs) between exons 3 and 4. Two models were used to investigate the degradation of CYP3A5 mRNA: a CYP3A5 minigene consisting of CYP3A5 exons and introns 3 to 6 transfected into MCF7 cells, and the endogenous CYP3A5 gene expressed in HepG2 cells. The 3'-untranslated region g.31611C>T mutation has no effect on CYP3A5 mRNA decay. Splice variants containing exon 3B were more unstable than wild-type (wt) CYP3A5 mRNA. Cycloheximide prevents the recognition of PTCs by ribosomes: in transfected MCF7 and HepG2 cells, cycloheximide slowed down the degradation of exon 3B-containing splice variants, suggesting the participation of nonsense-mediated decay (NMD). When PTCs were removed from pseudoexon 3B or when UPF1 small interfering RNA was used to impair the NMD mechanism, the decay of the splice variant was reduced, confirming the involvement of NMD in the degradation of CYP3A5 splice variants. Induction could represent a source of variability for CYP3A5 expression and could modify the proportion of splice variants. The extent of CYP3A5 induction was investigated after exposure to barbiturates or steroids: CYP3A4 was markedly induced in a pediatric population compared with untreated neonates. However, no effect could be detected in either the total CYP3A5 RNA, the proportion of splice variant RNA, or the protein level. Therefore, in these carriers, induction is unlikely to switch on the phenotypic CYP3A5 expression in carriers of CYP3A5*3/*3.

At clinically relevant concentrations the anaesthetic/amnesic thiopental but not the anticonvulsant phenobarbital interferes with hippocampal sharp wave-ripple complexes

PubMed Central

Papatheodoropoulos, Costas; Sotiriou, Evangelos; Kotzadimitriou, Dimitrios; Drimala, Panagiota

2007-01-01

Background Many sedative agents, including anesthetics, produce explicit memory impairment by largely unknown mechanisms. Sharp-wave ripple (SPW-R) complexes are network activity thought to represent the neuronal substrate for information transfer from the hippocampal to neocortical circuits, contributing to the explicit memory consolidation. In this study we examined and compared the actions of two barbiturates with distinct amnesic actions, the general anesthetic thiopental and the anticonvulsant phenobarbital, on in vitro SPW-R activity. Results Using an in vitro model of SPW-R activity we found that thiopental (50–200 μM) significantly and concentration-dependently reduced the incidence of SPW-R events (it increased the inter-event period by 70–430 %). At the concentration of 25 μM, which clinically produces mild sedation and explicit memory impairment, thiopental significantly reduced the quantity of ripple oscillation (it reduced the number of ripples and the duration of ripple episodes by 20 ± 5%, n = 12, P < 0.01), and suppressed the rhythmicity of SPWs by 43 ± 15% (n = 6, P < 0.05). The drug disrupted the synchrony of SPWs within the CA1 region at 50 μM (by 19 ± 12%; n = 5, P < 0.05). Similar effects of thiopental were observed at higher concentrations. Thiopental did not affect the frequency of ripple oscillation at any of the concentrations tested (10–200 μM). Furthermore, the drug significantly prolonged single SPWs at concentrations ≥50 μM (it increased the half-width and the duration of SPWs by 35–90 %). Thiopental did not affect evoked excitatory synaptic potentials and its results on SPW-R complexes were also observed under blockade of NMDA receptors. Phenobarbital significantly accelerated SPWs at 50 and 100 μM whereas it reduced their rate at 200 and 400 μM. Furthermore, it significantly prolonged SPWs, reduced their synchrony and reduced the quantity of ripples only at the clinically very high concentration of 400 μM, reported to affect memory. Conclusion We hypothesize that thiopental, by interfering with SPW-R activity, through enhancement of the GABAA receptor-mediated transmission, affects memory processes which involve hippocampal circuit activation. The quantity but not the frequency of ripple oscillation was affected by the drug. PMID:17672909

Effect of fusimotor stimulation on Ia discharge during shortening of cat soleus muscle at different speeds

PubMed Central

Appenteng, K.; Prochazka, A.; Proske, U.; Wand, P.

1982-01-01

1. In barbiturate-anaesthetized cats, the L7 and S1 dorsal and ventral roots were dissected to isolate functionally single afferents identified as primary endings of soleus muscle spindles, and motor filaments which exerted a fusimotor action on the afferents with limited action on extrafusal muscle. Up to seven filaments, with an action on a given primary ending, could be isolated and each was classified as exerting either a predominantly dynamic or static action. 2. Combined stimulation of these filaments, at rates up to 200 impulses/s could maintain afferent firing during muscle shortenings at speeds up to 200 mm/s. 3. Fusimotor stimulation could also maintain afferent firing at a target frequency of 100 impulses/s during muscle shortenings up to 200 mm/s. The timing, in relation to the onset of shortening, and the rates of fusimotor stimulation were found to be critical in achieving the target frequency. 4. Sinusoidal modulation of the frequency of fusimotor stimulation was used to study the conditions required to achieve constant afferent firing in the face of imposed sinusoidal length changes. 5. For given depths of modulation, the phase advance of fusimotor stimulation needed to produce minimum modulation of afferent firing (best compensation) increased with increasing frequency of the sinusoids. The compensation deteriorated with an increase in the frequency of the sinusoids and a change in the mean muscle lengths, although in some cases it could be restored by adjustments to the depth of modulation of fusimotor rate. This suggests that for movements of varying speeds and amplitudes, settings which are appropriate for shortening at a given velocity and mean muscle length, do not apply if either of these two variables are altered. 6. These findings demonstrate that the fusimotor system is potentially capable of eliciting constant afferent firing as envisaged in the `servo-assistance' hypothesis (Matthews, 1964, 1972; Stein, 1974). This, and the fact that constant afferent firing is not seen during normal unobstructed shortenings at velocities greater than 0·2 resting length/s (Prochazka, 1981), are used to argue that it is by choice rather than necessity that `servo-assistance' (as defined above) is not employed during normal movements. However, servo-assistance of a different form (involving modulated spindle afferent feed-back from both agonists and antagonists) remains a viable alternative. PMID:6216336

Maternal butalbital use and selected defects in the national birth defects prevention study.

PubMed

Browne, Marilyn L; Van Zutphen, Alissa R; Botto, Lorenzo D; Louik, Carol; Richardson, Sandra; Druschel, Charlotte M

2014-01-01

Butalbital is a barbiturate contained in combination products with caffeine and an analgesic prescribed for the treatment of migraine and tension-type headaches. Controversy exists as to whether butalbital should continue to be prescribed in the United States because of the potential for abuse, overuse headache, and withdrawal syndromes. Butalbital crosses the placenta but there is limited information about potential teratogenicity. To evaluate associations between butalbital and a wide range of specific birth defects. The National Birth Defects Prevention Study is an ongoing, case-control study of nonsyndromic, major birth defects conducted in 10 states. The detailed case classification and large number of cases in the National Birth Defects Prevention Study allowed us to examine the association between maternal self-reported butalbital use and specific birth defects. We conducted an analysis of 8373 unaffected controls and 21,090 case infants with estimated dates of delivery between 1997 and 2007; included were birth defects with 250 or more cases. An exploratory analysis examined groups with 100 to 249 cases. Seventy-three case mothers and 15 control mothers reported periconceptional butalbital use. Of 30 specific defect groups evaluated, adjusted odds ratios for maternal periconceptional butalbital use were statistically significant for 3 congenital heart defects: tetralogy of Fallot (adjusted odds ratio = 3.04; 95% confidence interval = 1.07-8.62), pulmonary valve stenosis (adjusted odds ratio = 5.73; 95% confidence interval = 2.25-14.62), and secundum-type atrial septal defect (adjusted odds ratio = 3.06; 95% confidence interval = 1.07-8.79). In the exploratory analysis, an elevated odds ratio was detected for 1 congenital heart defect, single ventricle. We observed relationships between maternal periconceptional butalbital use and certain congenital heart defects. These associations have not been reported before, and some may be spurious. Butalbital use was rare and despite the large size of the National Birth Defects Prevention Study, the number of exposed case and control infants was small. However, if confirmed in additional studies, our findings will be useful in weighing the risks and benefits of butalbital for the treatment of migraine and tension-type headaches. © Published 2013. This article is a U.S. Government work and is in the public domain in the USA.

Hair analysis to monitor abuse of analgesic combinations containing butalbital and propyphenazone.

PubMed

Ferrari, Anna; Tiraferri, Ilaria; Palazzoli, Federica; Verri, Patrizia; Vandelli, Daniele; Marchesi, Filippo; Ciccarese, Michela; Licata, Manuela

2015-11-10

Butalbital, a barbiturate, is present in analgesic combinations used by headache sufferers. Overuse/abuse of these combinations may cause dependence, chronic migraine, and medication-overuse headache (MOH). MOH is difficult to manage: it improves interrupting analgesic overuse, but requires monitoring, because relapses are frequent. A gas chromatography-mass spectrometry (GC-MS) method for hair analysis has been developed and validated to document abuse of an analgesic combination containing butalbital and propyphenazone by a patient with MOH. For over ten years the patient managed her headache using eight suppositories/day of an analgesic combination containing butalbital 150mg, caffeine 75mg, and propyphenazone 375mg per suppository. An outpatient detoxification treatment was carried out. After three weeks, the patient reduced the consumption to one suppository/day. At the first control visit, after three months from the beginning of detoxification, the patient increased the use of the combination to four suppositories/day and at the second control visit, after seven months from the beginning of detoxification, she was back to eight suppositories/day. At the two control visits, a hair sample was taken for determination of butalbital and propyphenazone. Moreover blood and urine samples for determination of butalbital were drawn at the beginning of detoxification treatment and at the two control visits. With the segmental analysis of two hair samples the medication history of ten months could be estimated. In the first hair sample, collected at the first control visit, in the distal segment, butalbital and propyphenazone concentrations were, respectively, 17.5ng/mg and 56.0ng/mg, confirming the prolonged abuse; in the proximal segment, concurrently with the detoxification treatment, butalbital and propyphenazone concentrations had reduced respectively to 5.45ng/mg and 11.1ng/mg. The second hair sample, collected at the second control visit, proved the fair course of the detoxification treatment in the distal segment and signalled relapse in the abuse of the analgesic combination in the proximal segment. In the clinical context, hair analysis can be advantageously used to monitor the abuse of analgesic combinations with butalbital, common among headache patients. The validation data showed that GC-MS method developed for determination of butalbital and propyphenazone was rapid, highly sensitive, specific and selective. Copyright © 2015 Elsevier B.V. All rights reserved.

THE INACTIVATION OF DILUTE SOLUTIONS OF CRYSTALLINE TRYPSIN BY X-RADIATION

PubMed Central

McDonald, Margaret R.

1955-01-01

The proteolytic activity of dilute solutions of clystalline trypsin is destroyed by x-rays, the amount of inactivation being an exponential function of the radiation dose. The reaction yield increases steadily with increasing concentration of trypsin, varying, as the concentration of enzyme is increased from 1 to 300 µM, from 0.068 to 0.958 micromole of trypsin per liter inactivated per 1000 r with 0.005 N hydrochloric acid as the solvent, from 0.273 to 0.866 with 0.005 N sulfuric acid as the solvent, and from 0.343 to 0.844 with 0.005 N nitric acid as the solvent. When the reaction yields are plotted as a function of the initial concentration of trypsin, they fall on a curve given by the expression Y α XK, in which Y is the reaction yield, X is the concentration of trypsin, and K is a constant equal to 0.46, 0.20, and 0.16, respectively, with 0.005 N hydrochloric, sulfuric, and nitric acids as solvents. The differences between the reaction yields found with chloride and sulfate ions in I to 10 µM trypsin solutions are significant only in the pH range from 2 to 4. The amount of inactivation obtained with a given dose of x-rays depends on the pH of the solution being irradiated and the nature of the solvent. The reaction yield-pH curve is a symmetrical one, with minimum yields at about pH 7. Buffers such as acetate, citrate, borate and barbiturate, and other organic molecules such as ethanol and glucose, in concentrations as low as 20 µM, inhibit the inactivation of trypsin by x-radiation. Sigmoid inactivation-dose curves instead of exponential ones are obtained in the presence of ethanol. The reaction yields for the inactivation of trypsin solutions by x-rays are approximately 1.5 times greater when the irradiation is done at 26°C. than when it is done at 5°C., when 0.005 N hydrochloric acid is the solvent. The dependence on temperature is less when 0.005 N sulfuric acid is used, and is negligible with 0.005 N nitric acid. The difficulties involved in interpreting radiation effects in aqueous systems, and in comparing the results obtained under different experimental conditions, are discussed. PMID:14367774

A Cysteine Substitution Probes β3H267 Interactions with Propofol and Other Potent Anesthetics in α1β3γ2L Gamma-Aminobutyric Acid Type A Receptors

PubMed Central

Stern, Alex T.; Forman, Stuart A.

2015-01-01

Background Anesthetic contact residues in γ-aminobutyric acid type A (GABAA) receptors have been identified using photolabels, including two propofol derivatives. O-propofol-diazirine labels H267 in β3 and α1β3 receptors, while m-azi-propofol labels other residues in intersubunit clefts of α1β3. Neither label has been studied in αβγ receptors, the most common isoform in mammalian brain. In αβγ receptors, other anesthetic derivatives photolabel m-azi-propofol labeled residues, but not βH267. Our structural homology model of α1β3γ2L receptors suggests that β3H267 may abut some of these sites. Methods Substituted cysteine modification-protection was used to test β3H267C interactions with four potent anesthetics: propofol, etomidate, alphaxalone, and R-5-allyl-1-methyl-5-(m-trifluoromethyl-diazirinylphenyl) barbituric acid (mTFD-MPAB). We expressed α1β3γ2L or α1β3H267Cγ2L GABAA receptors in Xenopus oocytes. We used voltage clamp electrophysiology to assess receptor sensitivity to GABA and anesthetics, and to compare para-chloromercuribenzenesulfonate (pCMBS) modification rates with GABA versus GABA plus anesthetics. Results Enhancement of GABA EC5 responses by equi-hypnotic concentrations of all four anesthetics was similar in α1β3γ2L and α1β3H267Cγ2L receptors (n ≥ 3). Direct activation of α1β3H267Cγ2L receptors, but not α1β3γ2L, by mTFD-MPAB and propofol was significantly greater than the other anesthetics. Modification of β3H267C by pCMBS (n ≥ 4) was rapid and accelerated by GABA. Only mTFD-MPAB slowed β3H267C modification (~2-fold; p = 0.011). Conclusions β3H267 in α1β3γ2L GABAA receptors contacts mTFD-MPAB, but not propofol. Our results suggest that β3H267 is near the periphery of one or both transmembrane inter-subunit (α+/β− and γ+/β−) pockets where both mTFD-MPAB and propofol bind. PMID:26569173

Managing epilepsy in women of childbearing age.

PubMed

Crawford, Pamela M

2009-01-01

Epilepsy affects the menstrual cycle, aspects of contraception, fertility, pregnancy and bone health in women. It is common for seizure frequency to vary throughout the menstrual cycle. In ovulatory cycles, two peaks can be seen around the time of ovulation and in the few days before menstruation. In anovulatory cycles, there is an increase in seizures during the second half of the menstrual cycle. There is also an increase in polycystic ovaries and hyperandrogenism associated with valproate therapy. There are no contraindications to the use of non-hormonal methods of contraception in women with epilepsy. Non-enzyme-inducing antiepileptic drugs (AEDs) [valproate, benzodiazepines, ethosuximide, levetiracetam, tiagabine and zonisamide] do not show any interactions with the combined oral contraceptive (OC). There are interactions between the combined OC and hepatic microsomal-inducing AEDs (phenytoin, barbiturates, carbamazepine, topiramate [dosages>200 mg/day], oxcarbazepine) and lamotrigine. Pre-conception counselling should be available to all women with epilepsy who are considering pregnancy. Women with epilepsy should be informed about issues relating to the future pregnancy, including methods and consequences of prenatal screening, fertility, genetics of their seizure disorder, teratogenicity of AEDs, folic acid and vitamin K supplements, labour, breast feeding and care of a child. During pregnancy, the lowest effective dose of the most appropriate AED should be used, aiming for monotherapy where possible. Recent pregnancy databases have suggested that valproate is significantly more teratogenic than carbamazepine, and the combination of valproate and lamotrigine is particularly teratogenic. Most pregnancies in women with epilepsy are without complications, and the majority of infants are delivered healthy with no increased risk of obstetric complications in women. There is no medical reason why a woman with epilepsy cannot breastfeed her child. The AED concentration profiled in breast milk follows the plasma concentration curve. The total amount of drug transferred to infants via breast milk is usually much smaller than the amount transferred via the placenta during pregnancy. However, as drug elimination mechanisms are not fully developed in early infancy, repeated administration of a drug such as lamotrigine via breast milk may lead to accumulation in the infant. Studies have suggested that women with epilepsy are at increased risk of fractures, osteoporosis and osteomalacia. No studies have been undertaken looking at preventative therapies for these co-morbidities.

Control of synthesis and release of radioactive acetylcholine in brain slices from the rat. Effects of neurotropic drugs

PubMed Central

Grewaal, D. S.; Quastel, J. H.

1973-01-01

1. Studies of the synthesis and release of radioactive acetylcholine in rat brain-cortex slices incubated in Locke–bicarbonate–[U-14C]glucose media, containing paraoxon as cholinesterase inhibitor, revealed the following phenomena: (a) dependence of K+-or protoveratrine-stimulated acetylcholine synthesis and release on the presence of Na+ and Ca2+ in the incubation medium, (b) enhanced release of radioactive acetylcholine by substances that promote depolarization at the nerve cell membrane (e.g. high K+, ouabain, protoveratrine, sodium l-glutamate, high concentration of acetylcholine), (c) failure of acetylcholine synthesis to keep pace with acetylcholine release under certain conditions (e.g. the presence of ouabain or lack of Na+). 2. Stimulation by K+ of radioactive acetylcholine synthesis was directly proportional to the external concentration of Na+, but some synthesis and release of radioactive acetylcholine occurred in the absence of Na+ as well as in the absence of Ca2+. 3. The Na+ dependence of K+-stimulated acetylcholine synthesis was partly due to suppression of choline transport, as addition of small concentrations of choline partly neutralized the effect of Na+ lack, and partly due to the suppression of the activity of the Na+ pump. 4. Protoveratrine caused a greatly increased release of radioactive acetylcholine without stimulating total radioactive acetylcholine synthesis. Protoveratrine was ineffective in the absence of Ca2+ from the incubation medium. It completely blocked K+ stimulation of acetylcholine synthesis and release. 5. Tetrodotoxin abolished the effects of protoveratrine on acetylcholine release. It had blocking effects (partial or complete) on the action of high K+, sodium l-glutamate and lack of Ca2+ on acetylcholine synthesis and release. 6. Unlabelled exogenous acetylcholine did not diminish the content of labelled tissue acetylcholine, derived from labelled glucose, suggesting that no exchange with vesicular acetylcholine took place. In the presence of 4mm-KCl it caused some increase in the release of labelled acetylcholine. 7. The barbiturates (Amytal, pentothal), whilst having no significant effects on labelled acetylcholine synthesis in unstimulated brain except at high concentration (1mm), diminished or abolished (at 0.25 or 0.5mm) the enhanced release of acetylcholine, due to high K+ or lack of Ca2+. The fall in tissue content of acetylcholine, due to lack of Ca2+, was diminished or abolished by pentothal (0.25 or 0.5mm) or Amytal (0.25mm). PMID:4722896

Responses of spinothalamic lamina I neurons to repeated brief contact heat stimulation in the cat.

PubMed

Craig, A D; Andrew, D

2002-04-01

It was recently shown that repeated heat stimulation, using brief contacts (<1 s) with a preheated thermode at sufficiently short interstimulus intervals (ISIs <5 s) and high temperatures (> or =51 degrees C), will elicit in humans a sensation of rapidly augmenting "second" (burning) pain with only a weak "first" (sharp) pain sensation. Most strikingly, at short intertrial intervals (ITIs >5 s) such summation will reset, or begin again at baseline. In the present experiments, the responses of nociceptive lamina I spinothalamic (STT) neurons in the lumbosacral dorsal horn of barbiturate-anesthetized cats were examined using this repeated brief contact heat paradigm. The neurons were classified as nociceptive-specific (NS, n = 8) or polymodal nociceptive (HPC, n = 8) based on their responses to quantitative thermal stimuli; all had receptive fields on the glabrous ventral hindpaw. A pneumatic piston was used to apply a thermode preheated to 34, 46, 49, 53, or 58 degrees C with a contact dwell time of approximately 0.7 s to the ventral hindpaw repeatedly (15 times) at ISIs of 2, 3, and 5 s, with 3-5 min between trials. The mean responses of the 16 nociceptive lamina I STT cells showed rapid temporal summation that was directly dependent on temperature and inversely dependent on ISI, with the greatest increases occurring between the 3rd and 10th contacts. The temporal profiles of this family of curves correspond with the psychophysical data on human sensation. Further analysis showed that this summation was due to the HPC cells, which all showed strong summation; in contrast, the NS cells showed little, if any. The HPC responses to the repeated heat stimuli lagged each contact by approximately 1 s, consistent with the strong, monosynaptic C-fiber input that is characteristic of HPC cells and also with the dependence of second pain on C-fiber nociceptors. HPC cells also displayed the reset phenomenon at short ITIs, again in correspondence with the psychophysical data. The summation and the reset displayed by HPC cells were not related to skin temperature. Thus the results presented in this study, together with those in the preceding article, demonstrate a double dissociation indicating that NS and HPC lamina I STT cells can subserve the qualitatively distinct sensations of first (sharp) and second (burning) pain, respectively. These findings support the concept that the lamina I STT projection comprises several discrete sensory channels that are integrated in the forebrain to generate distinct sensations.

Binaural interaction in low-frequency neurons in inferior colliculus of the cat. I. Effects of long interaural delays, intensity, and repetition rate on interaural delay function.

PubMed

Kuwada, S; Yin, T C

1983-10-01

Detailed, quantitative studies were made of the interaural phase sensitivity of 197 neurons with low best frequency in the inferior colliculus (IC) of the barbiturate-anesthetized cat. We analyzed the responses of single cells to interaural delays in which tone bursts were delivered to the two ears via sealed earphones and the onset of the tone to one ear with respect to the other was varied. For most (80%) cells the discharge rate is a cyclic function of interaural delay at a period corresponding to that of the stimulating frequency. The cyclic nature of the interaural delay curve indicates that these cells are sensitive to the interaural phase difference. These cells are distributed throughout the low-frequency zone of the IC, but they are less numerous in the medial and caudal zones. Cells with a wide variety of response patterns will exhibit interaural phase sensitivities at stimulating frequencies up to 3,100 Hz, although above 2,500 Hz the number of such cells decrease markedly. Using dichotic stimuli we could study the cell's sensitivity to the onset delay and interaural phase independently. The large majority of IC cells respond only to changes in interaural phase, with no sensitivity to the onset delay. However, a small number (7%) of cells exhibit a sensitivity to the onset delay as well as to the interaural phase disparity, and most of these cells show an onset response. The effects of changing the stimulus intensity equally to both ears or of changing the interaural intensity difference on the mean interaural phase were studied. While some neurons are not affected by level changes, others exhibit systematic phase shifts for both average and interaural intensity variations, and there is a continuous distribution of sensitivities between these extremes. A few cells also showed systematic changes in the shape of the interaural delay curves as a function of interaural intensity difference, especially at very long delays. These shifts can be interpreted as a form of time-intensity trading. A few cells demonstrated orderly changes in the interaural delay curve as the repetition rate of the stimulus was varied. Some of these changes are consonant with an inhibitory effect that occurs at stimulus offset. The responses of the neurons show a strong bias for stimuli that would originate from he contralateral sound field; 77% of the responses display mean interaural phase angles that are less than 0.5 of a cycle, which are delays to the ipsilateral tone.(ABSTRACT TRUNCATED AT 400 WORDS)

Anesthesia and critical-care delivery in weightlessness: A challenge for research in parabolic flight analogue space surgery studies

NASA Astrophysics Data System (ADS)

Ball, Chad G.; Keaney, Marilyn A.; Chun, Rosaleen; Groleau, Michelle; Tyssen, Michelle; Keyte, Jennifer; Broderick, Timothy J.; Kirkpatrick, Andrew W.

2010-03-01

BackgroundMultiple nations are actively pursuing manned exploration of space beyond low-earth orbit. The responsibility to improve surgical care for spaceflight is substantial. Although the use of parabolic flight as a terrestrial analogue to study surgery in weightlessness (0 g) is well described, minimal data is available to guide the appropriate delivery of anesthesia. After studying anesthetized pigs in a 0 g parabolic flight environment, our group developed a comprehensive protocol describing prolonged anesthesia in a parabolic flight analogue space surgery study (PFASSS). Novel challenges included a physically remote vivarium, prolonged (>10 h) anesthetic requirements, and the provision of veterinary operating room/intensive care unit (ICU) equivalency on-board an aircraft with physical dimensions of <1.5 m 2 (Falcon 20). Identification of an effective anesthetic regime is particularly important because inhalant anesthesia cannot be used in-flight. MethodsAfter ethical approval, multiple ground laboratory sessions were conducted with combinations of anesthetic, pre-medication, and induction protocols on Yorkshire-cross specific pathogen-free (SPF) pigs. Several constant rate infusion (CRI) intravenous anesthetic combinations were tested. In each regimen, opioids were administered to ensure analgesia. Ventilation was supported mechanically with blended gradients of oxygen. The best performing terrestrial 1 g regime was flight tested in parabolic flight for its effectiveness in sustaining optimal and prolonged anesthesia, analgesia, and maintaining hemodynamic stability. Each flight day, a fully anesthetized, ventilated, and surgically instrumented pig was transported to the Flight Research Laboratory (FRL) in a temperature-controlled animal ambulance. A modular on-board surgical/ICU suite with appropriate anesthesia/ICU and surgical support capabilities was employed. ResultsThe mean duration of anesthesia (per flight day) was 10.28 h over four consecutive days. A barbiturate and ketamine-based CRI anesthetic regimen supplemented with narcotic analgesia by bolus administration offered the greatest prolonged hemodynamic stability through an IV route (within multiple transport vehicles and differing gravitational environments). Standardization and pre-packaging of anesthesia, emergency pharmaceuticals, and consumables were found to facilitate the interchange of the veterinary anesthesia team members between flights. This operational process was extremely challenging. ConclusionsWith careful organization of caregivers, equipment and protocols, providing anesthesia and life support in weightlessness is theoretically possible. Unfortunately, human resource costs are extensive and likely overwhelming. Comprehensive algorithms for extended spaceflight must recognize these costs prior to making assumptions or attempting to provide critical care in space.

Drugs and falls in community-dwelling older people: a national veterans study.

PubMed

French, Dustin D; Campbell, Robert; Spehar, Andrea; Cunningham, Francesca; Bulat, Tatjana; Luther, Stephen L

2006-04-01

The aim of this study was to identify which specific medications within recognized major problematic drug categories that increase risk of falling were prescribed to veterans before their out-patient treatment for a fall. This was a retrospective, cross-sectional national secondary outpatient data analysis with an age- and sex-matched comparison group. The setting was the national Veterans Health Administration (VHA) ambulatory health care system in fiscal year (FY) 2004. The study population was VHA patients aged>or=65 years who had fall-related outpatient clinical health care encounters in FY 2004 (as indicated by diagnostic codes) and who received >or=1 outpatient medication during the study period. The age- and sex-matched comparison group consisted of an equal number of patients with nonspecific chest pain. The percentage of patients in each group receiving medications (at the time of the outpatient encounter) that affect the cardiovascular system (CVS), central nervous system (CNS), or musculoskeletal system (MSS) was compared with Bonferrom-adjusted P values. The study sample consisted of 20,551 patients; the comparison group included the same number of patients. More patients with fall-coded encounters used CNS drugs than those with nonspecific chest pain (42.05% vs 29.29%). Also, within the CNS category, more patients with fall-coded encounters used antiparkinsonian medications (3.67% vs 1.32%), Alzheimer's disease medications (ie, cholinesterase inhibitors [5.40% vs 2.35%]), anticonvulsants/barbiturates (8.95% vs 5.18%), antidepressants (22.50% vs 14.16%), antipsychotics (4.68% vs 2.01%), opioid analgesics and narcotics (11.21% vs 9.09%), and benzodiazepines (7.60% vs 5.96%) (all, P<0.002). More patients with nonspecific chest pain received CVS drugs compared with the fall-coded group (69.13% vs 63.07%; P<0.002). Within the CVS category, more patients in the nonspecific chest pain group received angiotensin-II receptor antagonists, angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, vasodilators, diuretics, and antiarrhythmics (all, P<0.002). No differences were noted between groups in the MSS category, except for NSAIDs, which more patients in the nonspecific chest pain group used than in the fall-coded group (6.44% vs 5.63%; P<0.002). In this study, subjects with a health care encounter for a fall (as indicated by diagnostic code) were prescribed significantly more CNS-category medications than subjects in the age- and sex-matched comparison group.

Inputs from regularly and irregularly discharging vestibular nerve afferents to secondary neurons in squirrel monkey vestibular nuclei. III. Correlation with vestibulospinal and vestibuloocular output pathways

NASA Technical Reports Server (NTRS)

Boyle, R.; Goldberg, J. M.; Highstein, S. M.

1992-01-01

1. A previous study measured the relative contributions made by regularly and irregularly discharging afferents to the monosynaptic vestibular nerve (Vi) input of individual secondary neurons located in and around the superior vestibular nucleus of barbiturate-anesthetized squirrel monkeys. Here, the analysis is extended to more caudal regions of the vestibular nuclei, which are a major source of both vestibuloocular and vestibulospinal pathways. As in the previous study, antidromic stimulation techniques are used to classify secondary neurons as oculomotor or spinal projecting. In addition, spinal-projecting neurons are distinguished by their descending pathways, their termination levels in the spinal cord, and their collateral projections to the IIIrd nucleus. 2. Monosynaptic excitatory postsynaptic potentials (EPSPs) were recorded intracellularly from secondary neurons as shocks of increasing strength were applied to Vi. Shocks were normalized in terms of the threshold (T) required to evoke field potentials in the vestibular nuclei. As shown previously, the relative contribution of irregular afferents to the total monosynaptic Vi input of each secondary neuron can be expressed as a %I index, the ratio (x100) of the relative sizes of the EPSPs evoked by shocks of 4 x T and 16 x T. 3. Antidromic stimulation was used to type secondary neurons as 1) medial vestibulospinal tract (MVST) cells projecting to spinal segments C1 or C6; 2) lateral vestibulospinal tract (LVST) cells projecting to C1, C6; or L1; 3) vestibulooculo-collic (VOC) cells projecting both to the IIIrd nucleus and by way of the MVST to C1 or C6; and 4) vestibuloocular (VOR) neurons projecting to the IIIrd nucleus but not to the spinal cord. Most of the neurons were located in the lateral vestibular nucleus (LV), including its dorsal (dLV) and ventral (vLV) divisions, and adjacent parts of the medial (MV) and descending nuclei (DV). Cells receiving quite different proportions of their direct inputs from regular and irregular afferents were intermingled in all regions explored. 4. LVST neurons are restricted to LV and DV and show a somatotopic organization. Those destined for the cervical and thoracic cord come from vLV, from a transition zone between vLV and DV, and to a lesser extent from dLV. Lumbar-projecting neurons are located more dorsally in dLV and more caudally in DV. MVST neurons reside in MV and in the vLV-DV transition zone.(ABSTRACT TRUNCATED AT 400 WORDS).

Synthesis, Characterization, Anticancer and Antibacterial Activity of Some Novel Pyrano[2,3-d]pyrimidinone Carbonitrile Derivatives.

PubMed

Aremu, Oluwole S; Gopaul, Kaalin; Kadam, Pramod; Singh, Moganavelli; Mocktar, Chunderika; Singh, Parvesh; Koorbanally, Neil A

2017-01-01

Pyrimidines have widespread activity and have shown potent antibacterial and anticancer activity. To synthesise a range of pyrimidine diones and test them for their antibacterial and anticancer activity. The pyranopyrimidin-2,4-dione derivatives (1-7) were synthesized in a one-pot reaction by reacting malononitrile and barbituric acid with several aromatic aldehydes in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) in aqueous medium. The compounds were tested for their antibacterial activity using the broth microdilution method and for their cytotoxicity against three cell lines, HeLa (cervical cancer), Caco-2 (human colon adenocarcinoma) and HEK 293 (human embryonic kidney cells) using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) assay. Compounds 1-7 were successfully synthesized in yields of >90%. The 3,4-dihydroxyaryl (3) and the 2,5- dimethoxyaryl (7) derivatives were novel. Compounds 3, 5 (4'-methoxy derivative) and 6 (2',3'-dimethoxy derivative) showed antibacterial activity comparable to or better than the standard ampicillin. All the test compounds 1-7 showed good anticancer activity. The IC50 values ranged from 3.46 to 37.13 μM (HeLa); 136.78 to 297.05 μM (Caco-2) and 137.84 to 333.81 μM (HEK293). The best activity was seen in the HeLa cell line when compared to the standard 5FU (5-Fluorouracil IC50 of 41.85 μM), with 1, 2, 5 and 7 having IC50 values of 10.64, 3.46, 4.36 and 4.44 μM respectively. Additionally, two representative compounds (1 and 7) found to be potent against the two cell lines (HeLa and HEK 293) were docked into the binding site of human kinesin Eg5 with the aim of predicting their binding propensities and to establish their mechanism of action. The Lipinski parameters of these compounds were also computed and analysed for their drug-likeness. Compound 6 is an excellent candidate for a broad spectrum antibiotic with MBCs of 45.6-365.2 μM, while both 3 and 6 have the potential to be developed into an antibiotic against MRSA, with MBCs of 183-199 μM. Since all synthesized compounds showed IC50 values of 10 μM or less especially against the HeLa cells, they can be considered good lead compounds for anticancer agents. Additionally, the docking simulations suggested a good binding affinity of the compounds with Eg5 and indicated their anti-cancer action, at least partially, through its inhibition. The predicted Lipinski descriptors also indicated the potential of these compounds as an orally active drug. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Repeated isoflurane exposure and neuroapoptosis in the midgestation fetal sheep brain.

PubMed

Olutoye, Olutoyin A; Sheikh, Fariha; Zamora, Irving J; Yu, Ling; Akinkuotu, Adesola C; Adesina, Adekunle M; Olutoye, Oluyinka O

2016-04-01

Advances in surgery and technology have resulted in increased in-utero procedures. However, the effect of anesthesia on the fetal brain is not fully known. The inhalational anesthetic agent, isoflurane, other gamma amino butyric acid agonists (benzodiazepines, barbiturates, propofol, other inhalation anesthetics), and N-methyl D aspartate antagonists, eg, ketamine, have been shown to induce neuroapoptosis. The ovine model has been used extensively to study maternal-fetal physiologic interactions and to investigate different surgical interventions on the fetus. The purpose of this study was to determine effects of different doses and duration of isoflurane on neuroapoptosis in midgestation fetal sheep. We hypothesized that repeated anesthetic exposure and high concentrations of isoflurane would result in increased neuroapoptosis. Time-dated, pregnant sheep at 70 days gestation (term 145 days) received either isoflurane 2% × 1 hour, 4% × 3 hours, or 2% × 1 hour every other day for 3 exposures (repeated exposure group). Euthanasia occurred following anesthetic exposure and fetal brains were processed. Neuroapoptosis was detected by immunohistochemistry using anticaspase-3 antibodies. Fetuses unexposed to anesthesia served as controls. Another midgestation group with repeated 2% isoflurane exposure was examined at day 130 (long-term group) and neuronal cell density compared to age-matched controls. Representative sections of the brain were analyzed using Aperio Digital imaging (Leica Microsystems Inc, Buffalo Grove, IL). Data, reported by number of neurons per cubic millimeter of brain tissue are presented as means and SEM. Data were analyzed using the Mann-Whitney U and Kruskal-Wallis tests as appropriate. A total of 34 fetuses were studied. There was no significant difference in neuroapoptosis observed in fetuses exposed to 2% isoflurane for 1 hour or 4% isoflurane for 3 hours. Increased neuroapoptosis was observed in the frontal cortex following repeated 2% isoflurane exposure compared to controls (1.57 ± 0.22 × 10(6)/mm(3) vs 1.01 ± 0.44 × 10(6)/mm(3), P = .02). Fetuses at 70 days gestation with repeated exposure demonstrated decreased frontal cortex neurons at day 130 when compared to age-matched controls (2.42 ± 0.3 × 10(5)/mm(3) vs 7.32 ± 0.4 × 10(5)/mm(3), P = .02). No significant difference in neuroapoptosis was observed between the repeated exposure group and controls in the hippocampus, cerebellum, or basal ganglia. Repeated isoflurane exposure in midgestation sheep resulted in increased frontal cortex neuroapoptosis. This persisted into late gestation as decreased neuronal cell density. While animal studies should be extrapolated to human beings with caution, our findings suggest that the number of anesthetic/sedative exposures should be considered when contemplating the risks and benefits of fetal intervention as certain fetal therapies may need to be repeated. Copyright © 2016 Elsevier Inc. All rights reserved.

Synthesis and characterization of lactose-based homopolymers, hydrophilic/hydrophobic copolymers, and hydrogels

NASA Astrophysics Data System (ADS)

Zhou, Wenjing

The focus of this dissertation is the synthesis and characterization of lactose-based functional polymers. Currently 60% of lactose, a by-product from the cheese industry, is being utilized and the remaining fraction represents a serious disposal problem because of the high biological oxygen demand. Therefore, further development of utilization of lactose is an important issue both for industry and environment. Herein, the syntheses of lactose-based polymers such glycopolymers, hydrophilic/hydrophobic copolymers, and hydrogels are reported. A brief review of lactose formation, physical properties, and production is presented in Chapter 1. Syntheses and applications of lactose derivatives such as lactitol, lactulose, lactaime, lactosylurea, lactosylamine, lactone, and barbituric derivative are documented. Previous work in lactose-based polymers include: (1) hydrogels from cross linking of LPEP, borate complexation of lactose-containing polymer, and copolymerization of lactose monomer with crosslinkers; (2) lactose-based polyurethane rigid foams and adhesives; and (3) lactose-containing glycopolymers are also included. Chapter 2 documents the synthesis of acrylamidolactamine and the free radical copolymerization of this monomer with N-isopropylacrylamide in the presence of BisA to make hydrogels. Swelling behavior of the hydrogels at different temperatures as well as DSC study of these hydrogels are also carried out to characterize the swelling transition and the organization of water in the copolymer hydrogels. In Chapter 3, novel monomer syntheses of N-lactosyl- N'-(4-vinylbenzyl)urea or N '-lactosyl-N,N-methyl(4-vinylbenzyl)urea are described. Polymerization of these new urea monomers using a redox initiator gave water-soluble homopolymers with molecular weights in the range of 1.9 x 103 to 5.3 x 106. Synthesis and polymerization of lactose-O-(p-vinylbenzyl)hydroxime are documented in Chapter 4. The resulting polymers had high molecular weight (106) and narrow polydispersity (Mw/Mn: 1.20--1.35). The Mark-Houwink equation was obtained as [eta] = 2.15 x 10-4Mv0.73. Hydrogels produced in the presence of N,N'-methylenebisacrylamide swelled as much as 21-fold in deionized water. Copolymerization of styrene with lactose-O-(vinylbenzyl)oxime in dimethylsulfoxide-toluene (1:1, v/v) using 2,2'-azobisisobutyronitrile as the initiator are discussed in Chapter 5. The resulting hydrophilic/hydrophobic copolymers were characterized by viscometry, TGA, DSC, GPC, and solubility tests in solvents of varied polarities. Chapter 6 documents the preparation of polystyrene beads with different length of oligo(ethylene glycol) crosslinkers. Swelling in different solvents, solvent accessibility, and reagent diffusion of these beads with different crosslinking density were studied and the results indicated that the PEG-crosslinked polymers showed slightly better solvent accessibility in polar solvents than the analogous DVB-crosslinked networks.

Subsurface imaging of water electrical conductivity, hydraulic permeability and lithology at contaminated sites by induced polarization

NASA Astrophysics Data System (ADS)

Maurya, P. K.; Balbarini, N.; Møller, I.; Rønde, V.; Christiansen, A. V.; Bjerg, P. L.; Auken, E.; Fiandaca, G.

2018-05-01

At contaminated sites, knowledge about geology and hydraulic properties of the subsurface and extent of the contamination is needed for assessing the risk and for designing potential site remediation. In this study, we have developed a new approach for characterizing contaminated sites through time-domain spectral induced polarization. The new approach is based on: (1) spectral inversion of the induced polarization data through a reparametrization of the Cole-Cole model, which disentangles the electrolytic bulk conductivity from the surface conductivity for delineating the contamination plume; (2) estimation of hydraulic permeability directly from the inverted parameters using a laboratory-derived empirical equation without any calibration; (3) the use of the geophysical imaging results for supporting the geological modelling and planning of drilling campaigns. The new approach was tested on a data set from the Grindsted stream (Denmark), where contaminated groundwater from a factory site discharges to the stream. Two overlapping areas were covered with seven parallel 2-D profiles each, one large area of 410 m × 90 m (5 m electrode spacing) and one detailed area of 126 m × 42 m (2 m electrode spacing). The geophysical results were complemented and validated by an extensive set of hydrologic and geologic information, including 94 estimates of hydraulic permeability obtained from slug tests and grain size analyses, 89 measurements of water electrical conductivity in groundwater, and four geological logs. On average the IP-derived and measured permeability values agreed within one order of magnitude, except for those close to boundaries between lithological layers (e.g. between sand and clay), where mismatches occurred due to the lack of vertical resolution in the geophysical imaging. An average formation factor was estimated from the correlation between the imaged bulk conductivity values and the water conductivity values measured in groundwater, in order to convert the imaging results from bulk conductivity to water conductivity. The geophysical models were actively used for supporting the geological modelling and the imaging of hydraulic permeability and water conductivity allowed for a better discrimination of the clay/lignite lithology from the pore water conductivity. Furthermore, high water electrical conductivity values were found in a deep confined aquifer, which is separated by a low-permeability clay layer from a shallow aquifer. No contamination was expected in this part of the confined aquifer, and confirmation wells were drilled in the zone of increased water electrical conductivity derived from the geophysical results. Water samples from the new wells showed elevated concentrations of inorganic compounds responsible for the increased water electrical conductivity in the confined aquifer and high concentrations of xenobiotic organic contaminants such as chlorinated ethenes, sulfonamides and barbiturates.

Screening for drugs of abuse (II): Cannabinoids, lysergic acid diethylamide, buprenorphine, methadone, barbiturates, benzodiazepines and other drugs.

PubMed

Simpson, D; Braithwaite, R A; Jarvie, D R; Stewart, M J; Walker, S; Watson, I W; Widdop, B

1997-09-01

Requirements for the provision of an efficient and reliable service for drugs of abuse screening in urine have been summarized in Part I of this review. The requirements included rapid turn-around times, good communications between requesting clinicians and the laboratory, and participation in quality assessment schemes. In addition, the need for checking/confirmation of positive results obtained for preliminary screening methods was stressed. This aspect of the service has assumed even greater importance with widespread use of dip-stick technology and the increasing number of reasons for which drug screening is performed. Many of these additional uses of drug screening have possible serious legal implications, for example, screening school pupils, professional footballers, parents involved in child custody cases, persons applying for renewal of a driving licence after disqualification for a drug-related offence, doctors seeking re-registration after removal for drug abuse, and checking for compliance with terms of probation orders; as well as pre-employment screening and work-place testing. In many cases these requests will be received from a general practitioner or drug clinic with no indication of the reason for which testing has been requested. This also raises the serious problems of a chain of custody, provision of two samples, stability of samples, and secure and lengthy storage of samples in the laboratory-samples may be requested by legal authorities several months after the initial testing. The need for confirmation of positive results is now widely accepted but it may be equally important to confirm unexpected negative results. Failure to detect the presence of maintenance drugs may lead to the patient being discharged from a drug treatment clinic and, if attendance at the clinic is one of the terms of continued employment, to dismissal. It seems likely that increasing abuse of drugs and the efforts of regulatory authorities to control this, will lead to the manufacture of more designer drugs. Production of substituted phenethylamines was facilitated by the drug makers' cook book, 'PIHKAL' (Phenethylamines I Have Known And Loved) by Dr Alexander Shulgin and Ann Shulgin, and production of substituted tryptamines is promised in their next book, TIHKAL. Looking to the future, laboratories will need to ensure that they can detect and quantitate an ever-increasing number of drugs and related substances. The question of confidence in results of drugs of abuse testing raised in 1993 by Watson has assumed even greater importance as a result of attention focused on the OJ Simpson trial in Los Angeles. Toxicological investigations are likely to be challenged more frequently in the future. Even if analyses have been performed by GC-MS, there is a need to establish the level of match between the spectrum of the unknown substance and a library spectrum which is considered acceptable for legal purposes. It will also be essential to ensure that computer libraries contain spectra for all substances likely to be encountered in drugs of abuse screening.

[History of anaesthesia in Belgium].

PubMed

De Rood, M

2012-01-01

Man has for a long time searched means of fighting pain, by administration of plant extracts such as poppy seed, jimson weed, henbane, mandrake and alcohol. These substances were given in the form of cataplasms, potions or clysters. Somniferous sponges, applied on the face, were known since Antiquity and have been in use in some countries up to the 13th century. Surgery and pain were inseparable till mid 19th century. Indications for surgery were few, even though some patients could benefit from these sedative drugs. The anesthetic properties of ether and nitrous oxide (laughing gas), known since the 18th century, were only recognized in the 19th century. William Morton, a dentist, was the first to successfully provide general anesthesia with ether in 1846 in Boston. News spread to England shortly afterwards. On the European continent, the first use of ether was due to 2 Belgian surgeons. Next came chloroform as novel anesthetic. They were administered via either a gauze or a mask by the general practitioner, a medical student or a nurse. Unlike England, the use of these drugs for obstetrical anesthesia (called anesthesia "a la reine", alluding to Queen Victoria who benefited from chloroform during childbirth) was never very popular in Belgium. Since the years 1880, the use of cocaine, then of novocaine allowed to perform local anesthesia, then local nerve blocks and spinal anesthesia, installed by the surgeon prior to operating. Since then, surgery experienced rapid progress, Belgium included. During the 1914-1918 first World War, these advances saved many human lives. When general anesthesia was necessary, it was cared for by another physician or a nurse. The interwar period did not see significant advances in anesthesia, except in intravenous anesthesia with barbiturates, appeared in the late 1930's. Intra- and postoperative complications were frequent. Apart from sulfonamides, antibiotics were non-existent. During the war 1940-45, there was no progress in anesthesia and surgery in Belgium. After the Liberation, Belgian doctors specifically trained in anesthesia by the British army, or elsewhere in non-occupied countries, will form the core of a new specialty, "anesthesiology-reanimation", who will fight to be recognized as a specialty in itself in Belgium. It will beneficiate from--and largely contribute to--the technical and scientific advances in the medical field. Initially based on clinical symptoms, monitoring and care of operated patients, during and after operation, will beneficiate from modern monitoring and other technical apparatus, which will allow the most audacious surgical technical performances in all domains. Postoperative and intensive care units will appear in the years 1960's. Nowadays, anesthesiologists work in all hospital settings, and also organize One-day clinics and Pain clinics. In Belgium, the quality of the clinical and scientific training of anesthesiologists is widely acknowledged, as well as clinical and experimental research.

Best practice guidelines for the management of women with epilepsy.

PubMed

Crawford, Pamela

2005-01-01

Being a woman with epilepsy is not the same as being a man with epilepsy. Epilepsy affects sexual development, menstrual cycle, aspects of contraception, fertility, and reproduction. MENSTRUAL CYCLE, EPILEPSY, AND FERTILITY: The diagnosis of epilepsy and the use of antiepileptic drugs (AEDs) present women of childbearing age with many problems; both the disease and its treatment can alter the menstrual cycle and fertility. CONTRACEPTION IN EPILEPSY: There are no contraindications to the use of nonhormonal methods of contraception in women with epilepsy (see Table 3). Nonenzyme-inducing AEDs (valproate sodium, benzodiazepines, ethosuximide, and levetiracetam) do not show any interactions with the combined oral contraceptive pill. There are interactions between the COCP and hepatic microsomal-inducing AEDs (phenytoin, barbiturates, carbamazepine, topiramate [doses above 200 mg/day], and oxcarbazepine) and also lamotrigine. SEXUALITY: The majority of women with epilepsy appear to have normal sex lives, although in some women with epilepsy, both the desire and arousal phases may be inhibited. PRECONCEPTION COUNSELING: Preconception counseling should be available to all women with epilepsy who are considering pregnancy. Women with epilepsy should be aware of a number of issues relating to future pregnancy, including methods and consequences of prenatal screening, genetics of their seizure disorder, teratogenicity of AEDs, folic acid and vitamin K supplements, labor, breast feeding, and childcare. PREGNANCY: The lowest effective dose of the most appropriate AED should be used, aiming for monotherapy where possible. Recent pregnancy databases have suggested that valproate is significantly more teratogenic than carbamazepine, and the combination of valproate sodium and lamotrigine is particularly teratogenic. Most pregnancies are uneventful in women with epilepsy, and most babies are delivered healthy with no increased risk of obstetric complications in women. BREAST FEEDING: All women with epilepsy should be encouraged to breastfeed their babies. The AED concentration profiled in breast milk follows the plasma concentration curve. The total amount of drug transferred to infants via breast milk is usually much smaller than the amount transferred via the placenta during pregnancy. However, as drug elimination mechanisms are not fully developed in early infancy, repeated administration of a drug such as lamotrigine via breast milk may lead to accumulation in the infant. THE CARE OF CHILDREN OF MOTHERS WITH EPILEPSY: Although there is much anxiety about the possible risks to a child from the mother's epilepsy, there is little published evidence. The risk of the child being harmed depends on the type of seizure and its severity and frequency, and this risk is probably small if time is taken to train mothers and caregivers in safety precautions. MENOPAUSE: During menopause, about 40% of women report worsening of their seizure disorder, 27% improve, and a third had no change. Hormone replacement therapy is significantly associated with an increase in seizure frequency during menopause, and this is more likely in women with a history of catamenial epilepsy. BONE HEALTH: Women with epilepsy are at increased risk of fractures, osteoporosis, and osteomalacia.

Historical development of modern anesthesia.

PubMed

Robinson, Daniel H; Toledo, Alexander H

2012-06-01

Of all milestones and achievements in medicine, conquering pain must be one of the very few that has potentially affected every human being in the world. It was in 1846 that one of mankind's greatest fears, the pain of surgery, was eliminated. This historical review article describes how the various elements of anesthesiology (gasses, laryngoscopes, endotracheal tubes, intravenous medications, masks, and delivery systems) were discovered and how some brilliant entrepreneurs and physicians of the past two centuries have delivered them to humanity. One name stands out amongst all others when the founder of modern anesthesia is discussed, William T.G. Morton (1819-1868). A young Boston Dentist, Dr. Morton had been in the search for a better agent than what had been used by many dentists: nitrous oxide. With Dr. Morton's tenacity driven by enthusiasm and discovery, he and renowned surgeon at Massachusetts General Hospital, John Collins Warren (1778-1856) made history on October 16, 1846 with the first successful surgical procedure performed with anesthesia. Dr. Morton had single-handedly proven to the world that ether is a gas that when inhaled in the proper dose, provided safe and effective anesthesia. One of the first accounts of an endotracheal tube being used for an airway comes from the pediatrician Joseph O'Dwyer (1841-1898). He used the metal "O'dwyer" tubes in diphtheria cases and passed them into the trachea blindly. Adding a cuff to the tube is credited to Arthur Guedel (1883-1956) and Ralph M. Waters (1883-1979) in 1932. This addition suddenly gave the practitioner the ability to provide positive pressure ventilation. The anesthesiologist Chevalier Jackson (1865-1958) promoted his handheld laryngoscope for the insertion of endotracheal tubes and its popularity quickly caught hold. Sir Robert Reynolds Macintosh's (1897-1989) breakthrough technique of direct laryngoscopy came after being appointed Nuffield professor of anesthetics at the University of Oxford in 1937. He was the first to describe the routinely placing of the tip of his newly re-designed laryngoscope in the epiglottic vallecula which is attached to the base of the tongue, thus when lifted exposed the entire larynx. Macintosh was genuinely astonished at what a great view he could achieve with his new blade and technique. The use of barbiturates as an intravenous anesthetic began in 1932. Sodium thiopental gained popularity after its use was described in detail by a Dr. John Lundy (1894-1973) of the Mayo Clinic. Other I.V. medications were tried over the past seventy years, but the newest induction drug which provided for a substantially shorter recovery period and seemed to actually suppress laryngeal reflexes has brought with it many benefits. Propofol, introduced clinically in 1977, demonstrated many positive effects even as an anti-emetic compound. Before October of 1846, surgery and pain were synonymous but not thereafter. As we entered the information age where the infrastructure of evidence based medicine and newer fields of genetics, transplantation, imaging radiology and even stem cells became quickly integrated into mainstream medicine, we can predict an excellent future on the progress to be made in anesthesia.

General unknown screening in hair by liquid chromatography-hybrid quadrupole time-of-flight mass spectrometry (LC-QTOF-MS).

PubMed

Broecker, Sebastian; Herre, Sieglinde; Pragst, Fritz

2012-05-10

The retrospective investigation of the exposure to toxic substances by general unknown screening of hair is still a difficult task because of the large number of possible poisons, the low sample amount and the difficult sample matrix. In this study the use of liquid chromatography-hybrid quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) was tested as a promising technique for this purpose. In the optimized procedure, 20mg hair were decontaminated with water and acetone and two times extracted by 18h incubation with 0.5ml of a mixture of methanol/acetonitrile/H(2)O/ammonium formate at 37°C. A mixture of deuterated standards from different drug groups was added for quantification and method control. The united extracts were evaporated to a residue of 0.5ml and 5μl were injected without clean-up for LC-QTOF-MS measurement (instrument Agilent 6530) with positive electrospray ionization and in data dependent acquisition mode. For peak identification the accurate mass data base and spectral library of the authors was used which contains accurate mass CID spectra of more than 2500 and theoretically calculated accurate mass data of more than 7500 toxicologically relevant substances. Validation at the example of 24 illegal drugs, their metabolites and benzodiazepines resulted in limits of detection of 0.003-0.015ng/mg, and limits of quantification of 0.006-0.021ng/mg with good accuracy and intra- and interday reproducibility. The matrix effect by ion suppression/enhancement was 72-107% for basic drugs and 42-75% for benzodiazepines. Yields of the hair extraction above 90% were determined for 59 drugs or metabolites. The method was applied to hair samples from 30 drug fatalities and from 60 death cases with known therapeutic drug intake at life time. Altogether 212 substances were identified with a frequency per drug of 1-40 (mean 4.2) and per case of 2-33 (mean 10.2), between them 35 illegal drug related substances and 154 therapeutic drugs. Comparison with the data known from case histories and from the analysis of blood, urine and gastric content showed only a low agreement, with many unexpected drugs detected and many reported drugs not detected in hair. Basic drugs and metabolites such as opioides, cocaine, amphetamines, several groups of antidepressants, neuroleptics, beta-blockers or the metamizole metabolite noramidopyrine were found with high frequency whereas acidic and several neutral drugs such as cannabinoids, salicylic acid, furosemide, barbiturates, phenprocoumone or cardiac glycosides could not be detected with sufficient sensitivity, mainly because of the low ion yield of positive ESI for these compounds. The advantage of a comprehensive acquisition of all substances is paid by a lower sensitivity in comparison to targeted screening LC-MS/MS procedures. In conclusion, the procedure of sample preparation and LC-QTOF-MS analysis proved to be a robust and sensitive routine method in which the qualitative screening for a wide variety of toxic substances in hair is combined with the quantitative determination of selected illegal drugs. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Evaluation of the effect of intensity of care on mortality after traumatic brain injury

PubMed Central

Thompson, Hilaire J.; Rivara, Frederick P.; Jurkovich, Gregory J.; Wang, Jin; Nathens, Avery B.; MacKenzie, Ellen J.

2008-01-01

Objectives To evaluate the effect of age on intensity of care provided to traumatically brain-injured adults and to determine the influence of intensity of care on mortality at discharge and 12 months postinjury, controlling for injury severity. Design Cohort study using the National Study on the Costs and Outcomes of Trauma (NSCOT) database. Risk ratio and Poisson regression analyses were performed using data weighted according to the population of eligible patients. Setting and Patients A total of 18 level 1 and 51 level 2 non-trauma centers located in 14 states in the United States and 1,776 adults aged 25−84 yrs with a diagnosis of traumatic brain injury. Measurements Injury severity was determined by the motor component of the Glasgow Coma Scale score, the Injury Severity Score, pupillary reactivity, and presence of midline shift. Factors evaluated as contributing to intensity of care included: admission to the intensive care unit, mechanical ventilation, placement of an intracranial pressure monitor, placement of a jugular bulb catheter, placement of a pulmonary artery catheter, critical care consultation, the number of specialty care consultations, mannitol use, treatment with barbiturate coma, decompressive craniectomy, number of nonneurosurgical procedures performed, the presence of a do-not-resuscitate order, and withdrawal of therapy. Main Results Controlling for injury-related factors, sex, and comorbidity, as age increased, the overall likelihood of receiving various interventions decreased. After controlling for injury severity, sex, and comorbidity, factors associated with higher risk of in-hospital death were: being aged 75−84 yrs (relative risk [RR] 1.32, 95% confidence interval [CI] 1.13, 1.55), pulmonary artery catheter use (RR 1.56, 95% CI 1.30, 1.86), intubation (RR 4.17, 95% CI 2.28, 7.61), the presence of a do-not-resuscitate order (RR 3.21, 95% CI 2.21, 4.65), and withdrawal of therapy (RR 2.33, 95% CI 1.69, 3.23). In contrast, a higher number of specialty care consultations (surgical consults: RR 0.63, 95% CI 0.54, 0.74; medical consults: RR 0.87, 95% CI 0.79, 0.95; and other consults: RR 0.43, 95% CI 0.26, 0.69) were associated with decreased risk of death. The results were similar for factors associated with death at 12 months, with the exception that the number of medical consultations was not significant, whereas the number of nonneurosurgical procedures performed was associated with lower risk of death (RR 0.96, 95% CI 0.92, 0.99), as was obtaining critical care consultation services (RR 0.84, 95% CI 0.71, 1.0). Conclusions There is a lower intensity of care provided to older adults with traumatic brain injury. Although the specific contributions of specialists to patient management are unknown, their consultation was associated with decreased risk of in-hospital death and death within 12 months. It is important that careproviders have an increased awareness of the potential contribution of multidisciplinary clinical decision making to patient outcomes in older traumatically brain-injured patients. PMID:18007264

EFFECT OF RADIATION ON RESPONSE TO ANESTHETIC AGENTS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zauder, H.L.; Orkin, L.R.

1963-07-01

An attempt was made to determine if prior irradiation modified the response to anesthesia or if any anesthetic or anesthetics are associated with an abnormally high or low mortality, following irradiation. Swiss mice were irradiated by a conventional radiotherapy machine utilizing 250-kv x rays with 1- mm aluiminum and 0.5 mm copper filtration. The half-value layer was 1.5 mm of copper, and with a target-skin distance of 70 cm; the dose rate in air was 52 r/ min. A dose-response curve, relating mortality at 30 days to the amount of radiation delivered gave an LD/sub 5/ of 350 r, LD/submore » 25/ of 450 r, and LD/sub 95/ of 750 r. A chamber for the anesthetization of small animals with a known, reproducible concentration of anesthetic agent was designed providing for constant circulation of the gas mixtures, explosive or nonexplosive. Utilizing this apparatus, groups of mice were andesthetized with 6% divinyl ether, 6% diethyl ether, 1.5% halothane, 1.8% trichlorethylene, and 18% cyclopropane. With the latter, oxygen was added to the chamber in sufficient quandtity to provide a concentration of 20 to 25%. Pentobarbital (Nembutal) 30 mg/kg, thiopental sodium (Pentothal) 70 mg/kg, or meperidine hydrochloride (Demerol) 25 mg/kg was injected intraperitoneally into mice with and without prior x radiation. There was no mortality associated with these dosages in the control animals. All drugs were administered to the irradiated animals on the 1st to 28th day postirradiation. In mice irradiated with an LD/sub 5/ (350 r) and anesthetized subsequently with divinyl ether, diethyl ether, or halothane, an increase in the mortality over control values was observed. This increase was greatest following divinyl ether; its administration 7 or more days following irradiation resulted in the death of 10 to 30% of the animals during the 45-min period of anesthetization. After 350 r, meperidine and pentobarbital did not increase montality, but thiopental increased markedly the number of deaths when administered on the 2nd, 4th, or 21st day postirradiation. After 450 r the mortality rate was increased markedly, but cyclopropane was associated with the least increase. As with the volatile agents, mortality following the parenterally administered agents increased as the dose of radiation increased, but no difference wss demonstrated between pentobarbital and its thio derivative. Sleeping time following both drugs was increased 3-fold over that in controls. The mortality following anesthesia in mice who received 750-r (LD/sub 95/) made it impossible to anesthetize these animals beyond the 7th day postirradiation. Again, a significant number of deaths under anesthesia occurred with divinyl ether, and sleeping time following the barbiturates was prolonged, but not beyond the 3-fold increase which was seen at 450 r. It is concluded that divinyl ether is associated with the highest overall mortality and cyclopropane with the lowest; decreasing the concentration of diethyl ether decreases the mortality. The cause of the increased mortality is unknown, since gross and microscopic examinations of autopsy material failed to reveal any differences accounting for these results. (BBB)« less

Allodynia Is Associated With Initial and Sustained Response to Acute Migraine Treatment: Results from the American Migraine Prevalence and Prevention Study.

PubMed

Lipton, Richard B; Munjal, Sagar; Buse, Dawn C; Bennett, Alix; Fanning, Kristina M; Burstein, Rami; Reed, Michael L

2017-07-01

In a population sample of persons with migraine treating with a single category of acute migraine medication, to identify rates and factors associated with acute treatment outcomes, including 2-hour pain freedom (2hPF), 24-hour pain response (24hPR), and 24-hour sustained pain response (24hSPR). Key predictors include acute treatment type (triptans and other medication categories), the influence of allodynia on response to medication, and the interaction between medication category and presence of allodynia in response to treatment among people with migraine. Cutaneous allodynia was previously associated with inadequate 2hPF, 24hPR, and 24hSPR (sustained response at 24 hours among those with adequate 2hPF) among people with migraine in the American Migraine Prevalence and Prevention (AMPP) Study. The AMPP Study obtained data from a representative US sample of persons with migraine by mailed questionnaire. The 2006 survey included 8233 people with migraine aged 18 or over who completed the Migraine Treatment Optimization Questionnaire (mTOQ). mTOQ was used to assess acute treatment outcomes including 2hPF, 24hPR, and 24hSPR. Eligible individuals used only a single category of acute prescription migraine treatments (n  =  5236, 63.6%). This sample was stratified into 5 categories of type of acute prescription headache medication used (triptans, nonsteroidal anti-inflammatory drugs, barbiturate-combinations, opioids, and opioid combinations and ergot alkaloids). Separate binary logistic regression models evaluated: (1) triptans vs other medication types; (2) presence of allodynia vs no allodynia; and (3) the interaction of medication category with allodynia. Sociodemographic variables, health insurance status, over-the-counter and preventive medication use were included as covariates. Odds ratios (OR) and 95% confidence intervals (CI) were generated for each acute treatment outcome. Among eligible participants, the mean age was 46 years, and 82.5% were women. The triptan use group had better outcomes than other medication groups for 2hPF (OR range: 2.00-2.63, all significant except ergot alkaloids) and 24hPR (OR range: 2.10-6.22, all significant). No significant medication effects were found for the 24hSPR outcome. The presence of allodynia was associated with significantly worse outcomes for both 2hPF (OR range: 1.42-1.55, all significant) and 24hPR (OR range: 1.30-1.32, all significant, except for ergot alkaloids, P  =  .051). Allodynia effects were not significant for the 24hSPR. The interaction between medication and allodynia was also not significant (OR range for 2hPF: .68-2.02; OR range for 2hPR: .35-1.34; OR range for 24hSPR: 1.21-2.72) in any of the models, suggesting allodynia is an important predictor of treatment response regardless of the medication group prescribed. The use of triptan medication was associated with significantly better 2hPF (except vs ergot alkaloids) and significantly better 24hPR outcomes compared with other acute medication categories. The presence of allodynia significantly increased the likelihood of an inadequate treatment response for both of these outcomes. Triptan use was generally associated with the best outcomes. Because allodynia was associated with inadequate outcomes for all medication groups, we suggest that allodynia is an area of unmet treatment need. © 2017 American Headache Society.

The clinical toxicology of γ-hydroxybutyrate, γ-butyrolactone and 1,4-butanediol.

PubMed

Schep, Leo J; Knudsen, Kai; Slaughter, Robin J; Vale, J Allister; Mégarbane, Bruno

2012-07-01

Gamma-hydroxybutyrate (GHB) and its precursors, gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD), are drugs of abuse which act primarily as central nervous system (CNS) depressants. In recent years, the rising recreational use of these drugs has led to an increasing burden upon health care providers. Understanding their toxicity is therefore essential for the successful management of intoxicated patients. We review the epidemiology, mechanisms of toxicity, toxicokinetics, clinical features, diagnosis, and management of poisoning due to GHB and its analogs and discuss the features and management of GHB withdrawal. OVID MEDLINE and ISI Web of Science databases were searched using the terms "GHB," "gamma-hydroxybutyrate," "gamma-hydroxybutyric acid," "4-hydroxybutanoic acid," "sodium oxybate," "gamma-butyrolactone," "GBL," "1,4-butanediol," and "1,4-BD" alone and in combination with the keywords "pharmacokinetics," "kinetics," "poisoning," "poison," "toxicity," "ingestion," "adverse effects," "overdose," and "intoxication." In addition, bibliographies of identified articles were screened for additional relevant studies including nonindexed reports. Non-peer-reviewed sources were also included: books, relevant newspaper reports, and applicable Internet resources. These searches produced 2059 nonduplicate citations of which 219 were considered relevant. There is limited information regarding statistical trends on world-wide use of GHB and its analogs. European data suggests that the use of GHB is generally low; however, there is some evidence of higher use among some sub-populations, settings, and geographical areas. In the United States of America, poison control center data have shown that enquiries regarding GHB have decreased between 2002 and 2010 suggesting a decline in use over this timeframe. GHB is an endogenous neurotransmitter synthesized from glutamate with a high affinity for GHB-receptors, present on both on pre- and postsynaptic neurons, thereby inhibiting GABA release. In overdose, GHB acts both directly as a partial GABA(b) receptor agonist and indirectly through its metabolism to form GABA. GHB is rapidly absorbed by the oral route with peak blood concentrations typically occurring within 1 hour. It has a relatively small volume of distribution and is rapidly distributed across the blood-brain barrier. GHB is metabolized primarily in the liver and is eliminated rapidly with a reported 20-60 minute half-life. The majority of a dose is eliminated completely within 4-8 hours. The related chemicals, 1,4-butanediol and gamma butyrolactone, are metabolized endogenously to GHB. CLINICAL FEATURES OF POISONING: GHB produces CNS and respiratory depression of relatively short duration. Other commonly reported features include gastrointestinal upset, bradycardia, myoclonus, and hypothermia. Fatalities have been reported. MANAGEMENT OF POISONING: Supportive care is the mainstay of management with primary emphasis on respiratory and cardiovascular support. Airway protection, intubation, and/or assisted ventilation may be indicated for severe respiratory depression. Gastrointestinal decontamination is unlikely to be beneficial. Pharmacological intervention is rarely required for bradycardia; however, atropine administration may occasionally be warranted. WITHDRAWAL SYNDROME: Abstinence after chronic use may result in a withdrawal syndrome, which may persist for days in severe cases. Features include auditory and visual hallucinations, tremors, tachycardia, hypertension, sweating, anxiety, agitation, paranoia, insomnia, disorientation, confusion, and aggression/combativeness. Benzodiazepine administration appears to be the treatment of choice, with barbiturates, baclofen, or propofol as second line management options. GHB poisoning can cause potentially life-threatening CNS and respiratory depression, requiring appropriate, symptom-directed supportive care to ensure complete recovery. Withdrawal from GHB may continue for up to 21 days and can be life-threatening, though treatment with benzodiazepines is usually effective.

Magnesium sulphate for preventing preterm birth in threatened preterm labour.

PubMed

Crowther, Caroline A; Brown, Julie; McKinlay, Christopher J D; Middleton, Philippa

2014-08-15

Magnesium sulphate has been used in some settings as a tocolytic agent to inhibit uterine activity in women in preterm labour with the aim of preventing preterm birth. To assess the effects of magnesium sulphate therapy given to women in threatened preterm labour with the aim of preventing preterm birth and its sequelae. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (last searched 31 January 2014). Randomised controlled trials of magnesium sulphate as the only tocolytic, administered by any route, compared with either placebo, no treatment or alternative tocolytic therapy (not magnesium sulphate) to women considered to be in preterm labour. At least two review authors assessed trial eligibility and risk of bias and undertook data extraction independently. The 37 included trials (total of 3571 women and over 3600 babies) were generally of moderate to high risk of bias. Antenatal magnesium sulphate was compared with either placebo, no treatment, or a range of alternative tocolytic agents.For the primary outcome of giving birth within 48 hours after trial entry, no significant differences were seen between women who received magnesium sulphate and women who did not (whether placebo/no alternative tocolytic drug, betamimetics, calcium channel blockers, cox inhibitors, prostaglandin inhibitors, or human chorionic gonadotropin) (19 trials, 1913 women). Similarly for the primary outcome of serious infant outcome, there were no significant differences between the infants exposed to magnesium sulphate and those not (whether placebo/no alternative tocolytic drug, betamimetics, calcium channel blockers, cox inhibitors, prostaglandin inhibitors, human chorionic gonadotropin or various tocolytic drugs) (18 trials; 2187 babies). No trials reported the outcome of extremely preterm birth. In the seven trials that reported serious maternal outcomes, no events were recorded.In the group treated with magnesium sulphate compared with women receiving antenatal placebo or no alternative tocolytic drug, a borderline increased risk of total death (fetal, neonatal, infant) was seen (risk ratio (RR) 4.56, 95% confidence interval (CI) 1.00 to 20.86; two trials, 257 babies); none of the comparisons between magnesium sulphate and other classes of tocolytic drugs showed differences for this outcome (10 trials, 991 babies). The outcomes of neonatal and/or infant deaths and of fetal deaths did not show differences between magnesium sulphate and no magnesium sulphate, whether compared with placebo/no alternative tocolytic drug, or any specific class of tocolytic drug. For most of the other secondary outcomes, there were no significant differences between magnesium sulphate and the control groups for risk of preterm birth (except for a significantly lower risk with magnesium sulphate when compared with barbiturates in one trial of 65 women), gestational age at birth, interval between trial entry and birth, other neonatal morbidities, or neurodevelopmental outcomes. Duration of neonatal intensive care unit stay was significantly increased in the magnesium sulphate group compared with the calcium channel blocker group, but not when compared with cox inhibitors or prostaglandin inhibitors. No maternal deaths were reported in the four trials reporting this outcome. Significant differences between magnesium sulphate and controls were not seen for maternal adverse events severe enough to stop treatment, except for a significant benefit of magnesium sulphate compared with betamimetics in a single trial. Magnesium sulphate is ineffective at delaying birth or preventing preterm birth, has no apparent advantages for a range of neonatal and maternal outcomes as a tocolytic agent and its use for this indication may be associated with an increased risk of total fetal, neonatal or infant mortality (in contrast to its use in appropriate groups of women for maternal, fetal, neonatal and infant neuroprotection where beneficial effects have been demonstrated).

[Early achievements of the Danish pharmaceutical industry-7].

PubMed

Grevsen, Jørgen V; Kirkegaard, Hanne; Kruse, Edith; Kruse, Poul R

2014-01-01

A/S GEA Farmaceutisk Fabrik was established as a family business in 1927 by the pharmacist Knud L. Gad Andresen who until then had been employed in the pharmaceutical industry. Gad Andresen wanted to run a company focusing on the development of generics, and he wanted this development to take place in a close cooperation with Danish physicians. This has indeed been achieved with success. In 1995 GEA was purchase'd by the American pharmaceutical company Bristol-Myers Squibb who in a press release characterized GEA as Denmark's second largest manufacturer of generics. Immediately after this takeover GEA's R&D department ceased the research in innovative products and from now on exclusively focused on the development of generics. Three years later GEA was sold to the German generic company Hexal who later on resold GEA to the Swiss generic company Sandoz. GEA changed ownership another couple of times until the last owner went bankrupt in 2011. GEA is yet again a model example of an early Danish pharmaceutical company which was established as an individual company, and which had a long commercial success with the production and marketing of generics. GEA's earliest products, the organotherapeutics, were not innovations. The innovative products were developed already in the 1890s in Denmark by Alfred Benzon, and later on copies followed a.o. from Medicinalco and from foreign companies before GEA marketed their generics. Therefore GEA had to promote their preparations as especially qualified medicinal products and to intimate that the products of the competitors were less "active'". At the end of the 1920s the Ministry of Health became aware of the fact that there might be health problems related to the none-existing control of both the or- ganotherapeutic preparations and actually also the other medicinal products of the pharmaceutical industry. Therefore the Ministry had requested the National Board of Health for a statement regarding this problem. The National Board of Health was, however, at that time of the opinion that there were no serious problems with organotherapeutics from those companies marketing such products. It requires studies in the unprinted journals of the Ministry of Health and the National Board of Health to find the background for and the causes of the request from the Ministry at this point concerning the control of the organotherapeutic products of the pharmaceutical industry. Neither were GEA's barbiturates innovative products. The "Gad Andresen Case" is interesting for two reasons. Firstly, it illustrates that the development of generics at this stage could not always take place exclusively in a pharmaceutical-chemical laboratory, but also required a certain minimum of clinical trials including human beings. Secondly, it shows that the industrial products had now slowly, but surely gained market shares and displaced the pharmacy-produced medicinal products to such an extent that it did not only worry the pharmacy owners and their trade orga- nization. Now this concern had also resulted in a counteract so that the pharmacies in the manufacture of their products had to copy the industrial products, however, in certain cases with a dubious result. Gealgica tablets and especially their content of fenacetine is not only a model example of how the opinion of the positive and negative properties of a medicinal product changes over time. It also shows how long time could pass before the health authorities took measures against a substance with problematic side effects in spite of the fact that less damaging substances had been available for a long time, in this case paracetamol. Medicinal products containing fenacetine were on the market for almost 100 years. On the contrary meprobamat is a model example of a drug substance where the opinion of its positive and negative properties changed essentially over a relatively short period. In spite of this it remained on the market for a little less than 40 years. Restenil and Trihistan are mentioned on Knud & Dagny Gad Andresen's homepage (in 2014) as new medicinal products developed by GEA. This is not quite correct. Both drug substances in these preparations had been developed in the USA. In Denmark GEA had the possibility to market these substances under GEA's own brand names along with corresponding foreign brand names. It can be concluded that GEA's own research on the whole was confined to the development of own patentable syntheses of already known drug substances. During the later marketing of generics GEA appealed to the national feeling of the Danish population in the same way as a.o. Pharmacia did in the 1920s. From the very start GEA specialized in the manufacture of generics, and GEA was able to follow this way with commercial success--as a Danish alternative--for almost 90 years.

Prevention of suicide and attempted suicide in Denmark. Epidemiological studies of suicide and intervention studies in selected risk groups.

PubMed

Nordentoft, Merete

2007-11-01

The suicide rates in Denmark have been declining during the last two decades. The decline was relatively larger among women than among men. All age groups experienced a decline except the very young with stable rates and the very old with increasing rates. The Universal, Selective, Indicated (USI) model recommended by Institute of Medicine was used as a framework for the thesis. Universal preventive interventions are directed toward the entire population; selective interventions are directed toward individuals who are at greater risk for suicidal behaviour; and indicated preventions are targeted at individuals who have already begun self-destructive behaviour. At the universal level, a review was carried out to highlight the association between availability of methods for suicide and suicide rate. There were mostly studies of firearms, and the conclusion of the review was that there was clear indication of restricted access to lethal means was associated with decline in suicide with that specific method, and in many cases also with overall suicide mortality. Restricting access is especially important for methods with high case fatality rate. Our own study indicated a beneficial effect on suicide rates of restrictions in access to barbiturates, dextropropoxyphen, domestic gas and car exhaust with high content of carbon monoxide. Although a range of other factors in the society might also be of importance, it was concluded that restrictions in access to dangerous means for suicide were likely to play an important role in reducing suicide rates in Denmark, especially for women. At the selective level, there are several important risk groups such as psychiatric patients, persons with alcohol and drug abuse, persons with newly diagnosed severe physical illness, all who previously attempted suicide, and groups of homeless, institutionalized, prisoners and other socially excluded persons. The thesis focused on homeless persons and psychiatric patients, especially patients with schizophrenia and related disorders. The thesis contains a review of the risk of suicide in homeless. In all the studies included, increased suicide mortality was found, and in the studies that evaluated suicide risk in different age groups, the excess suicide mortality was most dominant in younger age groups. Our own study revealed an increased risk of suicide, and in univariate analysis, significant predictors for suicide were found to be associated with shortest stay in hostel less than 11 days and more than one stay during one year. The thesis also contains a review of the risk of suicide in first-episode patients with schizophrenia, and it was concluded on the basis of the identified studies that long-term risk of suicide was not 10 percent as previously accepted, but lower. Risk factors for suicide among patients with schizophrenia were evaluated in case control studies, in nested case control studies, and in prospective studies. The following risk factors were the most important and frequently observed predictors: male gender, young age, short duration of illness, many admissions during last year, current inpatient, short time since discharge, previous and recent suicide attempt, co-morbid depression, drug abuse, poor compliance with medication, poor adherence to treatment, high IQ, and suicidal ideations. The results of analyses of psychotic symptoms as risk factor for suicide were contradictory, but a recent meta-analysis concluded that both hallucinations and delusions seemed to be protective; however, there was a non-significant tendency that command hallucinations were associated with higher suicide risk. Prevention of suicide in schizophrenia must especially focus on improving assessment of risk of suicide during inpatient treatment and the first week after discharge, and special attention must be paid to patients with one or more of the identified risk factors. There is a need for large randomised clinical trials evaluating the effect on suicide and suicide attempt of psychosocial and pharmacological treatment in schizophrenia. In our own study, we did not find any effect of integrated treatment on attempted suicide, but there was an effect on hopelessness and a trend toward lower prevalence of depression among patients in the integrated treatment. There were four suicides and one probable suicide (drowning) in standard treatment and one suicide in integrated treatment at two-year follow-up, but the study did not have sufficient power to detect these differences in proportion to who committed suicide; more than one thousand patients should have been in each treatment condition in order for these differences in proportion to be significant. At the indicated prevention level, a literature review was carried out regarding risk of suicide attempt and suicide in short-term, medium-term and long-term follow-up of persons who attempted suicide. It was concluded that the risk of repetition in short- and medium-term follow-up studies was approximately 16 percent, with lower risk among "first-evers" compared to repeaters. There was a large variation in repetition rate. The proportion who committed suicide in medium-term follow-up studies was 2.8 percent and in long-term follow-up studies was 3.5 percent (weighted mean) with clearly higher proportions in the Nordic studies than in the studies from UK. Risk factors for attempted suicide were previous suicide attempt, alcohol and drug abuse, depression, schizophrenia, previous inpatient treatment, self-discharge before evaluation, sociopathy, unemployment, frequent change of address, hostility, and living alone. Several of the predictors are overlapping and most of them were already identified in early studies of factors predictive of repetition of suicide attempt. Predictors of suicide were male gender, increasing age, previous suicide attempt, serious suicide attempt, alcohol and substance abuse, somatic disease, mental illness, and planning of suicide attempt, high suicidal intent score, violent suicide attempt or suicide attempt with severe lethality, and ongoing or previous psychiatric treatment. In our follow-up study from Bispebjerg Hospital, we found that the risk of suicide during a ten-year follow-up period among patients admitted in 1980 after self-poisoning was 30 times greater than in the general population. We also found increased mortality by all other causes of death. Predictors of suicide were several previous suicide attempts, living alone and increasing age. There are not many randomised clinical trials of psychosocial interventions aiming to reduce risk of repetition among suicide attempters. A Cochrane review concluded that evidence was lacking to indicate the most effective forms of treatment for deliberate self-harm patients. A recent randomised controlled trial showed a positive influence of cognitive behavioural therapy on repetition rate. Our own quasi-experimental study of effectiveness of two weeks' inpatient treatment in a special unit of young persons who had severe suicidal thoughts or who had attempted suicide showed that risk of repetition was reduced in the intervention group, and that the intervention group obtained a significantly greater improvement in Beck's Depression Inventory, Hopelessness Scale, Rosenberg Self-Esteem Scale and CAGE-score. The study of emergency outreach indicates that there are many persons in the community that experience a suicidal crisis, and that this group is an important target group for psychiatric emergency outreach. In our study of registration and referral practice in Copenhagen Hospital Cooperation, we conclude that not all suicide attempts were registered as such in the National Patient Register - in fact, only 37 percent. It must be concluded that the quality of the Danish Patient Register must be improved with regard to registration of suicide attempt. We found that psychiatric evaluation was planned in relation to almost all suicide attempts, but that it must be recommended to pay attention to escorting patients to psychiatric emergency in order to ensure that the patient actually attends the planned consultation. We found that patients who were referred after psychiatric evaluation to psychiatric treatment at outpatient facilities only received the planned treatment in approximately two-thirds of the cases; therefore, like Hawton et al. [Hawton et al., 1998; Hawton et al., 1999], we recommend that outpatient facilities adopt an assertive approach to patients who have attempted suicide. Danish suicide research is strong, primarily due to the possibilities for linking complete national registers providing detailed data and large sample sizes for suicide research, which is so far unique for the Nordic countries. This, combined with skilful use of epidemiological methods, had resulted in a remarkable series of papers highlighting risk of suicide in different risk groups, risk factors and protective factors. This activity must continue. In this work it is important to be aware of limitations in naturalistic studies such as the risk of interchanging cause and effect and the necessity to carry out control for confounders. Meta-analysis is a strong tool for summing up results of previous research. Meta-analyses can be used in reporting the evidence for effectiveness of interventions, but also for determining risk or identifying risk factors. A meta-analysis of risk factors of repetition of suicide attempt has not been carried out, and the quality of the identified studies did not allow a formal meta-analysis. Large randomised clinical trials examining the effectiveness of interventions on reducing rate of suicide attempt and suicide should have high priority. Suicide is a major public health problem and should be given high priority with regard to prevention and research. (ABSTRACT TRUNCATED)