bluuebunny/crossref_metadata_2025 huggingface dataset:
First seizure definitions and worldwide incidence and mortality
Authors: Hauser W. Allen , Beghi Ettore
Published: July 2010

Summary

While all patients with epilepsy experience seizures, not all individuals with seizures have epilepsy. Seizures may be acute symptomatic or unprovoked. Acute symptomatic seizures are seizures occurring at the time of a systemic insult or in close temporal association with a documented brain insult. Unprovoked seizures are seizures occurring in the absence of precipitating factors and may be caused by a static injury (remote symptomatic seizures) or a progressing injury (progressive symptomatic seizures). Unprovoked seizures may be single or recurrent (epilepsy). The incidence of acute symptomatic seizures is 29–39 per 100,000 per year. These predominate in men, in the youngest age class, and in the elderly. Traumatic brain injury, cerebrovascular disease, drug withdrawal, infarction, and metabolic insults are the commonest causes. The incidence of single unprovoked seizures is 23–61 per 100,000 person‐years. As with epilepsy, single unprovoked seizures predominate in men and in patients less than 12 months and older than 65 years. Studies on the mortality of acute symptomatic seizures are lacking. A standardized mortality ratio (SMR) of 2.3 has been reported in patients experiencing a single unprovoked seizure. The SMR in patients with a newly diagnosed unprovoked seizure ranges from 2.5 to 4.1 according to the study population and design. The SMR is highest in the youngest patients and in those with symptomatic seizures.
First seizure: EEG and neuroimaging following an epileptic seizure
Authors: Pohlmann‐Eden Bernd , Newton Mark
Published: July 2010

Summary

An early EEG (within 48 h) and high‐resolution magnetic resonance imaging (hr_MRI) are the methods of choice for an accurate diagnosis after a first seizure presentation. Together with a careful history and examination, they will allow definition of the epilepsy syndrome in two‐thirds of patients and help assess the individual risk for seizure recurrence, which is determined by the specific syndrome and is highest with focal epileptiform activity on EEG. Despite the heterogeneity of first seizure studies, EEG and etiology are consistently found to be the best predictors for seizure recurrence and prognosis. The additional yield of sleep‐deprived EEG and sleep EEG is uncertain; yet MRI is essential for detecting brain tumors and other structural bases for new epilepsy. The rate occurrence of remote symptomatic seizures increases significantly with age and the most common etiology in the elderly with a first seizure is stroke; however, its exact relevance to epileptogenicity is yet to be defined. There is a striking lack of systematic studies using early EEG and hr_MRI in order to better characterize epileptogenic areas and elucidate the mechanisms of seizure provocation.
The socioeconomic, cultural, and emotional implications of starting or withholding treatment in a patient with a first seizure
Authors: Heaney Dominic C. , Bell Gail S. , Sander Josemir W.
Published: July 2010

Summary

The decision to treat or not treat individuals who have suffered a single epileptic seizure is based on clinical factors, which are considered within the individual's social, cultural, and emotional environment. Even if optimally communicated, individuals and their carers will make different decisions about first seizures and their treatment, as they will judge the risks and benefits of treatment (or its deferment) in this wider context. There is a significant body of literature that describes the impact of established epilepsy on aspects of an individual's overall quality of life (QoL), and more recently evidence is emerging about the factors that may be important in 2 years after a single seizure on and off treatment. Little research, however, has considered the importance of nonclinical factors in individual's choices at the time of a first seizure, and in particular in an individual's decision to use or not use treatment. Understanding these issues may improve communication of risks and benefits to individuals, and may offer insight into the mechanisms by which social and socioeconomic disadvantage occur in epilepsy.
Tuberous sclerosis: A primary pathology of astrocytes?
Authors: Sosunov Alexander A. , Wu Xiaoping , Weiner Howard L. , Mikell Charles B. , Goodman Robert R. , Crino Peter D. , McKhann Guy M.
Published: July 2010

Summary

Purpose:

Cortical tubers are epileptogenic lesions in patients with tuberous sclerosis complex (TSC). Giant cells and dysplastic neurons are pathological hallmarks of cortical tubers. Severe astrogliosis, which is invariably present in tubers, has attracted much less attention. We hypothesize that the development of astrogliosis in cortical tubers constitutes a primary pathology of astrocytes and is directly related to TSC 1/2 mutations..

Methods:

To begin to test this hypothesis, we performed immunohistochemical and electron microscopic analysis of brain tuber tissue resected from epileptic TSC patients. We compared alterations in tuber astrocytes to those found in other acute and chronic human epilepsy pathologies.

Results:

We found that astrogliosis in tubers is comprised of a mixture of “gliotic” and “reactive” astrocytes. The majority of tuber astrocytes are “gliotic” astrocytes that are morphologically and immunophenotypically similar to astrocytes in areas of gliosis in hippocampal sclerosis (HS). However, specific immunostaining features differentiate TSC gliosis from HS gliosis. “Reactive” tuber astrocytes are large‐sized, vimentin positive cells in the vicinity of giant cells that show activation of the mammalian target of rapamycin (mTOR) pathway, consistent with mutated TSC gene function. These cells resemble acutely reactive human astrocytes seen in tissue resected from depth electrode implantation patients. Oligodendrocytes and NG2 expressing glial cells do not have any detectable alterations within tubers.

Conclusions:

We conclude that astrocytes are the type of glial cell selectively impacted in cortical tuber pathology. We propose that tubers may be dynamic lesions, with progression of astrocytes over time from “reactive” to “gliotic.” Tuber astrogliosis in TSC may represent a genetic “model” of gliosis that is phenotypically similar to gliosis seen in acquired human pathologies.
Comparison of Acupuncture to Injection for Myofascial Trigger Point Pain
Authors: Gazi Miriam C.B. , Issy Adriana M. , Ávila Ilíada P. , Sakata Rioko K.
Published: July 2010

Objectives:  Many treatments have been proposed for myofascial pain syndrome. The objective of this study was to compare the analgesic effect of acupuncture to trigger point injection combined with cyclobenzaprine chlorhydrate and sodium dipyrone.

Methods:  A randomized study was performed in 30 patients divided into 2 groups: G1 received trigger point injection with 0.25% bupivacaine twice weekly, and both cyclobenzaprine chlorhydrate 10 mg/day and sodium dipyrone 500 mg every 8 hours; G2 received classical and trigger point acupuncture twice weekly. All patients were instructed in physical exercise. The following parameters were evaluated: pain intensity rated on a numerical scale, number of trigger points, and quality of life before and 4 weeks after treatment.

Results:  The pain scores and the number of trigger points reduced significantly in both groups, with no significant difference between groups. Significant improvement in the quality of life scores was observed for some of the functional domains in the 2 groups, whereas there was no improvement of the general health status domain in either group or of the emotional domain in G1.

Conclusion:  Acupuncture, when compared with trigger point injection, combined with cyclobenzaprine chlorhydrate and sodium dipyrone provided similar pain relief and improvement in quality of life measures at 4 weeks. ▪
Judicial Reform as Insurance Policy: Mexico in the 1990s
Authors: Finkel Jodi
Published: July 2010

After seven decades of Mexican judicial subordination, President Ernesto Zedillo in 1994 introduced judicial reforms that increased the independence and judicial review powers of the judicial branch. The willful creation of a judiciary capable of checking the power of the president and the ruling PRI appears to counter political logic; but it makes sense as a political “insurance policy” to protect the ruling party from its rivals. PRI politicians, newly unable to control political outcomes at state and local levels and unsure if they would continue to dominate the national government in the future, opted to empower the Mexican Supreme Court as a hedge against the loss of office. This article argues that the likelihood of the reforms' producing an empowered judiciary increases as the ruling party's probability of reelection declines.
Aging Blow Fly Eggs Using Gene Expression: A Feasibility Study
Authors: Tarone Aaron M. , Jennings Kimberley C. , Foran David R.
Published: July 2010

Abstract:  Forensic entomology can aid death investigations by using predictable developmental changes to estimate the ages of flies associated with a body. In developmental stages that do not increase in size however, including the egg and pupa, it can be difficult to objectively refine an age estimate beyond the limits of the stage duration. Gene transcript levels, changing throughout development, represent a potential data source useful for objectively identify smaller units of developmental time. The expression of three genes (bcd, sll, cs) was profiled throughout the maturation of blow fly eggs to determine the feasibility of predicting age, identifying significant linear trends in expression during their development. Models estimating egg age made predictions within 2 h of true age when all expression data were available, while the presence/absence of cs transcripts identified two age classes, together indicating that gene expression can be used to more precisely predict blow fly age.
Phage display selection of peptides that home to atherosclerotic plaques: IL‐4 receptor as a candidate target in atherosclerosis
Authors: Hong Hai‐yan , Lee Hwa Young , Kwak Wonjung , Yoo Jeongsoo , Na Moon‐Hee , So In Seop , Kwon Tae‐Hwan , Park Heon‐Sik , Huh Seung , Oh Goo Taeg , Kwon Ick‐Chan , Kim In‐San , Lee Byung‐Heon
Published: July 2010

Imaging or drug delivery tools for atherosclerosis based on the plaque biology are still insufficient. Here, we attempted to identify peptides that selectively home to atherosclerotic plaques using phage display. A phage library containing random peptides was ex viv screened for binding to human atheroma tissues. After three to four rounds of selection, the DNA inserts of phage clones wer sequenced. A peptide sequence, CRKRLDRNC, was the most frequently occurring one. Intravenously injected phage displaying the CRKRLDRNC peptide was observed to home to atherosclerotic aortic tissues of low‐density lipoprotein receptor‐deficient (Ldlr−/–) mice at higher levels than to normal aortic tissues of wild‐type mice. Moreover, a fluorescein‐ or radioisotope‐conjugated synthetic CRKRLDRNC peptide, but not a control peptide, homed in vivo to atherosclerotic plaques in Ldlr−/– mice, while homing of the peptide to other organs such as brain was minimal. The homing peptide co‐localized with endothelial cells, macrophages and smooth muscle cells a mouse and human atherosclerotic plaques. Homology search revealed that the CRKRLDRNC peptide shares a motif of interleukin‐receptor (IL‐4) that is critical for binding to its receptor. The peptide indeed co‐localized with IL‐4 receptor (IL‐4R) at atherosclerotic plaques. Moreover, the peptide bound to cultured cells expressing IL‐4R on the cell surface and the binding was inhibited by the knock‐down of IL‐4R. These results show that the CRKRLDRNC peptide homes to atherosclerotic plaques through binding to IL‐4R as its target and may be a useful tool for selective drug delivery and molecular imaging of atherosclerosis.
Central Effects of Anticholinergic Drugs Measured by the Apomorphine Gnawing Test in Mice
Authors: Scheel‐Krüger J.
Published: July 2010

Apomorphine in doses ranging from 10 up to 60 mg/kg given subcutaneously to mice induces only weak gnawing behaviour and 10 mg/kg was without effect. The addition of anticholinergic drugs given 15 min. before 10 mg/kg apomorphine potentiated the gnawing behaviour. 9 tertiary and 3 quaternary drugs were tested. Among these some quinuclidinylesters, scopolamine and benztropine were found to be very active compared with atropine. The quaternary compounds showed much weaker activity than the corresponding tertiary analogues. The gnawing activity produced by atropine plus apomorphine was only weakly antagonized by the apomorphine antagonistic drug spiramide; physostigmine showed a better inhibitory effect and combined treatment with spiramide and physostigmine gave a pronounced antagonistic effect. Since the apomorphine gnawing behaviour is most probably related to an interaction with central dopamine receptors, these findings suggest there is a central counter balancing dopaminergic‐cholinergic system.
O‐Methylation of Simple Phenols in the Rat
Authors: Bakke Olav M.
Published: July 2010

Eleven simple mono‐, di‐ and thihydric phenols were given by stomach tube at a dose of 100 mg/kg body weight. The subsequent 48‐hour urines were hydrolyzed, extracted and analyzed by thin‐layer and gas chromatography and by infrared spectrophotometry. The mean extent of directO‐methylation was 6.9% with catechol, 6.0% with 4‐methylcatechol, 8.9% with 4‐ethylcatechol and 6.2% with pyrogallol. The preferred site of methylation was the middle hydroxyl group of pyrogallol and themetahydroxyl group of 4‐methylcatechol. Methoxyl groups were introducedorthoto the hydroxyl group of the monohydric phenols 4‐ethyl‐phenol,p‐cresol and phenol, but this occurred to a very small extent. NoO‐methylated metabolites were detected following the administration of resorcinol, hydroquinone, hydroxyquinol and phloroglucinol. There was no correlation between the extent ofO‐methylation of the simple phenols and their potencies as convulsant agents. Formation of anisoles andO‐methylation of more than one hydroxyl group were not observed with any of the compounds. The rats dosed with hydroxyquinol but not those given pyrogallol or phloroglucinol excreted small amounts of resorcinol. Metabolites produced by oxidation and unknown metabolites were also observed.
Effect of Nicotine Treatment on the Metabolism of Nicotine in the Mouse Liver in Vitro
Authors: Stålhandske Torbjörn , Slanina Premysl
Published: July 2010

14C‐nicotine was incubated with a 10000 × g supernatant fraction of liver homogenate from mice pretreated with nicotine for 3, 10 and 17 days respectively. The rate of metabolism was measured by the determination of the oxidative nicotine metabolite cotinine. After intraperitoneal injections of 5 mg/kg of nicotine three times daily for three days a 50% significant decrease in metabolism was observed. A 71% significant decrease in hepatic glycogen was also seen. Giving nicotine 27.8 and 24.5 mg/kg/24 hours in drinking water for 10 and 17 days respectively did not significantly change the metabolism or the hepatic glycogen levels.
Emetic and Gastric Secretory Stimulating Action by Esters of some Amino Acids
Authors: Elwin Carl‐Eric
Published: July 2010

Esters of amino acids reduce gastric acidity following intragastric administration but simultaneously exert an emetic effect. A series of experiments was designed on a total of 13 dogs to elucidate the mechanisms of the effects of ethyl‐ester of glycine, diethyl‐ester of glutamic acid, diisopropyl‐ester of glutamic acid, isopropyl‐ester of phenylalanine and isobutyl‐ester of valine. Oral administration or injection of the esters by means of a gastric cannula with free passage to the duodenum induced emesis in 17 of 23 experiments (74 %) on 6 dogs in an average time of 11 minutes. Occlusion of the duodenum with a Foley catheter distal to the pylorus prevented an emetic response during gastric administration. Emesis was induced in 47/57 administrations (82 %) on 10 dogs 0–10 cm distal to the pylorus by emetic threshold doses within an average time of 8 minutes. Emetic effect declined with distance from the pylorus and below 50 cm no emetic response occurred. The emetic threshold dose in general was 2–4 ml of the esters except for diethyl‐ester of glutamic acid, the threshold dose of which was 0.2–0.5 ml. A refractory period of 1–1 1/2 hour's duration to an emetic dose was observed. Hydrochlorides of esters tested showed a similar emetic pattern. In control experiments, copper sulphate induced vomiting from both the stomach and the duodenum in amounts indicating a more potent emetic action (0.025–0.25 g). Diethyl‐ester of glutamic acid was also administered intravenously, but amounts 2–6 times larger than the duodenal emetic dose did not evoke emesis. Blockade of the emetic effect was demonstrated by 0.4–2.0 % lidocaine (10–30 ml) and by 0.5–2.0 mg atropine administered locally in the duodenum, whereas the subcutaneous administration of atropine showed a less pronounced blocking effect. Esters of amino acids may act as local irritants. — Gastric administration of 1–2 ml of ester raised the pH to 7.0–7.6 immediately and this lasted for 5–15 min. Neither gastric nor duodenal administration increased the volume or total acid output of innervated or vagally denervated fundic pouches. Perfusion of the isolated, innervated antrum pouch, however, caused an increase of total acid output of the fundic pouch, indicating a release of the antral stimulatory hormone, gastrin.
Lethal Brain Concentrations of Nicotine in Mice of Different Ages
Authors: Stålhandske Torbjörn , Slanina Premysl
Published: July 2010

Albino mice aged 3 days, 12 days and 35 days, were injected intraperitoneally with lethal doses of14C‐nicotine. At death the concentrations of nicotine in the brain and blood were measured. Significant age dependent differences between lethal brain and blood concentrations and latent period before death occurred were found. The brains of mice aged 12 days were found to have the lowest and the brains of mice aged 35 days the highest nicotine concentration at death. The lethal concentration of nicotine in the blood was highest in mice aged 3 days and lowest in mice aged 12 days. Brain/blood ratios increased with age. The latent period before death occurred was shortest in mice aged 12 days and longest in mice aged 3 days. The significance of these conditions for age dependent differences in tolerance to nicotine is discussed.
Pharmacological Properties of Some Antirheumatic Salicylates
Authors: Åberg G. , Larsson K. S.
Published: July 2010

The anti‐inflammatory effect of acetylsalicylic acid, salicylsalicylic acid, sodium salicylate and salicylamide was investigated by means of the carrageenin‐induced oedema‐test in rats. Salicylamide in these experiments was found to be significantly less effective than the other compounds tested. With regard to the effect on35S‐sulphate incorporation into calf rib cartilagein vitrosalicylsalicylic acid was superior to the other compounds as it had an inhibitory effect of 70 % as compared with about 45 % for acetylsalicylic acid and about 35 % for salicylamide. The analgesic activity was investigated using the phenylquinone‐method on mice. Acetylsalicylic acid was found to be more active in this respect than the other salicylates. Gastric irritation was studied on the gastric mucosa of guinea‐pigs. After sodium salicylate and acetylsalicylic acid administration the mucosa became hyperaemic and in addition acetylsalicylic acid caused numerous erosions in the stomachs. Neither salicylsalicylic acid nor salicylamide gave any significantly increased rate of gastric irritation in the guinea‐pigs.
The Distribution, Elimination, and Biotransformation of14C‐Cloforex in the Mouse and Rat
Authors: Ryrfeldt Åke
Published: July 2010

The tissue distribution of radioactivity in mice was studied by whole body autoradiography after oral and intravenous administration of14C‐cloforex. A high uptake and persistence of activity was noted in the lungs and brain. A distinct difference in the distribution of activity in adipose tissue was obtained after oral and intravenous administration. A high activity was found in the fat tissue of mice which had received the drug intravenously, but no activity was found following oral administration. This difference may be due to the fact that very little or no cloforex is present in the circulation after oral administration. The excretion of radioactivity was slow. Twenty‐four hours after oral administration to rats about 50 % of the administered dose was eliminated, and after 1 week, about 90 %. Most of the activity was eliminated through the kidneys and only small amounts in the faeces and expired air. The tissue retention of activity is certainly of great importance in the slow elimination. The major metabolite in the rat, accounting for about 80 % of the total activity in 8–24 hours urine, was identified as chlorphentermine. The remaining activity was attributed to an unknown metabolite, which seemed to be some conjugate of chlorphentermine. No unchanged cloforex could be found in the urine.
Failure to Demonstrate Monoamine Oxidase Inhibition by Glyceryl Trinitrate in Vivo
Authors: Waldeck Bertil
Published: July 2010

Glyceryl trinitrate (GTN) or the monoamine oxidase (MAO) inhibitor nialamide was given to rats or mice which then received14C‐tyramine. Nialamide but not GTN increased the yield of the14C‐octopamine formed in the heart. In nialamide pretreated mice GTN possibly caused a slight increase in14C‐octopa‐mine. GTN given before or after3H‐noradrenaline had no effect on the uptake and retention of this amine in the mouse heart. Neither did it affect the uptake of3H‐metaraminol in this organ. It is concluded that GTN has no effect on the MAO responsible for thein vivometabolism of tyramine and noradrenaline. The existence of MAO systems with different substrate and inhibitor sensitivity is discussed.
Renal Lesions Induced by α‐Methyltyrosine Methylester and α‐Methyltyrosine
Authors: Magnusson Göran , Corrodi Hans , Hansson Eskil
Published: July 2010

The toxicity of α‐methyltyrosine methylester (H 44/68) and α‐methyltyrosine (H 9/88) in the rat was investigated in a four week subacute study. Both compounds induced renal lesions with formation of calculi in the urinary tract. The renal lesions were manifested by deposition of tubular crystals associated with regressive and inflammatory changes. The main sites of crystal deposition were the collecting tubules and the papillary ducts. The calculi consisted of α‐methyltyrosine. The investigation indicates that α‐methyltyrosine methylester is metabolized in the body to the less soluble α‐methyltyrosine and that α‐methyltyrosine is excreted through the kidneys. Crystals of α‐methyltyrosine are formed in the renal tubules and urinary tract probably due to a supersaturation of the urine.
The Action of Thioridazine and Promazine on Biological Membranes: Relationship between ATPase Inhibition and Membrane Stabilization
Authors: Landmark Knud , Øye Ivar
Published: July 2010

The effects of promazine and thioridazine on hypotonic haemolysis of human erythrocytes are compared with their effect on Na+‐K+‐ATPase of washed human erythrocyte ghosts. Promazine (5 × 10‐5‐ 5 × 10‐4M) and thioridazine (10‐5‐ 10‐4M) stabilize erythrocytes against hypotonic haemolysis, but have lytic effects at higher concentrations. Both drugs inhibit Na+‐K+‐ATPase of erythrocyte membranes. This inhibition is slight at drug concentrations which have a membrane‐stabilizing action, but is complete and irreversible at lytic concentrations of the drugs. Promazine and thioridazine also inhibit Na+‐K+‐ATPase in a membrane fraction prepared from rat hearts. The relative order of potency of the two drugs in this respect does not reflect their relative potency as general cardiac depressants. It is concluded that Na+‐K+‐ATPase is not a primary target for the action of promazine and thioridazine in the rat heart. It is suggested that inhibition of Na+‐K+‐ATPase by these agents is secondary to more general alterations of the physical properties of the cell membrane.
On the Presence ofp‐Hydroxynorephedrine in the Rat Brain and Heart in Relation to Changes in Catecholamine Levels after Administration of Amphetamine
Authors: Lewander Tommy
Published: July 2010

The brain and heart NA in rats was maximally decreased by 28–52% at 3–12 hours after 20 mg/kg intraperitoneally of dl‐amphetamine‐SO4. Control levels of NA were not reached until 96 hours after a single injection of amphetamine, while the drug disappeared from the brain and plasma within 12 hours. Amphetamine was found to disappear from rat tissues in a poly‐phasic pattern after intraperitoneal administration. The brain/plasma ratio was 9.0 ± 0.3 (mean ± S. D.). Parahydroxynorephedrine was identified in the brain and heart as a metabolite of the d‐isomer of amphetamine. Parahydroxynorephedrine, the apparent T1/2of which was estimated to be about 22 hours, seems to be responsible for the prolonged depletion in the brain and heart NA levels caused by amphetamine. However, there was not an exact stoichiometric relation between the NA deficit and the amount ofp‐hydroxynorephedrine present. After pretreatment with desmethylimipramine, which inhibits the parahydroxylation of amphetamine, the NA in the brain and heart was decreased by amphetamine but already returned to control levels in about 12 hours. It is concluded that the persistent depletion of brain and heart NA induced by amphetamine is caused by the incorporation ofp‐hydroxynorephedrine as a false transmitter into NA neurons.
On the Relation between Motor Activity and the Degree of Enzyme Inhibition Following Inhibition of Tyrosine Hydroxylase
Authors: Svensson Torgny H. , Waldeck Bertil
Published: July 2010

The inhibitor of tyrosine hydroxylase, α‐methyltyrosine methylester (H44/68), was given intraperitoneally to mice. Following this the motor activity was measured at varying intervals of time and as an index of the activity of tyrosine hydroxylase, the net amounts of3H‐noradrenaline and3H‐dopamine formed in the brain from3H‐tyrosine during one hour were assayed. The hydroxylation of tyrosine was markedly inhibited soon after the administration of the inhibitor while the motor activity declined more slowly. Sixteen hours after the administration of the inhibitor, the motor activity and the amine synthesis were normal and restored to 60 per cent of the normal respectively. The results are discussed in relation to previous data obtained in mice on endogenous brain catecholamine levels after a corresponding injection of H44/68. It is suggested that after inhibition of the synthesis, motor activity depends on the store of catecholamines. However, motor activity appears to be maintained at a low amine level provided that the synthesis is not inhibited.
Quantitative Estimation of 5‐Hydroxy‐3‐Indole Acetic Acid and 5‐Hydroxytryptophan in the Brain Following Isolation by Means of a Strong Cation Exchange Column
Authors: Lindqvist Margit
Published: July 2010

Brain tissue is extracted with perchloric acid. The pH of the extract is adjusted to 2.5 and passed through a Dowex 50 W‐X4 column. 5‐Hydroxy‐3‐indole acetic acid is eluted with 60 % aqueous methanol, and then 5‐hydroxytryp‐tophan is eluted with 0.1 M phosphate buffer, pH 6.5. Fluorometric assays are performed according to the method for 5‐hydroxytryptamine described by Andéen & Magnusson (1967). The results are satisfactory with regard to reproducibility, recovery, specificity, and sensitivity. If the above procedure is combined with that published by Atack & Magnusson (1970), then 7 different compounds can be estimated after a single column procedure.
Uptake, Metabolism and Excretion of Desmethylimipramine and its Metabolites in the Isolated Perfused Rat Liver
Authors: von Bahr Christer , Borgåa Olof
Published: July 2010

The isolated perfused rat liver was used in order to study the metabolism of the tricyclic antidepressant drug, desmethylimipramine (DMI), which is metabolized by oxidation and subsequent conjugation. DMI labelled with tritium in a position in which it is not eliminated by metabolism, was used. Extraction procedures were developed which allowed a separation of DMI and its hydroxyl‐ated and conjugated metabolites. DMI and its metabolites were measured in perfusate plasma, bile and liver. DMI disappeared quickly from the plasma and reappeared in high concentrations in liver and bile. The drug was highly bound to proteins in perfusate plasma, while the conjugated metabolites were not bound at all. The red blood corpuscles contained approximately ten times higher concentrations of DMI than perfusate plasma but no conjugated metabolites. Only small amounts of unconjugated hydroxylated metabolites were found in perfusate plasma, liver and bile in contrast to the conjugated metabolites which occurred in considerable amounts in perfusate plasma and bile. DMI was bound to the microsomal fraction of the liver cell. The conjugated metabolites appeared mainly in the cytoplasm of the liver cell.
The Action of Dopamine on Arterial Blood Pressure in the Rat
Authors: Rubenson A.
Published: July 2010

The mean arterial blood pressure in conscious normotensive Sprague‐Dawley rats was recorded by means of in‐dwelling arterial catheters. Dopamine hydrochloride (DA) was infused intravenously from 0.04 μg/min. up to 0.22 μg/min. The infusions always resulted in a hypertensive reaction. Intravenous injections of DA (1–50 μg/kg) or noradrenaline bitartrate monohydrate (NA) (0.02–0.5 μg/kg) were given before and after phenoxybenzamine (PBZ) (5 mg/kg); protriptyline (PTP) (10 mg/kg) and nialamide (100 mg/kg). The DA injections alone resulted in a pressor action. PBZ blocked or considerably diminished the pressor action of DA. PTP did not result in a clear‐cut augmentation of the blood pressure response to DA like that seen after the various equipotent NA doses tested. Furthermore, there was no prolongation of the duration of the pressor action of DA after PTP, though this was found after NA. Nialamide did not alter the magnitude of the pressor action of DA and NA. However, the hypertensive response of L‐DOPA (25 mg/kg) was markedly augmented by pretreatment with nialamide (10 mg/kg).
Effects of 5‐Hydroxytryptophan on Arterial Blood Pressure, Body Temperature and Tissue Monoamines in the Rat
Authors: Henning Matts , Rubenson Allan
Published: July 2010

The mean arterial blood pressure in conscious rats was recorded by means of in‐dwelling arterial catheters. DL‐5‐hydroxytryptophan (5‐HTP) 200 mg/kg intraperitoneally lowered the blood pressure significantly after 20 min. Following the administration of the peripheral decarboxylase inhibitor L‐α‐hydrazino‐α‐methyl‐β‐(3,4‐dihydroxyphenyl) propionic acid (MK 486) 100 mg/kg intraperitoneally, 5‐HTP 200 mg/kg intraperitoneally caused only a slight lowering of the blood pressure after 1–2 hrs. 5‐HTP 50 mg/kg given intraperitoneally after a combined pretreatment with aMAOinhibitor (nialamide) 100 mg/kg intraperitoneally andMK486 100 mg/kg produced characteristic effects on gross behaviour after 20 min. No significant effects of 5‐HTP on the blood pressure were observed in these experiments. 5‐HTP200 mg/kg intraperitoneally caused a hypothermia which was prevented byMK486 100 mg/kg. After pretreatment with nialamide andMK486 as in the blood pressure experiments, 5‐HTP 50 mg/kg produced an initial hypothermia followed by a pronounced rise in body temperature. 5‐HTP 200 mg/kg intraperitoneally resulted in a marked accumulation of 5‐hydroxytryptamine (5‐HT) in the heart and brain. Pretreatment with MK 486 100 mg/kg prevented the increase in heart 5‐HT but did not change that in the brain. Brain dopamine (DA) but not brain and heart noradrenaline (NA) decreased significantly. 5‐HTP 50 mg/kg after the administration of nialamide and MK 486 increased the brain 5‐HT but caused no change in heart 5‐HT. Nialamide and MK 486 per se increased brain DA and NA significantly; 5‐HTP largely prevented the increase in brain DA but not in brain NA. It is concluded that 5‐HTP has a hypothermic and a hypotensive action due to the effect of 5‐HT on the extracerebral structures, while the hyperthermic effect may have a central nervous origin. 5‐HT formed from 5‐HTP lowers brain DA by displacement.
Effect of Pregnancy, Castration, Testosterone, Ethisterone, Oestradiol Benzoate and Stilboestrol on the Exchangeable Sulphate Pool and on Sulphate Incorporationin Vivointo Costal Cartilage of the Mouse
Authors: Herbai Georg
Published: July 2010

The influence of different endocrine conditions and the effects of sex hormones on the sulphate incorporation ratein vivointo costal cartilage were studied in mice by a method which allows a correction of the sulphation rates for alterations in the exchangeable sulphate pools of the animals. Oestrous cycle variations had no measurable effect, but castration of both male and female mice decreased the size of the sulphate pool and sulphation rate of cartilage, while pregnancy had the opposite effect. Testosterone propionate (dose range: 1 μg‐1 mg/day × 6) and ethisterone (dose range: 40 μg‐5 mg/day × 6) stimulated weight gain but had a rather weak effect on the sulphate pools and incorporation rates. Oestradiol benzoate and diethylstilboestrol given to growing mice in doses of 1 μg‐1 mg/day × 6 caused a dose‐dependent growth retardation and a decrease in the size of the total sulphate pool and that per g body weight. The drugs also elicited a graded inhibition of sulphation rate of cartilage in both sexes. Stilboestrol (20 μg/day × 6) also inhibited growth and decreased sulphation rate in 12‐days old suckling mice. Adult male and female animals treated with oestradiol benzoate in the doses described above, displayed only small weight changes but a marked and dose‐dependent decrease in the sulphation rate. Inhibition of sulphate incorporation rate always went together with growth retardation in growing mice but the former effect was produced by lower doses of oestradiol benzoate.
The Penetration of Quinine, Salicylic Acid, PAS, Salicyluric Acid, Barbital and Lithium across the Vitreous Barrier of the Rabbit Eye
Authors: Søorensen Per Nellemann
Published: July 2010

By intravenous infusion into rabbits anaesthetized with urethane or barbital the plasma level of a number of drugs was kept constant. The drug concentrations were determined in the vitreous body, aqueous humour, lens, and plasma. The steady state distribution ratios across the blood‐vitreous barrier was found to be: for quinine 1.35, salicylic acid: 0.42 and 1.0 (at plasma concentrations 150 and 900 μmol/l respectively), PAS (p‐aminosalicylic acid): 0.65, salicyluric acid: 0.05, barbital: 0.75. The distribution rate across the blood‐aqueous barrier was found to be for quinine: 0.25, salicylic acid: 0.8 and 1.0 (at plasma concentrations 150 and 900 μmol/l), salicyluric acid: 0.1, barbital: 0.95. The permeability constants for the penetration of the drugs into the vitreous body were calculated, quinine: 2.2 × 10–1, salicylic acid: 1.4 × 10–2, barbital: 1.2 × 10–2, PAS: 8.5 × 10–3, lithium: 6.9 × 10–4, salicyluric acid: 5.3 × 10–5, and into the aqueous humour, quinine, salicylic acid, barbital, and PAS: 1.1 — 1.5 × 10–2, lithium: 6.2 × 10–3, salicyluric acid: 2.9 × 10–4, all per minute. The partly ionized drugs penetrated the vitreous barrier according to the lipid solubility of the unionized form, thus penetration across the aqueous barrier was dependent on both the lipid solubility of the unionized form and the dissociation constant. Li+penetrated into the vitreous body predominantly from the anterior region of the eye and the partly ionized drugs through the whole exchange area. The injection of 25 μl 0.9 % NaCl or liquefaction of the vitreous body with hyaluronidase gave little change in the rate of Li+penetration, while that of PAS was decreased by half. The ratio between the salicyluric acid concentration in the water phase of the lens and the aqueous humour averaged 3.6 (1.1 — 5.6), suggesting that salicyluric acid was transported into the lens against a concentration gradient.
Effects of Acute and Chronic Amphetamine Intoxication on Brain Catecholamines in the Guinea Pig*
Authors: Lewander Tommy
Published: July 2010

The effects of amphetamine on central and peripheral catecholamines have been studied in guinea pigs, since in this species, unlike several others, amphetamine is not metabolized byp‐hydroxylation. Twenty mg/kg of dl‐amphe‐tamine‐sulphate given intraperitoneally caused a 40 % decrease in brain and heart noradrenaline, a 13 % decrease in brain dopamine and a 60 % decrease in homo‐vanillic acid in the caudate nucleus, four hours after its administration. The changes in tissue catecholamine levels and the increase in motor activity followed the time‐course of the amphetamine concentrations both in the brain and plasma. After chronic administration of amphetamine at 12 hourly intervals for 7 or 18 days, there was a further decrease in brain and heart catecholamine and homovanillic acid levels. A 4‐fold increase in the 3‐O‐methylated metabolites of noradrenaline and dopamine in brain after the administration of amphetamine to guinea pigs pretreated with nialamide and an increase in the urinary excretion of NA (13‐fold) and adrenaline (3‐fold) provided evidence for an amphetamine induced release of central and peripheral catecholamines as has previously been reported in rats and cats. Amphetamine disappeared from brain and plasma with an apparent half‐life of 2.5–3.1 hours. Only amphetamine and hippuric acid were recovered in the urine after the administration of radioactively labelled amphetamine. Nop‐ or βhydroxylated metabolites of amphetamine were present in the brain or heart tissues in the guinea pig. The results show that acute and chronic amphetamine administration causes changes in endogenous catecholamines in guinea pigs similar to those found previously in rats in spite of differences in the metabolism of amphetamine between the two species.
Salicylate‐Induced Foetal Damage During Late Pregnancy in Mice: A Comparison between Sodium Salicylate, Acetylsalicylic Acid and Salicylsalicylic Acid
Authors: Eriksson Margareta
Published: July 2010

Three salicylate derivatives i. e. sodium salicylate, acetylsalicylic acid and salicylsalicylic acid were tested and compared in A/Jax mice with regard to their effect on foetal damage on day 17 of gestation. The substances were administered by stomach tube in a dose constituting 2/3 of the LD50 dose in adult mice. Twentyfour hours after administration of each of the three derivatives an increased incidence of foetal death and haemorrhages were found. The highest incidence was found in the acetylsalicylic acid treated group. Four hours after administration all the salicylate derivatives caused a reduction in foetal liver glycogen. The control suspension however, also significantly reduced the glycogen content. The results are discussed in relation to the recommendations for drug testing. The advantage of comparing different drug derivatives for the study of the underlying mechanism responsible for their pharmacological actions is emphasized.
Salicylate‐Induced Foetal Damage in Two Mouse Strains: Studies on the Distribution of14C‐Labelled Salicylic Acid
Authors: Eriksson Margareta , Larsson K. Sune
Published: July 2010

The distribution of salicylate was studied in pregnant and non‐pregnant mice of the A/Jax and CBA strains. These strains were selected because of their different susceptibility to salicylate‐induced foetal damage. Labelled salicylic‐1‐14C‐acid (1 μci) was injected intramuscularly together with 10 mg sodium salicylate as cold carrier in a volume of 0.1 ml distilled water/20 g bodyweight. The animals were sacrificed at different intervals from half an hour to 8 hours after the injection and the radioactivity in the maternal blood and liver and in the foetuses was determined by liquid scintillation counting. The non‐pregnant mice showed initially a higher radioactivity in the blood than in the females on day 14 or 17 of gestation. The amount of liver radioactivity was similar in pregnant and non‐pregnant animals and remained practically unchanged during the period of study. The foetal radioactivity was relatively high compared to that in the maternal liver. No strain difference were observed either on gestation day 14 or on day 17. The foetal radioactivity did not decrease during the first 4 hours after salicylate treatment on day 17 of gestation at which time foetal damage had already been produced.
A Comparison of the Inhibition by Cardiac Glycosides of the Isolated Intestine from the Rat and the Guinea Pig
Authors: Briseid Gudrun , Briseid Kjell
Published: July 2010

A method described by Bieltvedt & Briseid (1966) and Bieltvedt (1967) for the determination of the inhibition by cardiac glycosides of the isolated, histamine‐stimulated guinea pig ileum was modified to estimate the inhibition of the acetylcholine‐stimulated rat jejunum. The glycoside concentrations causing 50 % inhibition of submaximal, isotonic contractions were determined, and the procedure was based on 20‐minute contact periods between the muscle preparations and the cardioactive substances, and then 22‐minute equilibration periods with chemical stimulation. The degree of inhibition was found to depend on the potassium content of the Tyrode solutions used. In a low potassium Tyrode solution (1.8 mM) the inhibition of the rat intestine by cardiac glycosides was found to be of the same order of magnitude as the inhibition of the guinea pig intestine. When the potassium chloride concentration was increased to 2.7 mM, the well known species difference was observed, the concentration of cardiac glycoside required for inhibition of the rat intestine being about 30 times higher than that required for inhibition of the guinea pig intestine. The range of potency of the different cardiac glycosides and aglycones which were tested in the low potassium. Tyrode solution, was the same for the two species. Presupposing an inhibition of Na+, K+‐activated transport ATPases as the basic mechanism for the inhibition by cardiac glycosides of the isolated intestine preparations, a theory of qualitative differences between the transport enzymes in the two species is advanced. In the rat intestine the presence is suggested of one ATPase which is rather resistant to inhibition by cardiac glycosides, but sensitive to a reduction in potassium concentration, in addition to a glycoside‐susceptible ATPase also present in the guinea pig intestine.
Effect of Carbon Tetrachloride Induced Progressive Liver Damage on Drug‐Metabolizing Enzymes and Cytochrome P‐450 in Rat Liver
Authors: Vorne Martti , Arvela Pentti
Published: July 2010

Rats were given 2 ml carbon tetrachloride per kg body weight subcutaneously 3 times a week. After 2, 4, 8, and 16 weeks the activities of drug‐metabolizing enzymes and glucose‐6‐phosphate dehydrogenase and cytochrome P‐450 content of liver microsomes were determined. Demethylation of N‐methyl‐aniline decreased progressively, and after 16 weeks of carbon tetrachloride administration it was 25 % of the control activity. Hydroxylation of hexobarbital also decreased progressively and after 16 weeks it was too low to be measured. Conjugation ofp‐nitrophenol did not decrease until 8 weeks of carbon tetrachloride administration, when the animals had developed liver cirrhosis. As cirrhosis became more severe, there was only a slight further decrease in conjugative activity, and after 16 weeks, 40 % of the conjugative activity was still recorded. Nitroreductase activity remained near the control level for the first 8 weeks, but after 16 weeks it was only 36 % of the activity of corresponding control animals. Cytochrome P‐450 content decreased progressively, and after 16 weeks it was too low to be measured. Glucose‐6‐phosphate dehydrogenase activity remained 2–3 times as great as in the controls throughout the 16‐week administration period.
Metabolism of Pentachloroethane in the Mouse
Authors: Yllner Sven
Published: July 2010

Pentachloroethane was given subcutaneously to mice (1.1–1.8 g/kg) and the excretion was followed for 3 days. About one third of the dose (range 12–51 %) was expired unchanged. The metabolized part was excreted mainly as trichloroethanol (16–32 % of the dose) and trichloroacetic acid (9–18 %) in the urine. The expired air also contained trichloroethylene (2–16 %) and tetrachloroethylene (3–9 %) indicating both dechlorination and dehydrochlorination of pentachloroethane. The latter reaction was found to be non‐enzymatic. The metabolites were identified by paper chromatography, gas chromatography and mass spectrometry, and the Fujiwara reaction was used for the quantitative determination of trichloroacetic acid and of trichloroethanol after oxidation to this acid. At least part of the urinary metabolites must be formed via trichloroethylene and its metabolite chloral hydrate. The latter compound may also be formed from pentachloroethane by hydrolytic fission of carbon‐chlorine bonds.
Effects of Chlorpromazine and Propranolol on Left Ventricular Systolic Pressure, ECG, and K+Efflux in the Isolated Perfused Rat Heart
Authors: Langslet Asbjørn , Ryg Morten
Published: July 2010

Isolated rat hearts perfused with a perfusate from which K+had been omitted and replaced by Rb+had a spontaneous rate of contraction which was about 5 % slower than that of the hearts perfused with K+‐containing perfusate, while the electrically driven hearts had a contractile force which was about 10 % lower. Isoprenaline and glucagon caused a maximal increase in contractile force of 60 % and 50 % respectively which is equal to the increase obtained with a K+‐containing perfusate. Chlorpromazine (C), d,l‐propranolol (d,l‐P) and d‐propranolol (d‐P) in concentrations from 10‐5M to 5 × 10‐5M caused dose dependent decreases in a) the heart rate from 135 ± 7 beats/min. (mean ± S. D.) (4 controls) to a minimum of 62 (C), 61 (d,l‐P) and 60 (d‐P). b) impulse conduction velocity expressed as PQ‐1 from 12 ± 2.1 sec. (4 controls) to a minimum of 6.6 (C), 4.9 (d,l‐P) and 4.8 (d‐P). c) left ventricular systolic pressure from 95 ± 3 mmHg (4 controls) to a minimum of 56 (C), 45 (d,l‐P) and 44 (d‐P). d) potassium efflux from 4.2 ± 0.2 meq√g dry weight × 10‐2(8 controls) to a minimum of 2.9 (C), 2.7 (d,l‐P) and 2.6 (d‐P). It is suggested that the effects can be explained as secondary to drug induced changes in the cell membrane.
Metabolism of Chloroacetate‐1‐14C in the Mouse
Authors: Yllner Sven
Published: July 2010

Chloroacetic‐1‐14C acid was given intraperitoneally and the elimination of radioactivity was followed for 3 days. 82–88 per cent was found in the urine and about 8 per cent in the expired air. The faeces (contaminated with urine) contained 0.2–3 per cent and 2–3 per cent remained in the animal. Examination of the urine by paper chromatography showed 2 major metabolites, S‐carboxymethyl‐L‐cysteine and thiodiacetic acid, and small amounts of glycolic acid. The amounts were estimated by isotope dilution analysis giving the following results (percentage of urinary activity): Chloroacetic acid 6–22, S‐carboxymethyl‐L‐cysteine 33–43 (free) and 1–6 (conjugated), thiodiacetic acid 33–42, glycolic acid 3–5 and oxalic acid 0.1–0.2. Carboxymethylcysteine was found to be the precursor of thiodiacetic acid but not of carbon dioxide. When glycolate‐1‐14C was given intraperitoneally, 60–70 per cent of the radioactivity was eliminated as carbon dioxide. Two metabolic pathways are suggested for chloroacetic acid: (1) A major one with an initial formation of S‐carboxymethyl glutathione which is converted to S‐carboxymethylcysteine, part of which is further metabolized to thiodiacetic acid, and (2) a minor one involving a probably enzymatic hydrolysis of the carbon‐chlorine bond with the formation of glycolic acid which is mainly oxidized to carbon dioxide.