bluuebunny/crossref_metadata_2025 huggingface dataset:
Late Seizure Recurrence after Multiple Subpial Transections
Authors: Orbach Darren , Romanelli Pantaleo , Devinsky Orrin , Doyle Werner
Published: July 2010

Summary: We studied long‐term outcome (range, 28–89 months; mean, 56 months) after multiple subpial transections (MSTs) for medically refractory epilepsy. Forty‐three (79.6%) of 54 patients had a consistent significant reduction in seizure frequency, and 27 (50%) of the 54 were either entirely seizure free or virtually so. However, 10 (18.6%) patients sustained an increase in seizure frequency several years after surgery, after showing initial postoperative improvement. This suggests that late seizure recurrence is a more important problem in cases in which MST has been performed than for pure resections.
Antiepileptic Drugs in Mood‐Disordered Patients
Authors: Gajwani Prashant , Forsthoff Anna , Muzina David , Amann Benedikt , Gao Keming , Elhaj Omar , Calabrese Joseph R. , Grunze Heinz
Published: July 2010

Summary:  Bipolar disorder is a common, recurrent, often severe mental disorder that, without adequate treatment, is associated with high rates of morbidity and mortality. We review the evidence on the efficacy of a spectrum of antiepileptic drugs (AED) in bipolar disorder. Most studies have been carried out with carbamazepine (CBZ), valproate (VPA), and lamotrigine (LTG). All three of these AEDs have been shown to be of value in the management of patients with bipolar illnesses. VPA and CBZ seem to exert stronger antimanic effects and, to a lesser degree, acute antidepressant efficacy. LTG seems to be effective against depression and mania, with a more robust activity against depression. No firm evidence supports a role for vigabatrin, tiagabine, topiramate, or levetiracetam in these disorders.
Antiepileptic Drugs and the Regulation of Mood and Quality of Life (QOL): The Evidence from Epilepsy
Authors: Selai Caroline , Bannister Debbie , Trimble Michael
Published: July 2010

Summary:  We review the literature on the influence of antiepileptic drugs (AEDs) on mood and quality of life in patients with epilepsy. Although many anecdotal reports cover a spectrum of AEDs, most of the controlled data have come from studies of carbamazepine and lamotrigine. Both of these compounds appear to have positive effects on mood, and these data parallel the effects noted in nonepilepsy populations. AEDs that are γ‐aminobutyric acid (GABA)ergic tend to have negative effects on mood, and an affective disorder is often noted as a treatment‐emergent effect. It is speculated that the amygdala is an important anatomic structure in the cerebral circuits that regulate mood in affective disorders but also in epilepsy, and an effect of AEDs on such circuits aids mood stability in both populations of patients.
The burden of normality: A framework for rehabilitation after epilepsy surgery
Authors: Wilson Sarah J. , Bladin Peter F. , Saling Michael M.
Published: July 2010

Summary  This paper describes a conceptual framework that generates a modus operandi for rehabilitation after epilepsy surgery derived from regular longitudinal and prospective follow‐up of patients and families. The framework focuses on patient experiences of undergoing surgery placed within the context of the family and broader community. It adopts a holistic view of patient care to understand the complex interactions between neurobiological and psychosocial factors that determine surgical outcome in the eyes of the patient, family, and clinical team. It emphasises the importance of anticipating postoperative adjustment issues using a preventive treatment approach.
Genetically seizure‐prone or seizure‐resistant phenotypes and their associated behavioral comorbidities
Authors: McIntyre Dan C. , Gilby Krista L.
Published: July 2010

Summary  It was questioned whether amygdala kindling, a model of temporal lobe epilepsy, is under genetic control, and is associated with comorbid behavioral features. Initially, rats were selectively bred for speed of amygdala kindling, and, in subsequent generations, were assessed in behavioral paradigms to measure activity, emotionality, impulsivity, and learning. Clearly kindling was under genetic control, as two strains were developed to be either Fast or Slow to kindle, and each was associated with different neurological, electrophysiological and behavioral features. Behaviorally, the Fast rats appear much like humans with attention deficit hyperactivity disorder (ADHD), showing easy distraction, hyperactivity and impulsivity, compared to Slow rats.
Screening for bone health in epilepsy
Authors: Sheth Raj D. , Harden Cynthia L.
Published: July 2010

Summary  Elderly and young patients with epilepsy are at risk for fractures from seizure and antiepileptic drug (AED) related falls and from epilepsy and AED related lowered bone mass. Enzyme inducing AEDs are often implicated, although, nonenzyme inducing medications may also impact epilepsy bone disease. Screening for bone health with direct measures, such as bone densitometry by dual‐energy x‐ray absorptiometry (DEXA) and indirectly via biochemical markers of bone turnover may help identify patients who are at increased risk for fractures and offer an opportunity for intervention.
The treatment of the first seizure: The risks
Authors: Perucca Emilio
Published: July 2010

Summary

The risks associated with prescribing antiepileptic drugs (AEDs) in a person who had a single unprovoked seizure fall into three domains: (1) the risk that treatment will not be effective in preventing seizure relapse, and the consequences thereof; (2) the risks of a person's life being affected by the psychological, social, and legal aspects of receiving treatment for a seizure disorder; (3) the health risks associated with intake of antiepileptic medication. This article with focus on the latter, addressing in particular concerns related to adverse drug effects. Serious or life‐threatening adverse reactions are very uncommon in people started on AEDs, although some (e.g., teratogenic effects) can be a major concern in specific patient groups. Nonserious adverse reactions leading to withdrawal of treatment are relatively common, although in most cases these are reversible following removal of the offending agent. Adverse effects associated with prolonged treatment and not leading to drug withdrawal are an important concern, because such effects are often under‐recognized and may affect significantly quality of life. Additional risks relate to the occurrence of drug–drug interactions. In all cases, risks can be minimized by careful selection of the AED to be used (with particular consideration of individual characteristics which contraindicate a specific AED, or predispose to specific adverse effects), gradual dose titration, choice of an appropriate target dose and, most important of all, careful monitoring of clinical response.
Neuroimaging in the Clinical Diagnosis of Dementia: Observations from a Memory Disorders Clinic
Authors: Borghesani Paul R. , DeMers Shaune M. , Manchanda Vivek , Pruthi Sumit , Lewis David H. , Borson Soo
Published: July 2010

OBJECTIVES: To determine how often neuroimaging confirms, clarifies, or contradicts initial diagnoses of late‐life cognitive disorders.

DESIGN: Retrospective case review.

SETTING: Outpatient clinic specializing in memory disorders.

PARTICIPANTS: One hundred ninety‐three consecutively referred cognitively impaired patients.

MEASUREMENTS: Diagnoses using research criteria were developed for each patient at the first visit and ranged from cognitive impairment without dementia to dementias of single, complex, or indeterminate etiology. Structural (noncontrast magnetic resonance imaging) and perfusion (technetium‐99m ethyl cysteine dimer single photon emission computed tomography) images were categorized together as normal, suggestive of specific diseases, or abnormal/not diagnostic.

RESULTS: When a single neurodegenerative disease was suspected clinically (n=94), imaging confirmed the diagnosis in 50, contradicted the diagnosis in 32, and was abnormal/not diagnostic in 12. When more than one neurodegenerative etiology was clinically suspected (n=21), imaging assigned a single diagnosis in 13 and only cerebrovascular disease in one and was abnormal/not diagnostic in seven. In dementia not otherwise specified (NOS) (n=33), imaging suggested a specific etiology in 23 and was abnormal/not diagnostic in 10. Abnormal/not diagnostic images were more common in cognitive disorder NOS (n=25, 68%) than in other clinical groups (22%, chi‐square=22.8 P<.001). Neuroimaging indicators of cerebrovascular disease were common (60% prevalence) but not predicted by the presence of vascular risk factors alone.

CONCLUSION: Overall, neuroimaging confirmed, clarified, or contradicted the initial clinical diagnosis in more than 80% of patients, whereas fewer than 20% had abnormal/not diagnostic patterns. Imaging suggested a complex dementia etiology in 21% of cases clinically thought to be caused by a single process, whereas 46% of complex clinical differential diagnoses appeared to reflect a single causal pattern. Further work is needed to determine whether refinement of clinical diagnoses using specialized neuroimaging improves clinical decision‐making and patient outcomes.
Antifibrillatory Effect of Some β‐Adrenergic Receptor Blocking Agents Determined by a New Test Procedure in Mice
Authors: Hermansen Keld
Published: July 2010

Mice which were exposed to high concentrations of methylchloroform (1,1,1, trichloroethane) vapour died in cardiac fibrillation. Pretreatment 30 min. before the administration of methylchloroform gave the following antifibrillatory ED50's expressed in mg/kg intraperitoneally: β‐adrenergic blocking agents: Propranolol: 1.7; (+)‐propranolol: 45; (‐)‐propranolol 0.6; 1‐(isopropylamino)‐3‐(o‐phenoxyphenoxy)‐2‐propanol, HC1 (Ph QA 33): 6.5; 1‐(isopropylamino)‐3‐(o‐allylphenoxy)‐2‐propanol, HC1 (H 56/28 = aptin®): 19; 4‐(2‐isopropylamino‐1‐hydroxyethyl) methane sulphonanilide, HC1 (MJ 1999): 24; 2‐(isopropylamino)‐1‐(p‐nitrophenyl) ethanol, HC1 (INPEA): 50; dichloroisoprenaline (DCI): no effect; α‐adrenergic blocking compounds: chlorpromazine: > 50; phenoxybenzamine, HC1 (dibenzyline®): no effect, phentolamine (regitin®): > 100. None of some commonly used antiarrhythmics: antazoline, HC1; lidocaine, HC1; phenytoin; procainamide, HC1 (pronestyl®) or quinidine sulphate had any effect. The most favourable therapeutic index (LD50/ED50) was found for (‐)‐propranolol ∼ 200. The method appears particularly suitable for evaluation of compounds with antagonistic action on cardiac β‐receptors and in this respect appears to be highly sensitive.
Evidence for Adrenergic Mediation of Ouabain induced Arrhythmias in the Guinea Pig
Authors: Hermansen Keld
Published: July 2010

Oubain in a dose of 7.5 μg/min. was infused intravenously into urethane anaesthetized guinea pigs weighing from 250–500 g. The incidence of cardiac fibrillation and the cardiotoxic dose (fibrillation, cardiac arrest) were determined in groups of (1) untreated controls. (2) adrenalectomized, (3) reserpinized, 5 mg/kg subcutaneously, (4) reserpinized + adrenalectomized, (5) reserpinized + noradrenaline pretreated animals (100 μg/kg intravenously 15 min. before ouabain). All animals were kept at a constant rectal temperature of 34°. The pressor response to tyramine (0.1 and 1 mg/kg intravenously) was tested during the same experimental conditions. All animals died in fibrillation except those in (4) in which only 50% showed fibrillation. The sensitivity to ouabain (minimal fibrillatory dose, LD100) was only slightly decreased in (2) while the LD100 was increased from 239 ± 10 μg/kg to 375 ± 15 μg/kg in (3) and 466 ± 17 μg/kg in (4). Infusion of noradrenaline into reserpinized animals caused a partial recovery of the normal ouabain sensitivity as the LD100 decreased from 375 ± 15 μg/kg to 302 ± 11 μg/kg (P < 0.001). The pressor response to tyramine showed features almost similar to the ouabain sensitivity except that the sensitivity to tyramine could not be regained by a noradrenaline infusion in reserpinized guinea pigs. The results indicate that the ouabain cardiotoxicity in the guinea pig is at least to some extent mediated through a release of catecholamines and may explain the species dependent difference in potency of some β‐adrenergic blocking agents on ouabain arrhythmias.
Studies on the Subcutaneous Absorption in Mice VIII: Influence of Connective Tissue Ground Substance on the Absorption of Subcutaneously Injected Depots of Sodium and Chloride
Authors: Secher‐Hansen E.
Published: July 2010

A standard volume of 80 μl of physiological saline or of pure water was injected subcutaneously in mice. In both cases the electrolyte composition of the depots was the same 15 minutes later, at which time the injected volumes had not been significantly reduced. The sodium concentration in the depot corresponded to that of the plasma, while the chloride concentration corresponded to approximately 50 per cent of that of the plasma. The missing anions could probably be accounted for by the non‐diffusible polyanions of the connective tissue ground substance. Radioactive sodium ions were cleared significantly more slowly than radioactive chloride ions, these in turn being significantly slower than the radioactive water molecules, after the subcutaneous injection of physiological saline or water depots containing the radioactive ions in tracer concentrations.
Experimentally Induced Cough in Man by Citric Acid Aerosol. An Evaluation of a Method
Authors: Winther Finn Ø.
Published: July 2010

Ten healthy males underwent three test periods with an interval of one hour. Each test period consisted of five inhalations of a citric acid aerosol. The number of coughs after each inhalation was registered. A placebo tablet was given immediately after the first test period. Statistical analysis of the results showed a small reduction in the number of coughs from the first to the second test period, but no significant reduction from the second to the third test period. The reduction might have been due to a placebo reaction. It is concluded that the method may be useful in evaluating an antitussive agent provided the investigation is carried out as a double blind test with placebo.
The Influence of 2,4‐Dinitrophenol on Metabolic Changes Caused by Ethanol in the Perfused Rat Liver
Authors: Vendsborg P. B. , Schambye P.
Published: July 2010

The experiments were undertaken in order to investigate the mechanism by which ethanol inhibits the tricarboxylic acid cycle. Isolated livers were perfused with human erythrocytes suspended in an artificial “plasma”. Ethanol was added 45 min. after the start of the perfusions. In some experiments dinitrophenol was added after ethanol. The O2 consumption in the perfused rat liver was unaltered by the addition of ethanol to the medium, whereas the CO2 production fell considerably, resulting in a decrease in the RQ from 0.8 to 0.4. The addition of ethanol caused an increase in both lactate/pyruvate and hydroxybutyrate/acetoacetate ratios in the perfusion medium. When DNP was added to the perfusion medium, half an hour after the addition of ethanol, both the O2 uptake and CO2 production increased. The RQ increased from 0.4 to 0.6. The lactate/pyruvate ratio was increased by the addition of DNP because the amount of lactate liberated from the liver was increased, while the pyruvate concentration was almost unchanged. The addition of DNP caused a fall in the hydroxybutyrate/acetoacetate ratio from 2.2 to 0.6, and a net disappearance of ketone bodies was observed. An opposite change in the extra‐ and intramitochondrial NADH/NAD ratio was observed, favouring the hypothesis that they are really independent of each other. A correlation between the intramitochondrial NADH/NAD ratio and the tricarboxylic acid cycle inhibition was demonstrated.
Prevention of Mephenesin Intoxication by Catatoxic Steroids
Authors: Selye Hans
Published: July 2010

The purpose of these experiments was to determine whether pretreatment with certain steroids could protect against mephenesin poisoning. In rats, the muscular paralysis (gaged in terms of an arbitrary scale) and the mortality induced by mephenesin (30–60 mg/100 g body weight given subcutaneously) are inhibited by various catatoxic steroids such as ethyloestrenol, SC‐11927, spironolactone and norbolethone (10 mg/100 g body weight twice daily by stomach tube) beginning four days before treatment with the muscle relaxant. Conversely, under comparable conditions, steroids previously shown to possess little or no catatoxic potency in other test systems (prednisolone, progesterone, oxandrolone, triamcinolone, desoxycorticosterone, hydroxydione) exhibited no protective effect under the same conditions. Apparently, the protective effect of various steroids against mephenesin intoxication parallels their catatoxic potency in other tests.
The Effects of Guanethidine, Pre‐ and Postganglionic Nerve Division on the Rat Superior Cervical Ganglion: Cholinesterases and Protein
Authors: Jensen‐Holm Jens , Juul Per
Published: July 2010

Administration of guanethidine (20 mg/kg for 8–14 days) to rats induced a pronounced reduction in the activity of specific and non‐specific cholin‐esterase accompanied by an increase of protein content of the superior cervical ganglion. These effects were not changed by pre‐ or postganglionic nerve division. Consequently a direct ganglionic effect of guanethidine is assumed. Iso‐prenaline and propranolol had no effects on the parameters measured, and these drugs did not influence the action of guanethidine. Hence the ganglionic changes induced by guanethidine do not seem to be due to a beta‐stimulating activity. A few other drugs were investigated: furosemide, pentolinium, atropine, phentolamine, desipramine, and alpha‐methyldopa, but none of these caused any significant changes in the ganglionic cholinesterases and protein. Bethanidine eventually induced cholinesterase changes similar to those of guanethidine, but further studies are needed.
Central and Peripheral Effects of Anticholinergic Compounds
Authors: Albanus Lennart
Published: July 2010

The pharmacological effects of aryl and cycloalkylaryl glycolates of piperidin, tropine and quinuclidin have been studied in relation to atropine and scopolamine. Peripheral effects (heart rate, salivation, pupil size) have been studied in dogs in relation to their behavioural effects under standardized conditions. The anticholinergic activity was further investigated on the mouse pupil and on the blood‐pressure response to acetylcholine in cats anaesthetized with pentobarbital. In dogs all the glycolates elicited behavioural effects, especially on locomotion, similar to those seen following atropine and scopolamine. Even high doses of methyl atropine produced effects indistinguishable from those produced by atropine and scopolamine. The most active compounds affected behaviour at a dose of 10 μg per kilogram body weight given subcutaneously. All compounds elicited anticholinergic activity i.e. tachycardia, mydriasis, inhibition of salivation and block of AcCh response. The most potent compounds on behaviour were quinuclidinylesters of phenyl and/or thienyl glycolic acid which also had the strongest and most prolonged classical anticholinergic effects. The results indicate that behavioural effects are related to anticholinergic activity but that other factors such as lipid‐solubility and metabolism interfere with the central activity.
The Effect of d‐Tubocurarine on the Kinetics of Decamethonium Uptake by Mouse Kidney Slices
Authors: Holm Jan
Published: July 2010

The effect of d‐tubocurarine on the kinetics of the decamethonium uptake by mouse kidney slices was studied. Slices were incubated (1 hour) in a Krebs‐Ringer bicarbonate medium (37°, pH 7.4) in the presence of14C‐decame‐thonium and d‐tubocurarine. With increasing d‐tubocurarine concentration the14C‐slice‐to‐medium concentration ratio decreased towards a constant value (1.3) regardless of the decamethonium concentration used. The decamethonium uptake can thus be divided into two components, one which is sensitive to d‐tubocurarine (curare‐sensitive) and one which is not (curare‐insensitive). The latter component increased proportionally with the external decamethonium concentration. The curare‐sensitive component, which showed saturation with increasing decamethonium concentration, had a maximum capacity of 1100–1280 μM kg‐1, h‐1and a half saturation concentration of 175–180 μM. The latter component was inhibited by d‐tubocurarine with an inhibitor constant of 12 μM and the inhibition was in accordance with competitive antagonism. The result suggest that decamethonium is taken up by two distinct processes, one mediated by a carrier and one by a passive diffusion into the cells. Furthermore the carrier is common to both decamethonium and d‐tubocurarine.
Effect of Benzanthrone on the Body Level of Ascorbic Acid in Guinea Pigs
Authors: Pandya K. P. , Singh G. B. , Joshi N. C.
Published: July 2010

The effect of benzanthrone on the blood, adrenal and liver ascorbic acid levels in adult male guinea‐pigs has been investigated. Benzanthrone and ascorbic acid were administered intraperitoneally and orally in doses of 25 mg and 50 mg/kg body weight respectively. Benzanthrone alone caused significant decrease of ascorbic acid levels in the blood, adrenal and liver. Supplementation of ascorbic acid appreciably restored the blood ascorbic acid. However, adrenal and liver ascorbic acid levels were restored only to some extent. Histochemical examination of ascorbic acid in the adrenal revealed almost similar changes. The mortality rate due to benzanthrone toxicity (500 mg/kg) was lowered by 40% in non‐scorbutic as compared to scorbutic guinea‐pigs.
Inhibition of Carrageenin‐Induced Rat Paw Oedema by Substances Causing a Reduction of Kininogen and Prekallikrein in Plasma
Authors: Briseid Kjell , Arntzen Finn Cato , Dyrud Olav Kjell
Published: July 2010

The acute, anti‐inflammatory effect of bradykinin, ellagic acid, hista‐mine, padutin ®, serotonin, trasylol® and trypsin was tested against carrageenin‐induced rat paw oedema, and the in vivo effects of the same substances on parameters of the plasma kinin system was also examined. The substances were injected intraperitoneally and oedema was induced half an hour later. Groups of 5 test‐ and 5 control rats were used, and measurements of initial paw volumes and of volumes after 1, 2 and 3 hours were used for calculating the inhibition values. All the substances tested, except padutin, inhibited the development of oedema and except for padutin and trasylol, caused a fall in total kininogen. Apart from bradykinin and padutin, the substances also reduced the amount of pre‐kallikrein. The kininogen fractions activated by rat plasma kallikrein and by rat urine kallikrein were determined in order to calculate the 3 kininogen fractions S1I, s1II and S2 (Briseid et al. 1970a). All the substances tested caused a fall in the amount of S1II and only trypsin in the amount of S1I, while none of the substances altered the amount of S2. A significant correlation between the effects on factors involved in the plasma kinin system and the anti‐oedema effects provides evidence for the presence of a causal relationship.
Metabolism of Chlorpromazine andp‐Nitrobenzoic Acid in the Liver, Intestine and Kidney of the Human Foetus
Authors: Pelkonen Olavi , Vorne Martti , Jouppila Pentti , Käarki Niilo T.
Published: July 2010

The ability of the liver, intestine and kidney to metabolize chlor‐promazine (CPR) andp‐nitrobenzoic acid (NBA) was studied in the human foetus. Low levels of CPR metabolizing activity were present in all the tissues studied, but only the liver and intestine were capable of metabolizing NBA. We were not able to detect any cytochrome P‐450 in the liver microsomal fraction. The enzymes metabolizing CPR and NBA are located in the liver microsomes, they require NADP and the 100,000 × g supernatant fraction or NADPH2for full activity, are inhibited by carbon monoxide, and have Michaelis constants of the same order of magnitude as found in the enzymes from experimental animals. The above mentioned characteristics of the foetal enzymes strongly suggest that they belong to the same class of NADPH2‐dependent mixed function oxidases which are detected in the livers of adult humans and animals and which are thought to be responsible for the greater part of oxidative and reductive drug metabolism.
Methaemoglobin Formationin Vitroby 6‐Amino Metabolites of DNOC and DNBP
Authors: Frøslie Arne
Published: July 2010

The six compounds DNOC, DNBP, 6‐ANOC, 6‐ANBP, 6‐AcANOC and 6‐AcANBP were investigated for their methaemoglobin‐forming effect on bovine erythrocytesin vitro, and also, for comparative reasons, on erythrocytes from horse, dog, pig and man. Only the amino‐nitrophenols showed any methaemoglobin‐forming effect. The activity was somewhat different for the different species, the haemoglobin in dog erythrocytes in particular being more easily oxidized than the haemoglobin in erythrocytes from the other species. Differences were also recorded between the two amino‐nitrophenols, 6‐ANOC being more active than 6‐ANBP in the bovine erythrocytes, while 6‐ANBP was more active in the pig and horse erythrocytes. In the dog and man there was a little difference between the two substances. The results are discussed in relation to the di‐nitrophenols' comparative toxicology, in particular in relation to the ruminants' special position as regards the metabolism and the toxicity of these substances.
Studies on the Reaction of Chloromethane with Human Blood
Authors: Redford‐Ellis M. , Gowenlock A. H.
Published: July 2010

Chloromethane was shown to react with human plasma and erythrocytes. Using 14C‐CH3Cl, it was found that in plasma radioactivity was bound only by albumin. On hydrolysis the major reaction product was S‐methylcysteine; small amounts of 1‐ and 3‐methylhistidine were found. In plasma, the bound radioactivity corresponds to only 2–3% of the uptake measured using unlabelled CH3Cl, suggesting that other, unidentified volatile products are formed. In erythrocytes, approximately 40% of the uptake was bound by GSH forming S‐methylglutathione. The reaction appeared to be enzyme‐catalysed. Loss of thiol groups of plasma protein and erythrocytes and inhibition of oxygen uptake of erythrocytes could not be demonstrated. S‐Methylglutathione was neither lost from erythrocytes during separation and washing, nor was it hydrolysed. It is postulated that some of the cases of anaemia reported following exposure to chloromethane may be due to lack of erythrocyte GSH.
Studies on the Reaction of Chloromethane with Preparations of Liver, Brain and Kidney
Authors: Redford‐Ellis M. , Gowenlock A. H.
Published: July 2010

Chloromethane reacted with rat and guinea pig brain, liver and kidney. Using 14C‐CH3Cl with rat tissue homogenates, the bound radioactivity corresponded with the uptake in the liver and kidney but was lower in the brain. 14C‐S‐methylglutathione (GSMe) and 14C‐S‐methylcysteine (S‐MeCys) were formed by liver, which did not hydrolyse 14C‐GSMe, so that the 14C‐S‐MeCys must have been formed directly. Both reactions appear to be enzyme‐catalysed. In the kidney and brain, 14C‐S‐MeCys and 14C‐GSMe were formed and methylation of cysteine SH‐groups in the mixed insoluble proteins was demonstrated. Traces of radioactivity were found in methionine in the kidney proteins. The kidney and brain homogenates hydrolysed 14C‐GSMe. Rapid losses of radioactivity during processing in some kidney experiments suggest that volatile products are formed, but this is not due to fission of S‐methyl groups of S‐MeCys or GSMe. The level of binding was lower in heated tissues, especially in the water‐soluble fraction. Inhibition of respiration of rat brain and inhibition of two thiol‐dependent enzymes could not be demonstrated. It is suggested that loss of GSH and intracellular accumulation of GSMe may account for some of the clinical features of intoxication.
The Distribution and Metabolism of Cortisol under the Influence of Non‐Steroidal Antirheumatic Drugs
Authors: Jansen Jens Aas , Schou Jens
Published: July 2010

Guinea pigs were pretreated for three days with two daily doses of sodium salicylate 400 mg/kg (S), phenylbutazone 24 mg/kg (P) or indomethacin 8 mg/kg (I). None of the drugs produced any effects on the concentrations of cortisol in the plasma, plasma ultrafiltrate or the skin which were significantly different from the control values. The values found after S were, however, higher than after P. The biological half life (t1/2) of exogenous 4‐14C‐cortisol and the apparent volume of distribution (Vd) was unchanged by S. P tended to increase Vd while I tended to produce a reduction. The results do not support the theory of a displacement of cortisol from plasma protein as a basis for the antirheumatic effect of the drugs.
Effects of Sexual Hormones on the Adrenergic Innervation and the Monoamine Oxidase Activity in the Rat Ventral Prostate
Authors: Müntzing Jonas
Published: July 2010

Intact and castrated rats were injected intramuscularly with polyoestradiol phosphate, (PEP), (estradurin®), 8 mg/kg, or with vehicle. Other rats were castrated and injected intramuscularly with testosterone‐hexyloxyphenyl‐propionate (A), (andradurin®), 60 mg/kg, alone or in combination with PEP. After 20 days the adrenergic innervation of the ventral prostate was studied histochemically. It was found that the normally sparse innervation, restricted to the stroma, was markedly increased by those treatments which reduced the androgenic influence on the prostate. This increased innervation was accompanied by an increase of histochemically and biochemically demonstrable monoamine oxidase (MAO).
The Binding of Toluidine Blue and Chlorpromazine to Isolated Rat Mast Cell Granules
Authors: Popova Anna D. , Slorach Stuart A. , Uvnäs Börje
Published: July 2010

The uptake and release of toluidine blue (ToB) and chlorpromazine (CPZ) by isolated rat mast cell granules and the displacement of histamine from such granules by these two substances have been studied in order to elucidate the mode of binding of ToB and CPZ to mast cell granules. The uptake maxima for both ToB and CPZ were found to exceed greatly the uptake maximum for histamine (> 10 mμmol cf. 2.5 mμmol per μg granule protein). ToB‐loaded granules exposed to increasing concentrations of CPZ progressively released the dye and took up CPZ. This provides support for the hypothesis advanced by Popova (1965) that the loss of colour and the acquisition of fluorescence by mouse mast cells stained supravitally with ToB and then exposed to CPZ is due to a displacement of the dye from its granule binding sites by CPZ. It is not possible from the present study to define precisely the mode of binding of ToB or CPZ to rat mast cell granules. The binding appears to be more complex than the simple ionic binding to a cationic binding site which has been proposed for histamine (Uvnäset al.1970).
The Influence of Benzquinamide, Oxypertine and Prenylamine on Monoamine Levels and on Monoamine Effects in the Spinal Cord
Authors: Andén Nils‐Erik , Fuxe Kjell
Published: July 2010

Benzquinamide (100 mg/kg given intraperitoneally), oxypertine (60 or 65 mg/kg given intraperitoneally) and prenylamine (30 mg/kg given intraperitoneally), like reserpine (2.5 mg/kg, intraperitoneally), all produced a reduction of the spinal cord noradrenaline and 5‐hydroxytryptamine levels both cranial and caudal to a spinal cord transection in rats, indicating an effect independent of nerve impulses. All four drugs lowered the noradrenaline levels more than 5‐hydroxytryptamine and increased the flexor reflex activity after monoamine oxidase inhibition. These findings support the view that benzquinamide, oxypertine and prenylamine have a reserpine‐like mode of action. However, the increase in flexor reflex activity obtained after treatment with L‐3,4‐dihydroxphenylalanine was reduced by benzquinamide and oxypertine but not by prenylamine, thus also suggesting a noradrenaline receptor blocking action of the former two drugs.
Metatyrosine‐Induced Reversal of the Suppression of the Conditioned Avoidance Response in Reserpine‐Treated Rats
Authors: Engel Jörgen
Published: July 2010

DL‐Metatyrosine (200 mg/kg intraperitoneally) administration after peripheral DOPA decarboxylase inhibition caused a temporary reversal of reserpine‐induced (5 mg/kg intraperitoneally) suppression of a conditioned avoidance response in the rat, both with and without pretreatment with a dopamine‐β‐hydroxylase inhibitor, bis‐(4‐methyl‐1‐homopiperazinylthiocarbonyl)‐disulfide, (FLA‐63, 10 mg/kg intraperitoneally); but the duration of the reversal was shorter after FLA‐63. After the injection of DL‐metatyrosine there was a rapid and marked accumulation of metatyramine and a smaller accumulation of the β‐hydroxylated metabolite, metaoctopamine. FLA‐63 pretreatment prevented the metaoctopamine accumulation. Some of the behavioural effects observed after DL‐metatyrosine may be due to displacement of endogenous noradrenaline not depleted by reserpine. The increase in locomotor activity after DL‐metatyrosine was not affected by the dopamine‐β‐hydroxylase inhibitor. The results provide further support for the hypothesis that dopamine is important for elementary motor functions (e.g. locomotor activity) whilst additional noradrenaline receptor stimulation is essential for more complex and integrated hebaviour (e.g. a conditioned avoidance response).
Plasma Protein Binding of Diphenylhydantoin in Man
Authors: Lunde Per Knut M.
Published: July 2010

Abstract:The plasma protein binding of diphenylhydantoin (DPH) in heparinized plasma from adult volunteers, DPH‐treated adult patients with epilepsy, normal and hyperbilirubinaemic newborn infants was investigated, using an ultrafiltration technique (14C‐labelled DPH). At room temperature (16 μg DPH/ml plasma) the bound fraction of DPH in 15 adult volunteers and 13 normal infants (cord blood) was 92.6 ± 0.7 and 89.4 ± 1.4 %, respectively. At 37° the unbound fraction of DPH was increased by some 60 %. Similar data were obtained in adult patients. Among a series of 15, mostly acidic drugs addedin vitroin concentrations which may be obtained during therapy, only salicylic acid, sulfafurazole and phenylbutazone caused marked decrease in DPH‐binding. Dilution experiments showed different patterns with regard to the bound and the unboundamounts(μg/ml) of DPH, depending on whether plasma was diluted only (constant DPH‐concentration) or both DPH and plasma were diluted to the same extent. In a group of 20 hyperbilirubinaemic newborn infants a correlation existed between the unbound fraction of DPH and the total concentration of plasma bilirubin. A competition between DPH and bilirubin for similar binding sites on the albumin molecule is suggested.
Generic Inequivalence ‐ Clinical Observations
Authors: Prescott Laurie F. , Nimmo John
Published: July 2010

Abstract: Different preparations of a drug containing the same amount of active chemical in stable form are “chemically equivalent”. Unless they have identical biological activity under clinical conditions, however, they cannot be considered generic equivalents. Differences in drug formulation affecting availability for absorption are a frequent cause of generic inequivalence. The truth of the matter is that although drug formulation has been studied extensively in vitro, the clinical significance and extent of generic inequivalence is unknown. Minor changes in the formulation of prednisone, diphenylhydantoin and dicoumarol produced alarming variation in clinical effect, although each preparation conformed to official standards. In experimental studies, generic inequivalence has been demonstrated in preparations of tolbutamide, phenacetin, nitrofurantoin, chloramphenicol, tetracycline and a combination of triamterene and hydro‐chlorothiazide. In some cases, inequivalence could be explained by differences in tablet disintegration, dissolution rate and particle size. Preliminary studies with different dosage forms of paracetamol suggest that significant generic inequivalence might occur with some drugs only in certain individuals (“slow absorbers”). The risk of generic inequivalence is increased with enteric coated and delayed release preparations since absorption may be poor and erratic. Apart from active drug, modern tablets and capsules usually contain many other substances. Some of these may occasionally contribute to generic inequivalence in the form of unsuspected toxicity.
In Vitro Studies on the Uptake of 14C‐Labelled Tetraethylammonium in Mouse Kidney*
Authors: Holm Jan
Published: July 2010

Tetraethylammonium (TEA) uptake was studied in mouse kidney slices. The slices were incubated in Krebs‐Ringer bicarbonate medium (37°, pH 7.4) containing 14C‐TEA, and the 14C‐slice‐to‐medium (S/M) concentration ratio was measured. TEA (2 μM) was rapidly accumulated in oxygen‐carbon dioxide (95:5) atmosphere, and a steady state with S/M ratio approximating 20 was obtained within 1/2 hr. The radioactive material extracted corresponded chromato‐graphically to authentic TEA. The S/M ratio was significantly reduced in the presence of metabolic inhibitors or various quaternary and tertiary amines. In nitrogen‐carbon dioxide (95:5) atmosphere the S/M ratio (2 μM) reached a constant value around 1 within 1/2 hr. Incubation at 19° markedly depressed the 3 min. S/M ratio, but had no effect on the steady state S/M ratio (1/2 hr). Under anaerobic conditions TEA uptake (mmol/kg tissue; 1/2 hr incubation) was directly proportional to the external TEA concentration. The aerobic uptake consisted of two components: a saturable one (maximum capacity 2 mmol/kg; half saturation concentration 140 μM) and one that increased proportionally with the external concentration. It is concluded that TEA is taken up against a concentration gradient by a saturable, energy dependent process which is inhibited by structural analogues.
Cortisol Distribution and Metabolism in Guinea Pigs after High Doses or Treatment for Three Weeks with Indomethacin, Phenylbutazone or Chloroquine
Authors: Jansen Jens Aas , Schou Jens
Published: July 2010

Guinea pigs were pretreated for three days with two daily doses intra‐peritoneally of phenylbutazone 100 mg/kg (P) or indomethacin 100 mg/kg (I ‐ 100 × 6), or for three weeks with daily single intraperitoneal injections of indomethacin 20 mg/kg (I ‐ 20 × 21) or chloroquine 35 mg/kg (C). P increased the total plasma concentration of cortisol from 441 ± 39 to 658 ± 85 ng/ml (P < 0.05) while there were no significant changes in skin cortisol (101 ± 18 to 163 ± 24 ng/g) or plasma ultrafiltrate cortisol (119 ± 12 to 179 ± 45). I ‐ 100 × 6 did not significantly change the cortisol concentrations in the plasma 630 ± 105, skin 155 ± 60 or ultrafiltrate 184 ± 62. I ‐ 20 × 21 and C caused no change in the cortisol values. The concentration of cortisol in the skin, however, is well correlated to the concentration of freely diffusible cortisol in the plasma, and for I‐100 × 6 there was a good correlation between the concentration of the drug in the plasma and the percentage of ultrafiltrable cortisol in the plasma. None of the drug treatments changed the plasma half‐life (t1/2) of exogenous 4‐14C‐cortisol significantly. I and C did not change the apparent volume of cortisol distribution, while P tended to increase the volume. The results do not support the theory of a displacement of cortisol from the plasma protein as a basis for the antirheumatic effect of the drugs.
On the Elimination of 5‐Hydroxyindoleacetic Acid and Homovanillic Acid from Cerebrospinal Fluid
Authors: Anderson Hugo , von Esen Clam , Roos Björn‐Erik
Published: July 2010

Abstract:The effect of carinamide, probenecid and zoxazolamine was studied in the brain and cerebrospinal fluid of the dog, rabbit and rat. There were considerable differences between these species with regard to the effectiveness of the active out‐transport mechanism for acid monoamine metabolites.
5‐Hydroxyindole Acetic Acid and Homovanillic Acid in Cerebrospinal Fluid after Intrathecal and Intravenous Administration of Probenecid to Normal and Hydrocephalic Dogs
Authors: Andersson Hugo , von Essen Claes , Roos Björn‐Erik
Published: July 2010

Abstract:This study has shown that intrathecal instillation of probenecid gives a lower elevation of the acid metabolites than intravenous administration of the drug, providing the concentration of the drug in the cerebrospinal fluid is the same. Furthermore, we have reason to believe that it is possible to block almost completely the active out transport of 5‐hydroxyindole acetic acid from the cerebrospinal fluid by high doses of probenecid given intravenously or intrathecally. This does not seem to be the case with homovanillic acid.
Substrates for Kinin‐Releasing Enzymes in Human Plasma
Authors: Briseid Kjell , Venneröd Anne Marie , Andrew Erik
Published: July 2010

Abstract:Indirect evidence has been provided of the presence of 3 kininogen fractions: The average amounts of kinin released by human plasma kallikrein (1.2 μg/ml plasma) and by human urine kininogenase (2.4 μg/ml plasma) when added up exceeded the amount of kinin released by combined use of the two enzyme preparations (3.0 μg/ml plasma). Methods were as described by BRISEIDet al. (1968). It is suggested that plasma kallikrein released kinin from 2 kininogen fractions, SI′ and SI″, and that urine kallikrein released kinin from 2 kininogen fractions, S1″ and S2. Repeated incubation with each of the kininogenase preparations did not increase the yield of kinin. Soybean trypsin inhibitor did not reduce the amount of kinin released by urine kallikrein. In control experiments a leucine aminopeptidase preparation transformed kallidin to bradykinin, but did not increase the kinin activity of the urine kallikrein incubates. Experiments carried out . with plasma kallikrein and padutin in 60°‐heated plasma supported the assumption of the 3 kininogen fractions.
Absorption and Elimination of Polychlorinated Biphenyls (PCB) in Goldfish*
Authors: Hattula Marja Liisa , Karlog Ole
Published: July 2010

Abstract: The absorption, accumulation and elimination of PCB (Clophen A50) in goldfish was studied. To ensure well‐defined and reproducible PCB concentrations in the water phase (0.01, 0.05, 0.10 and 0.50 p.p.m.) the experiments were made in aluminium foil containers. A rapid uptake and accumulation was observed but only slight changes in the relative composition of the absorbed PCB's were found. In the elimination experiment it was found that the content of PCB in the fish was halved during the first three weeks of the experimental period but that the half‐life for PCB rose during the experiment.
The Distribution Pattern of a Series of Tricyclic and Bicyclic Thymoleptics Compared with their Lipophilic Properties and Binding to Plasma Proteins
Authors: Jørgensen A. , Hansen V. , Overø K. Fredricson
Published: July 2010

Abstract: Eight thymoleptic drugs were labelled with carbon‐14. Four of the drugs were of the tricyclic type (amitriptyline/nortriptyline and melitraced litracen), the others belonged to the bicyclic phthalane and thiophthalane structures. The drugs were given intravenously to male albino rats in doses of 5 mg/kg. At fixed times after injection the animals were killed by exsanguination. Blood was collected and examined together with different organs for contents of radioactivity. Chromatographic estimations were made on extracts of the brain. The relative lipophilic properties of the drugs were determined as well as the binding to plasma proteins. The concentration of radioactivity in the lungs was in all cases higher after a secondary than after the corresponding tertiary amitte. In the brain the initial concentrations were highest after the tertiary amines, but at later periods the concentrations were almost the same after a tertiary and the corresponding secondary amine. Among the tertiary and the secondary amines, respectively, the drugs of the tricyclic type showed the highest brain concentrations. The chromatographic estimations of brain extracts showed that after the administration of a tertiary amine, the parent drug accounted for almost all radioactivity, while after a secondary amine the N‐demethylation product was present in considerable amounts. The lipophility studies showed that the tertiary amines were in all caws much more lipophilic than their corresponding secondary amines. The data for the binding to plasma proteins did not show any general trend. It is concluded that the penetration of drugs into the brain is only partly explained by the lipophility of the drugs. The binding to plasma proteins does not seem to influence the distribution.

Particular attention is drawn to the astonishing finding, that more N‐demethylated metabolites are found after secondary amines than after tertiary amines, though the latter are N‐demethylated at a higher rate.
Modification by L‐DOPA Methylester (H 19/61) of Amphetamine‐Induced Brain Catecholamine Changes, Thermal Responses and Toxicity in Developing Mice
Authors: Alhava Eeva
Published: July 2010

Abstract:The effect of 150 mg/kg of L‐DOPA methylester on brain catecholamines was studied in adult and developing mice aged 3‐5 days and 13‐15 days. Noradrenaline was moderately increased in the developing brain but dopamine showed a manyfold increase. The increase of dopamine was less pronounced in adult brain. High doses of dl‐amphetamine (50‐160 mg/kg) injected to L‐DOPA pretreated mice further increased the dopamine levels in the developing brain. The adult brain catecholamines were remarkably depleted, provided the observation period was 4 hours after amphetamine. Amphetamine lowered the body temperature in mice aged 13‐15 days; the fall was dose‐dependent and potentiated by pretreatment with L‐DOPA. In adult mice amphetamine caused hyperthermia which was not modified by L‐DOPA. L‐DOPA did not change the mortality rates induced by amphetamine in developing mice, but infant mice pretreated with L‐DOPA showed a lower brain amphetamine concentration after death than the mice given amphetamine only. In adult mice GDOPA enhanced amphetamine toxicity. Special attention is paid to the importance of different turnover rates of catecholamines during development as well as to the complex action of amphetamine on enzymes regulating catecholamine turnover. It is assumed that the hypothermia of developing mice after amphetamine might result from the primary effect of amphetamine on dopaminergic mechanisms.
The Effect of Dopamine and Noradrenaline Antagonists on Amphetamine Induced Locomotor Activity in Mice and Rats
Authors: Rolinski Zbigniew , Scheel‐Krüger Jørgen
Published: July 2010

Abstract:The effect of noradrenaline antagonists, aceperone, phenoxybenzamine and dihydroergotamine and neuroleptic drugs with dopamine receptor blocking properties, i. e. haloperidol, perphenazine, trifluperazine, spiramide and pimozide was tested on the locomotor and rearing activity induced by amphetamine, 2.5 mg/kg, in rats. In general it was found that the neuroleptic drugs in very low doses, haloperidol, 0.10 mg/kg; perphenazine, 0.05 mg/kg; trifluperazine, 0.15 mg/kg; spiramide, 0.05 mg/kg and pimozide, 0.15 mg/kg produced complete inhibition of the amphetamine activities, whereas much higher doses of aceperone, 20 mg/kg and phenoxybenzamine, 20 mg/kg only produced partial antagonism. Dihydroergotamine (20 mg/kg) produced no significant effect on the amphetamine locomotor and rearing activity. In mice trifluperazine (0.2 and 0.4 mg/kg) produced a very marked inhibitory effect, whereas spiramide (0.15 and 0.20 mg/kg) produced a significant but short‐lasting effect on the locomotor activity after 4 and 8 mg/kg d‐amphetamine. Aceperone (5 and 10 mg/kg) and phenoxybenzamine (10 mg/kg) also produced a strong antagonistic effect on the motility. Furthermore α‐methyltyrosine (250 and 350 mg/kg), an inhibitor of the biosynthesis of dopamine and noradrenaline, produced complete inhibition, whereas FLA‐63 (20 and 40 mg/kg), an inhibitor of the formation of noradrenaline produced partial inhibition. In conclusion these results indicate that the locomotor effect in mice and rats after amphetamine is dependent on both dopaminergic and noradrenergic mechanisms. However, dopamine may be regarded as most significant, since the amphetamine motility only seems possible in the presence of functional active dopamine receptors.