bluuebunny/crossref_metadata_2025 huggingface dataset:
The Combined Effect of Ethanol and Phenobarbital on the Activities of Hepatic Drug Metabolizing Enzymes in Rats
Authors: Luoma P. , Vorne M.
Published: July 2010

Abstract:The effect of feeding ethanol (15 % v/v) and/or phenobarbital (0.05 % w/v) in drinking water on the rate of metabolism of methylaniline andp‐nitrobenzoic acid, and on the microsomal protein and cytochrome P‐450 contents in rat liver was studied. Animals treated with ethanol for 3 days showed an increase in N‐demethylation of methylaniline of 88 %, whereas the nitroreduction of p‐nitrobenzoic acid was inhibited by 47 %. Ethanol and phenobarbital had a synergistic action on N‐demethylation. Ethanol inhibited the induction of nitroreduction by phenobarbital. Ethanol, like phenobarbital, increased microsomal protein and they acted synergistically in this respect. Ethanol, like phenobarbital, caused a significantly greater increase in rnicrosomal cytochrome P‐450 than in microsomal protein content, and they also acted synergistically on cytochrome P‐450.
Metabolism of Alprenolol in Liver Microsomes, Perfused Liver and Conscious Rat
Authors: Borg K. O. , Eklund B. , Skånberg I. , Wallborg M.
Published: July 2010

The affinity and metabolism of alprenolol, a β‐receptor antagonist, in rat liver microsomes, perfused liver and in the conscious rat were studied. Alprenolol elicited a type I difference spectrum with a spectral dissociation constant, Ks, of 0.34 μM. The apparent Michaelis‐Menten constant, Kmin rat liver microsomes was 25 μM and in the 9000xg supernatant fraction 17 μM. In re‐circulating perfusions of rat liverin situalprenolol at an initial concentration of 4.3 μg/ml was rapidly eliminated from the perfusate with a clearance close to the flow rate of the perfusate. The concentration in the perfusate of total metabolites increased rapidly to a high level. In conscious rat with permanent cannulas the blood concentration of alprenolol was determined after intravenous and oral administration of 2.0 mg/kg. The bioavailability of orally given alprenolol was 4 per cent of the given dose. The elimination after intravenous administration was bi‐exponential with a half‐life time of the β‐phase of about 40 minutes.
Studies on the Role of Calcium in the Anaphylactic Histamine Release from Isolated Rat Mast Cells
Authors: Grosman Nina , Diamant Bertil
Published: July 2010

The anaphylactic histamine release from isolated, sensitized rat mast cells was studied. Before incubation the mast cells were kept concentrated (106cells/ml) in either calcium‐free buffer (these cells are denoted Mc) or buffer containing 1 mM‐CaCl2(denoted McCa). The cells were diluted 100 to 400 times when exposed to antigen. The histamine release from Mc and McCa exposed to antigen plus CaCl, was identical, but significantly lower than observed for McCa incubated with antigen alone. EDTA (1 mM) abolished the effect of CaCl2in the incubation medium. Pre‐incubation of McCa in the absence of calcium decreased the response to antigen, and optimal reduction of histamine release was observed within one minute at 37° and five minutes at 21°. The time courses for the anaphylactic histamine release in the presence of calcium from Mc and McCa were identical at both 21° and 37°. The release from McCa in the absence of calcium was considerably faster at both temperatures.
Pentazocine and Aspirin for Pain Following Oral Surgery
Authors: Ahlström Ulf , Kahnberg Karl‐Erik , Roos Björn‐Erik
Published: July 2010

In a double‐blind clinical study, a comparison was made of pentazocine, aspirin and placebos, in varying dosage levels, following oral surgery. These were administered orally to 378 patients during the first 24 hours following surgical removal of impacted mandibular third molars. The patients were divided into eight groups which were found to be homogeneous with respect to age, sex, weight and eruptive state of the tooth involved. They were given pentazocine at four dose levels and aspirin and placebos at three dose levels. In all 60 patients had no pain during the 24 hours following surgery. There were no significant differences in between the results among the eight patient groups, with regard to which drug they had received. The majority of patients slept well. However, patients who received aspirin slept significantly better than those receiving pentazocine or placebos. Of 136 patients reporting side effects, there were significantly more complaints from the patients taking pentazocine than from those treated with aspirin or placebos.
Decreased Cardiac Toxicity of Adriamycin and Daunorubicin when Bound to DNA
Authors: Langslet Asbjørn , Øye Ivar , Lie Sverre O.
Published: July 2010

The acute cardiotoxic effects of adriamycin and daunorubicin have been studied in isolated, perfused rat hearts. Both drugs caused a dose‐dependent decrease in rate and contractile force as well as changes in the ECG indicating a general retardation of impulse propagation. The presence of 0.47 mg/ml of herring sperm DNA in the perfusate greatly reduced the cardiotoxic effect of both drugs. The reduced toxicity is probably due to the binding of the drugs to DNA.
The Irritant Effects of Dilute Solutions of Dibenzoxazepine (CR) on the Eye and Tongue
Authors: Ballantyne Bryan , Swanston D. W.
Published: July 2010

Median threshold concentrations for the sensory irritant material dibenz(b.f)‐1:4‐oxazepine (CR) to produce blepharospasm were found to be 7.9 × 10‐5 M for the rabbit, 3.5 × 10‐5 M for the guinea pig and 8.6 × 10‐7 M for man. The threshold concentration to produce sensation on the human eye was 4.9 × 10‐7 M. Extrapolation of log‐probit plots for sensation on the human eye suggests that 3.3 × 10‐6 M would be incapacitating. The median threshold concentration of CR required to produce sensation on the human tongue was 2.1 × 10‐6 M; a concentration 4.3 times that required to produce sensation on the eye. These values have been compared with those previously estimated for the sensory irritant material o‐chlorobenzylidene malononitrile (CS). Species variation in responses and the problems of predicting comparative irritancy in man from animal studies are discussed.
Selenium Carrier Proteins in Mouse Plasma
Authors: Sandholm Markus
Published: July 2010

The selenium carrier proteins in mouse plasma were studied using 75Se‐selenite and a crossed immunoelectrophoresis‐autoradiography.

The selenite was not bound to plasma proteins in vitro unless erythrocytes were present. Intravenously administered selenite was attached to the same proteins as the selenite‐Se metabolized by the erythrocytes in vitro.
Metabolism of Desmethylimipramine in Human Foetal and Adult Liver Microsomes
Authors: von Bahr Christer , Rane Anders , Orrenius Sten , Sjöqvist Folke
Published: July 2010

Abstract:The hydroxylation of the tricyclic antidepressant drug, desmethylimipramine, has been studied by the use of isolated liver microsomes from human foetuses and adults. Desmethylimipramine was hydroxylated in both foetal and adult human liver microsomes. Thin‐layer chromatography of a chloroform extract of the incubate indicates that desmethylimipramine is aromatically hydroxylated in position 2.
Binding of Digitoxin to Human Serum Proteins: Influence of pH on the Binding of Digitoxin to Human Albumin
Authors: Brock Axel
Published: July 2010

Abstract: The binding of digitoxin to albumin was studied under various conditions with regard to electrolytes and pH. Considerable variations of Na, K, Ca and Mg within the range of clinical relevance did not influence the binding of digitoxin to albumin. Under the influence of excessive concentrations of digitoxin this binding followed the simple law of mass action with an average number of binding sites of about 0.5 independent of pH. The intrinsic association constants were about twice the apparent association constants, calculated in another way and with the assumption of one binding site per molecule of albumin. The binding of digitoxin to albumin was shown to depend on the pH of the medium with a maximum association constant at pH = 4.8 (intrinsic association constant, K = 5 x 105 l/mol). The binding of digitoxin to human serum proteins was shown to be equal to that of the binding to albumin. Under conditions relevant for clinical interpretations the binding of digitoxin to other proteins was insignificant.
Effects of Diazepam and Ethanol on Heart Rate and Galvanic Skin Responses
Authors: Danielsen A. , Haffner J. F. W. , Mørland J. , Setekleiv J. , Frivik P. T. , Strøms$aether C. E.
Published: July 2010

Abstract: Heart rate (HR), heart rate variability (HRV), and the amplitude and frequency of galvanic skin responses (GSR) were studied in nine healthy young males 2–3 hrs after oral administration of either placebo, diazepam (10 and 20 mg per 70 kg body weight), ethanol (0.78 and 1.22 ml/kg), or combined administration of diazepam (10 mg) and ethanol (0.78 ml/kg). When examinations were performed in resting subjects, ethanol produced significant increases in heart rate, as did combined administration of ethanol and diazepam. Heart rate variability, supposedly correlated to reaction time, was reduced by combined administration of the two drugs. The frequency of the GSR was reduced by both ethanol and 20 mg diazepam, while the amplitude was increased by 10 mg diazepam and reduced by 20 mg diazepam, although not significantly, and was reduced on one occasion by ethanol. Stimulation by mental arithmetic increased all parameters, and more so after drug treatment than after placebo. The results are discussed in relation to the possible effects of diazepam on the autonomic nervous system, and also in relation to the psychophysiological activation theory which presupposes that increased activation is related to increased sympathetic activity. It is concluded that the parameters used are not reliable as indicators of whether a drug is deactivating or not.
Half‐life and Renal Excretion of Trimethoprim in Swine
Authors: Nielsen Poul , Rasmussen Folke
Published: July 2010

Abstract: Experiments in swine showed that the half‐life of trimethoprim was on an average 2 hours 15 minutes and the apparent volume of distribution was 1.4. In addition to glomerular filtration both active tubular secretion and back diffusion are involved in the renal handling of trimethoprim. The back diffusion is greatly influenced by the pH of the urine.
On the Interaction Between Caffeine and Barbiturates with Respect to Locomotor Activity and Brain Catecholamines
Authors: Waldeck Bertil
Published: July 2010

Abstract:Mice were first given 10 mg/kg caffeine or saline, and 30 min. later pentobarbitone, 4 to 32 mg/kg. Both drugs caused an increased locomotor activityper se. However, when 16 mg/kg pentobarbitone was given after caffeine, the effects appeared to be more than additive. Similar results were obtained when phenobarbitone was substituted for pentobarbitone, and also when the order caffeine‐phenobarbitone was reversed. In another experiment mice received reserpine, 10 mg/kg, 6 hrs before the combined treatment with ET495 and clonidine, which are known to stimulate central dopamine (DA) and noradrenaline (NA) receptors respectively. Caffeine, but not pentobarbitone, markedly enhanced the reversal of the reserpine‐induced suppression of locomotor activity elicited by ET 495 + clonidine. Caffeine and pentobarbitone in combination were not more effective than caffeine alone in this respect. There were no obvious changes in the whole‐brain levels of NA and DA after treatment with caffeine or pentobarbitone or both. However, when combined, the two drugs caused a decreased disappearance of DA following inhibition of tyrosine hydroxylase by α‐methyl‐p‐tyrosine. It is suggested that central catecholamine mechanisms are involved in the interaction between caffeine and barbiturates.
The Effect of N‐acetylhomocysteine and its Thiolactone on the Distribution and Excretion of Mercury in Methyl Mercuric Chloride Injected Mice
Authors: Aaseth Jan
Published: July 2010

Abstract: The distribution and excretion of mercury was studied in mice given a single intravenous dose of 5 μmol/kg of methyl mercuric chloride. Intravenous treatment with N‐acetylhomocysteine (10 mmol/kg) increased the urinary excretion of mercury. The corresponding thiolactone mixed into the feed of the mice turned out to be more effective in removing mercury from the body. The toxicity of the thiolactone seemed to be remarkably low compared to other sulphur containing agents. Mercury deposited in the brain was mobilized by oral administration of the thiolactone even if the treatment was delayed until 5 days after the injection of methyl mercury. The results indicate that the formation of a N‐acetylhomocysteine‐methyl‐mercuric‐complex is responsible for this effect.
Cerebrospinal‐Fluid Concentrations of Diazepam and its Metabolites in Man
Authors: Kanto J. , Kangas L. , Siirtola T.
Published: July 2010

Abstract: Plasma and cerebrospinal‐fluid (CSF) concentrations of diazepam, its main metabolite, N‐demethyldiazepam, and free oxazepam were studied gas chromatographically in 49 patients suffering from neurological diseases, after a 10 mg intramuscular dose of diazepam. These determinations were made in three other patients after repeated intramuscular doses of 10 mg diazepam. In seven of the patients both free and plasma protein‐bound diazepam, and N‐demethyldiazepam were determined by ultracentrifugation after a single dose of 10 mg intramuscular diazepam. After a single dose of diazepam there was only 2–3% of the total plasma concentration of diazepam and 1–4% of that of N‐demethyldiazepam in the CSF. After repeated doses of diazepam the same values were 3% and 4%, respectively. The plasma protein binding capacity of diazepam was 98% and that of N‐demethyl‐diazepam 97%. Free diazepam and N‐demethyldiazepam concentrations in the plasma were in equilibrium with their CSF concentrations. No accumulation of diazepam and N‐demethyldiazepam could be found in the CSF. No free oxazepam was found.
A New Method for Homogenization of Bone Exemplified by Measurement of Trimethoprim in Human Bone Tissue
Authors: Hansen Ib , Nielsen M. Lykkegaard , Nielsen J. Boss
Published: July 2010

Abstract: A new method for the homogenization of bone tissue is introduced. The method includes a reproducible size of particles (median 0.89 μ) and allows investigation of tissue samples down to 100 mg. Using this method of bone homogenization, the penetration of trimethoprim (TMP) into normal human bone was examined in 10 patients with fracture of the femoral neck. A microbiological method was used to determine the concentration, using Bacillus pumilus as test organism. Separate determinations were made of the TMP concentration in bone marrow, spongy bone and compact bone. Evaluated on the basis of the sensitivity of Staphylococcus aureus to TMP, a therapeutic level of TMP seems to be obtained in bone marrow and spongy bone, but not in compact bone.
Concentration of Tricyclic Antidepressants in Plasma, Heart and Skeletal Muscle after their Intravenous Infusion to Anaesthetized Rabbits
Authors: Elonen E. , Linnoila M. , Lukkari I. , Mattila M. J.
Published: July 2010

Abstract: In order to compare the toxic concentrations of four different tricyclic antidepressants in the heart and plasma, 5 mg/kg of amitriptyline, doxepin, nortriptyline or protriptyline were infused intravenously over 5 min. into anaesthetized rabbits. The concentrations of the antidepressants five minutes after the termination of the infusion were measured by gas chromatography in the plasma, heart ventricles, and femoral muscle. On average, the concentrations in the heart were 40 to 200 times higher than those measured in plasma, the concentration of protriptyline being highest. The heart/plasma concentration ratios were higher for protriptyline and amitriptyline than for nortriptyline and doxepin. The toxicity of the antidepressants correlated neither to their heart concentrations nor to their heart/plasma concentration ratios. It seems that the different acute cardiotoxicity of tricyclic antidepressants cannot be explained by their different concentrations in the plasma or in the heart muscle only, but they seem to have different toxic potencies.
The Effect of Some Ionized and Neutral Surfactants and Bile Acids upon Sodium and Water Transport from Tied Jejunal Loops in Anaesthetized Rats
Authors: Sund Reidar Bredo
Published: July 2010

Abstract: Surfactants of diverse types, viz. dioctylsulphosuccinate, cetrimonium bromide, benzalkonium chloride, Lubrol$rG WX, Triton$rG X100, desoxicholic acid, cholic acid and glycodesoxicholic acid all affected jejunal transport of sodium and water in the same way as previously shown for dodecylsulphate: From hypotonic sodium chloride solutions, they inhibited net water absorption or induced secretion in a dose dependent manner; from hypertonic sodium salt solutions net sodium absorption was enhanced. The results indicate that, with increasing doses of surfactant, diffusion becomes increasingly important as the determinant of net sodium transport, suggesting that the surfactants cause increased passive permeability of the intestinal epithelium. Taurodesoxicholic acid caused inhibition when tested with hypotonic saline, and by analogy is assumed to act in the same way as the above mentioned surfactants. Some of the non‐ionic surfactants tested did not influence jejunal transport.
The Effect of a Calcium‐antagonistic Drug, Nifedipine, on the Mechanical and Electrical Activity of the Isolated Rat Atrium
Authors: Refsum* Helge , Landmark Knud
Published: July 2010

Abstract:Effects of a calcium‐antagonistic drug, nifedipine, on the mechanical and electrical behaviour of isolated rat atria were investigated in the concentration range from 0.5 to 1000 μg/l. Nifedipine caused a dose‐dependent decrease in the spontaneous atrial rate and amplitude of contractions, and atrial arrest occurred in some experiments with the highest drug concentrations. The drug also caused a dose‐dependent decrease in contractile force of stimulated left atria, while the threshold current required to drive the atria was unchanged. The effective refractory period was unaltered in the concentration range between 0.5 and 500 μg/l since the maximum following frequency at which the atria could respond to stimulation was unchanged. Nifedipine caused a dose‐dependent increase in the sinus node recovery time. The present study indicates that calcium ions are necessary for pacemaker activity in the sino‐atrial node, but not essential for maintaining atrial refractoriness and excitability.
Amphetamine Toxicity in Temperature‐Acclimatised Mice
Authors: Harri Mikko N. E.
Published: July 2010

AbstractD‐Amphetamine toxicity was tested in mice previously acclimatised to 5, 21 and 31°. When the measurements were carried out at 21°, mice acclimatised to lower ambient temperatures were more sensitive to amphetamine than those acclimatised to higher ones, as judged from the LD50‐values obtained. However, when measured at 14°, toxicity was similar for 5°‐ as for 21°‐acclimatised mice, while it was greater for 31°‐acclimatised mice. Aggregation increased amphetamine toxicity the more so the greater the toxicity had been in isolated animals. The body temperature of mice under the influence of amphetamine was inversely related to the previous temperature of acclimatisation, and it was always lower at 14° than at 21°. Aggregation did not influence the hyperthermic effect of amphetamine, while it tended to decrease the hypothermia caused by the drug. The differences in amphetamine toxicity between animals acclimatised to different temperatures can be accounted for by differences in (physiological) relation to the (same) experimental situation, rather than by differences in susceptibility to the drug.
Effect of Antidiuretic Drugs in Rats with Lithium‐induced Polyuria
Authors: Christensen Sten
Published: July 2010

AbstractThe effect of various antidiuretic drugs was studied in rats with lithium‐induced polyuria. Constant polyuria (urine volume > 150 ml/24 hrs, Uosm< 200 mosmol/kg) was induced in male Wistar rats by administration of LiCl in the food for 2–3 months before the experiments. Body weight, food consumption and urine volume and osmolality were recorded daily. After a 7 days control period, drugs were administered once or twice daily for 7 days. Bendroflumethiazide, 0.4, 2 and 10 mg/kg daily orally, produced a reversible, dose‐dependent antidiuretic response as indicated by a decrease in free water clearance. After 10 mg/kg, negative free water clearance was induced and the urine flow was reduced to one third. Diazoxide, chlorpropamide and carbamazepine did not significantly affect urine volume or osmolality at dose levels producing no effects on food consumption or body weight. The antidiuretic response to a thiazide diuretic and the lack of response to drugs known to have antidiuretic action in pituitary diabetes insipidus, lend support for the nephrogenic basis of the concentration defect induced by lithium.
Elimination of Trimethoprim, Sulphadoxine and their Metabolites in Goats
Authors: Nielsen Poul , Rasmussen Folke
Published: July 2010

Abstract The elimination of trimethoprim and sulphadoxine after intravenous administration has been investigated in experiments on goats. Trimethoprim is metabolized to a great extent in the goat liver and the biliary excretion was almost equal to the urinary excretion in experiments with continuous intravenous infusion of trimethoprim. More than 99 % of the amount excreted in bile consists of metabolites of trimethoprim. In contrast it was almost exclusively the unchanged drug which was excreted in the saliva. Sulphadoxine is metabolized to a much smaller extent in goats than trimethoprim and the biliary and salivary excretion seemed without significance in comparison to the urinary excretion.
Metrizamide in Experimental Urography. VI. Effects of Renal Contrast Media on Urinary Solutes
Authors: Golman Klaes , Almén Torsten
Published: July 2010

Abstract The ratio between the maximum iodine concentrations obtained in the urine during osmotic diuresis after intravenous injection of the contrast media metrizamide, sodium iocarmate and sodium diatrizoate, should theoretically be 6:4:3. To confirm this, the renal excretion of the three media and the main urinary solutes was investigated in rabbits with a catheter in both ureters. The contrast media were injected in iodine‐equivalent amounts at two dose levels, both relevant for urographic examinations. Urine samples were collected within the first hour after the injection. Blood pressure was also recorded. After low solute loading the excretion of potassium was depressed. A positive linear correlation was found between the excretion rates of potassium and sodium and all data fitted the same line regardless of the contrast medium. After injection of the sodium salts the sodium recovery was less than the corresponding iodine recovery at low solute loading and greater at the highest solute loading. Free water reabsorption was not related to the contrast medium. The ratio between the maximum iodine concentrations in the urine after injection of the high dose of the contrast media was found to be 148:120:75.
Acute Effects of Oxazepam, Diazepam and Methylperone, alone and in Combination with Alcohol on Sedation, Coordination and Mood
Authors: Molander Lars , Duvhök Christina
Published: July 2010

Abstract Effects on critical flicker fusion frequency (CFFF), coordination and mood were studied after single oral doses of placebo, alcohol (0.5 ml ethanol/kg b. wt.), oxazepam (10, 20 and 40 mg), diazepam (5, 10, 20 and 40 mg) and methylperone (10, 25 and 50 mg), given either alone, or simultaneously with alcohol or with delayed alcohol administration. Methylperone was found to have a depressant effect similar to or greater (on a weight basis) than that of diazepam and oxazepam respectively. The correlation between sedative and antianxiety effect is discussed. The decrease in CFFF was parallelled by a decreased coordination ability. Alcohol alone had no effect on our parameters, but when given simultaneously with the drugs, it markedly increased the effect of diazepam, while the effect of oxazepam and methylperone were affected to a much lesser degree. The effect of the drugs on psychomotor skills and the interaction between alcohol and the drugs have important implications when treating out‐patients. Methylperone as a potential anti‐anxiety agent is discussed.
Effect of Subacute Treatment with Hypnotics, Alone or in Combination with Alcohol, on Psychomotor Skills Related to Driving
Authors: Saario I. , Linnoila M.
Published: July 2010

AbstractThe effect of two weeks' treatment with amylobarbitone, flurazepam, a combination of methaqualone and diphenhydramine, or glutethimide, and their interaction with alcohol, was examined in 40 healthy volunteers in two double blind cross‐over trials. The drugs and placebo were given orally every night between 10 and 11 p.m. for two weeks, the treatment periods alternating in random order. Psychomotor skills were tested on the 7th and 14th treatment mornings by a choice reaction test, two co‐ordination tests and a divided attention task 30, 90 and 150 minutes after the previous administration of alcohol or placebo. After both trials were over the subjects of the latter trial were tested once more after one night's deprivation of sleep. Amylobarbitone and flurazepam alone impaired eye‐hand co‐ordination whereas the residual effect after methaqualone and diphenhydramine or glutethimide on psychomotor performance was negligible. Amylobarbitone and flurazepam also enhanced the alcohol induced impairment of co‐ordinative skills. Deprivation of sleep did not impair psychomotor performance. The subjects regarded flurazepam and the combination of methaqualone and diphenhydramine as more potent hypnotics than glutethimide or amylobarbitone. Flurazepam and the combination caused most of the side‐effects reported by the subjects.
Binding of Digitoxin to Human Serum Albumin: Influence of Free Fatty Acids, Bile Acids, and Protein Unfolding on the Digitoxin‐Albumin Interaction
Authors: Brock Axel
Published: July 2010

Abstract The binding of digitoxin to purified human serum albumin was studied under equilibrium conditions. The binding affinity was uninfluenced by the strongly bound free fatty acids of the albumin. All bile acids studied were found to inhibit the binding of digitoxin to albumin. Cholic acids and desoxycholic acid induced a competitive inhibition of the digitoxin‐albumin interaction without any physical signs of protein unfolding. Surface active organic anions, known to produce conformational changes of albumin, were found to be powerful inhibitors of the digitoxin‐albumin interaction.
Application of Granulation–Tissue Slices and Matrix–Free Tendon Cells in the Screening of Connective Tissue–Active Indoles
Authors: Kulonen Eino , Lehtinen Pirjo , Potila Marita
Published: July 2010

Abstract Four new synthetic indoles have been found to suppress the synthesis of collagen both in incubated granuloma–slices and in detached embryonic–chick tendon cells as well as to decrease the secretion of collagen to the extracellular space, the latter of which was also inhibited by a membrane–active detergent. The effects of serotonin and indomethacin were studied as a background and data are presented on the association of serotonin to plasma membrane fractions. The synthesis of collagen in vitro is suggested as a useful test in the preliminary screening of potential antirheumatic drugs.
Polyethylene Glycol as a Solvent for Diazepam: Bioavailability and Clinical Effects after Intramuscular Administration, Comparison of Oral, Intramuscular and Rectal Administration, and Precipitation from Intravenous Solutions
Authors: Korttila K. , Sothman A. , Andcrsson P.
Published: July 2010

Abstract The bioavailability of diazepam (10 mg) was compared in a doubleblind cross–over manner in two studies on 15 healthy subjects. Serum diazepam levels were measured and the occurrence of pain at the injection site as well as fatigue was noted 20, 40, 60, 90 and 180 min. after the administration of 0.15 mg/kg of diazepam to seven subjects. Three intramuscular preparations were used: valium® (Roche), diapam® (Orion) and 301–K 2/74 (Orion). The last–mentioned preparation contained only half the propylene glycol contained in the other preparations, and polyethylene glycol (Macrogol) was the main solvent. The other eight subjects were similarly tested after the administration of diazepam orally, intramuscularly and rectally. In addition the precipitation of diazepam from intravenous solutions was investigated with diazepam in both solvents. Bioavailability and fatigue were similar after each treatment. 301–K 2/74 and its solvent placebo caused significantly less pain in the thigh than valium® or diapam®. The results suggest that an intramuscular injection of diazepam, deep into vastus lateralis muscle, and rectal and oral administration result in comparable bioavailability and clinical effects. A reduction in the amount of propylene glycol solvent used was associated with less pain at the injection site. When diapam® was injected into an infusion tube at a rate of 5 mg/min., the rate of infusion of 5 % glucose or 0.9 % saline had to be as fast as 20 ml/min. in order to prevent visible precipitation, whereas no precipitation was observed when 301–K 2/74 was injected at the 5 mg/min. rate into infusions moving at 5 ml/min. Further clinical studies with intramuscular and intravenous 301–K 2/74 are warranted.
A Comparison between some Effects of Two Pure Chlorobiphenyls (2,4′,5–trichlorobiphenyl and 2,2′, 4,4′, 5,5′–hexachlorobiphenyl) on the Hepatic Drug Metabolizing System in the Female Mouse
Authors: Örberg Jan
Published: July 2010

Abstract The effects of two pure chlorobiphenyls (2,4′,5–trichlorobiphenyl and 2,2′,4,4′,5,5′–hexachlorobiphenyI) on the hepatic drug metabolizing system, and the elimination rate from the liver of the two chlorobiphenyls have been studied in the female mouse. The results obtained show that: 1. The two chlorobiphenyls are both potent inducers of the hepatic drug metabolizing system. 2. The hexachlorobiphenyl is a more potent inducer of the hepatic drug metabolizing system than the trichlorobiphenyl. 3. The trichlorobiphenyl is eliminated from the liver much faster than the hexachlorobiphenyl.
Elimination of Thallium in Rats as Influenced by Prussian Blue and Sodium Chloride
Authors: Manninen V. , Mälkönen Marjatta , Skulskii I. A.
Published: July 2010

AbstractThe effect of Prussian Blue in protecting rats against lethal doses of thallium was investigated. Treatment with Prussian Blue increased the survival of rats from 0% to 50%. The elimination rate of thallium was increased in all the tissues studied, including the brain. Faecal thallium excretion was increased about three–fold. Treatment with hypertonic sodium chloride improved the short–term survival but the total mortality was unchanged.
Protein Binding of Phenprocoumon in the Absence and Presence of Furosemide
Authors: Foged L. , Husted S. , Andreasen F.
Published: July 2010

AbstractA modification of a fluorometric assay for phenprocoumon is described. The sensitivity of the method has been increased so that the lower limit is 5 ng/ml. By an ultrafiltration technique, phenprocoumon (PPC), in therapeutic concentrations, was bound to the extent of 99.9%,both in undiluted plasma and in Krebs–Henseleit (K–H) solutions containing 4 g human serum albumin (HSA)/100 ml. An increase in the pH from 6.05 to 8.02 in phosphate buffers containing 0.2 g HSA/100 ml yielded an increase in the apparent association constant for PPC binding to HSA from 0.562–1061/mol to 1.195–1061/mol, while the number of PPC mol bound per mol albumin remain unchainged (1.05 and 1.03 respectively). A reduced binding of PPC in undiluted plasma containing increasing concentrations of furosemide have been observed. Scatchard plots based on binding studies in K–H solutions containing 0.2 g HSA/100 ml indicate a competitive nature of the albumin binding of PPC and furosemide.
The Metabolism of Biphenyl. II. Phenolic Metabolites in the Rat
Authors: Meyer Trygve , Scheline Ronald R.
Published: July 2010

AbstractThe metabolic conversion of biphenyl to phenolic metabolites was studied in the rat. The metabolites were identified by mass spectrometry and quantified by gas chromatography following conversion to their trimethylsilyl (TMS) ethers. The main route of excretion was via the urine, and the major part (22.3 %) of the biphenyl metabolites was excreted in the first 24 hrs. The total urinary recovery 96 hrs after administration was 29.5 % of the dose and the metabolites detected were conjugates of mono–, di– and tri–hydroxy derivatives of biphenyl as well as the meta– and para–methyl ethers of the catecholic compounds. The two main urinary metabolites were 4–hydroxybiphenyl (7.7 %) and 4,4′–dihydroxybiphenyl (11.4 %). The experiments also showed that biphenyl has to be hydroxylated and then conjugated before it appears in the rat bile. Thus, 5.2% of the dose was found in the 24 hrs bile as conjugates, mainly of 4–hydroxy–, 4,4′–dihydroxy– and 3,4,4′–trihydroxy–biphenyl. Faecal excretion of phenolic biphenyl derivatives was found to be of minor importance, but 4.7 % of the dose was detected during the first 24 hrs after dosing. The following previously undetected metabolites of biphenyl were found: 3,4′–dihydroxy–, 3,4,4′–trihydroxy–, 3,4′–dihydroxy–4–methoxy– and 4,4′–dihydroxy–3–methoxy–biphenyl.
Effects of Aminooxyacetic Acid and Baclofen on Catalepsy, Striatal Homovanillic Acid Increase and Antinociception Caused by Methadone in Rats
Authors: Kääriäinen Ilpo , Vikberg Pasi
Published: July 2010

Abstract The effects of aminooxyacetic acid (AOAA) and baclofen on the catalepsy, striatal homovanillic acid (HVA) increase and antinociception caused by methadone were studied in rats. Antinociceptive responses were tested by the electric foot–shock method. A new type of stimulator unit which delivered nearly constant current over a wide range of output voltage and which was noiseless was designed and its construction is described. AOAA (25 mg/kg) which increases the cerebral concentration of δ–aminobutyric acid (GABA) and baclofen (10 mg/kg), a structural analogue of GABA, did not change the catalepsy induced by methadone (5 mg/kg). AOAA (25 and 50 mg/kg) alone did not alter the striatal HVA content and had no effect on the methadone– induced HVA increase. Baclofen (10 mg/kg) increased the striatal HVA content by 19% (P < 0.01) and reduced the methadone–induced HVA increase by 36 % (P < 0.01). AOAA (25 mg/kg) and baclofen (5 mg/kg) had no antinociceptive effect but they increased significantly the antinociception caused by methadone (2 and 5 mg/kg). These results suggest that narcotic analgesics might cause catalepsy and increase striatal dopamine turnover by some other mechanism than neuroleptics. The results support the suggestion that GABA might be involved in pain mechanisms.
Characterization of the Adrenergic Beta‐Receptor in the Urinary Bladder of Man and Cat
Authors: Nergårdh A. , Boréus L. O. , Naglo A.‐S.
Published: July 2010

AbstractThe corpus‐fundus of the urinary bladder of man and cat was studiedin vitrowith respect to type of beta‐adrenergic receptors. In both species beta‐adrenergic stimulation produced marked relaxation but species differences were apparent. In the cat bladder only beta1receptors were found. In the human bladder the beta‐receptors had neither beta1‐ nor beta2‐characteristics. It is suggested that the beta‐adrenergic receptors in the corpus‐fundus of the human bladder are of a third type.
Metabolic Actions of some Sympathomimetic Amines and their Acetyl Derivatives in the Rabbit
Authors: Marvola Martti
Published: July 2010

AbstractTo study how acetylation affects the activity of sympathomimetic amines the effects of tyramine, amphetamine ephedrine, phenylephrine, orci‐prenaline and salbutamol and of their O‐ and N‐acetyl derivatives on blood glucose and free fatty acid concentrations were studied in the rabbit. Hyperglycemia was induced by all parent compounds except amphetamine which tended to have a weak hypoglycaemic action. Hyperlipaemia in the doses used was induced by ephedrine and orciprenaline but not by the other parent compounds. Usually acetylation decreased the metabolic effects of the compounds but O‐acetylation of tyramine and salbutamol caused hyperlipaemia and O‐acetylation of ephedrine increased its fatty acid‐mobilizing action, perhaps as a consequence of increased lipid solubility of the compounds. The ultimate effects of the O‐acetyl derivatives were probably at least partly due to deacetylation at their sites of action. Hence O‐acetylation of sympathomimetics could perhaps be used to induce drug latentiation.
Decreased Erythrocyte Glutathione Peroxidase Activity in Neuronal Ceroid Lipofuscinosis (NCL) ‐ Corrected with Selenium Supplementation
Authors: Westermarck Tuomas , Sandholm Markus
Published: July 2010

Abstract A decreased glutathione peroxidase (GPX) activity was demonstrated in erythrocytes from 12 patients with neuronal ceroid lipofuscinosis (NCL). The enzyme activity was corrected to normal levels by selenium (Se) supplementation.
Chronic Copper Poisoning in Sheep. I. The Relationship of Methaemoglobinemia to Heinz Body Formation and Haemolysis during the Terminal Crisis
Authors: Søli Nils E. , Frøslie Arne
Published: July 2010

AbstractThe values of haematocrit, total haemoglobin in plasma, methaemo‐globin percentages in erythrocytes and plasma, the osmotic fragility of the erythrocytes, and the occurrence of Heinz bodies were investigated during the terminal crisis in 4 cases of experimental chronic copper poisoning in sheep. At the beginning of the crisis, which lasted for well over one day, 10–20 per cent methaemoglobin was detected in the erythrocytes, before any haemolysis occurred. Later on severe haemolysis developed, and maximum levels of haemoglobin in the plasma were close to 2.5 g/100 ml. During the haemolytic stage both methaemoglobin and haemoglobin were detected in the plasma at approximately the same proportions as in the erythrocytes. No changes were observed in the osmotic fragility of the red cells until the onset of the haemolysis. It is concluded that the methaemoglobin formation is mainly an intra‐corpuscular process and that most of the methaemoglobin detected in plasma in chronic copper poisoning in sheep, comes from the erythrocytes.
Chronic Copper Poisoning in Sheep. II. The Distribution of Soluble Copper‐, Molybdenum‐, and Zinc‐binding Proteins from Liver and Kidney
Authors: Norheim Gunnar , Søli Nils E.
Published: July 2010

Abstract The concentrations of copper, molybdenum, and zinc in the soluble protein fraction from sheep liver and kidney were determined after gel filtration. Samples from grazing sheep as well as from copper poisoned sheep were tested. In normal sheep the copper‐binding proteins were separated into 3 different fractions. In copper poisoned sheep, as well as in grazing sheep with high copper concentrations, only 2 main fractions were seen. Molybdenum was only found in the high molecular weight protein fraction. The distribution of the zinc‐binding proteins varied according to the degree of copper accumulation. The low molecular weight zinc‐binding protein fraction was only seen in sheep with liver copper concentrations lower than 40 μg/g wet weight. In copper poisoned sheep a major part of the kidney copper was found in the low molecular weight protein fraction. At post mortem the bile copper concentrations in the copper poisoned sheep were only 2–4 times higher than those of the control animals.
Effect of Methysergide and Indomethacin on the Anaphylactic Contraction of the Rat Isolated Uterus (Schultz‐Dale Response)
Authors: Nielsen Aage Theil
Published: July 2010

AbstractThe anaphylactic contraction (Schultz‐Dale response) of the isolated uterus from actively sensitized rats was partially suppressed by methysergide, 1.5 μg/ml. Although the inhibitory effect of indomethacin, 3.5 μg/ml, was only slight, the combination of indomethacin and methysergide abolished the response almost completely. These observations indicate that, although serotonin must be the primary mediator of the anaphylactic uterine response, prostaglandin is also involved. Metiamide, a histamine H2‐receptor antagonist, 10 μg/ml, did not affect the anaphylactic response, suggesting that histamine was not released in amounts sufficient to counteract the uterine contracting mediators.
Cyclophosphamide Effect on Collagen Metabolism in Granulation Tissue, Skin, and Aorta of Rats
Authors: Hansen T. Mørk , Lorenzen I.
Published: July 2010

Abstract Granulation tissue was produced in rats by subcutaneous implantation of viscose cellulose sponges. Cyclophosphamide 10 mg/kg was given daily intraperitoneally to 15 rats from the day of sponge implantation. Fifteen rats served as pair‐fed controls, and 15 rats served as non‐starved controls. After 14 days of treatment the animals were decapitated. Groups of 3 rats were given 50 μci 14C‐proline intraperitoneally 1, 3, 6, 12, or 24 hours before death. The aorta, skin, and granulation tissue were examined. Cyclophosphamide caused no effect on collagen of the aorta, while in skin, the only detectable effect was a decrease in 14C‐OH‐proline biosynthesis. In granulation tissue, cyclophosphamide caused a fall in the dry weight, a decrease in 14C‐proline uptake and 14C‐OH‐proline synthesis, as well as an increase in the alpha‐amino nitrogen to OH‐proline ratio in purified collagen. These results indicate that cyclophosphamide inhibits the synthesis of proteins, including collagen, and inhibits the hydroxylation of proline in collagen. No effect of cyclophosphamide could be detected on the amount of salt soluble OH‐proline or on collagen cross‐linking. The registered effects of cyclophosphamide on granulation tissue is probably of importance with regard to the anti‐inflammatory action of cyclophosphamide. This action as well as the tissue differences in the sensitivity of cyclophosphamide may be of relevance to the clinical application of cytostatics in rheumatological diseases.
Inhibition of Apomorphine‐induced Hypermotility in Rats by Chlorpromazinc, Perphenazine, Thioridazine and Melperone
Authors: Lassen Jørgen Buus
Published: July 2010

AbstractHypermotility in rats produced by various subcutaneous doses of apo‐morphine (ap) was studied. The neuroleptics chlorpromazine, perphenazine, thioridazine and melperone were administered subcutaneously 30 minutes before ap. The four neuroleptics were found to inhibit ap‐induced hypermotility. When the dose of ap was increased, higher doses of the neuroleptics were required to inhibit the hypermotility. By varying the dose of chlorpromazine, thioridazine and melperone partial ap‐antagonism was found, but increase of the perphen‐azine‐dose resulted in complete ap‐inhibition. Hypermotility produced by ap is presumably dependent on direct stimulation of dopamine (DA)‐receptors. Neuroleptics blocking some, but not all, DA‐receptors may cause no, or weak parkinsonian side effects.
Effect of a Selective 5‐HT Uptake Inhibitor ‐ Lu 10‐171* ‐ on Rat Brain 5‐HT Turnover
Authors: Hyttel John
Published: July 2010

Abstract Changes in endogenous concentrations of 5‐HT and 5‐HIAA as well as the turnover rate of 5‐HT was studied in rat brain after treatment with a new potent and selective inhibitor of the neuronal 5‐HT reuptake mechanism, Lu 10‐171 (1‐(3‐(dimethylamino)propyl)‐1‐(p‐fluorophenyl)‐5‐phthalancarbonitrile). After a single dose of Lu 10‐171 the concentration of 5‐HIAA was reduced from 1 to 24 hours after treatment, whereas that of 5‐HT was practically unchanged, indicating decreased turnover of 5‐HT in the brain. This was confirmed using three different methods for measuring 5‐HT turnover. Thus the rate of 5‐HIAA accumulation in the brain after probenecid was reduced after Lu 10–171. Likewise treatment with Lu 10‐171 led to a decreased fall in 5‐HT and an increased fall in 5‐HIAA after inhibition of 5‐HT synthesis with parachloro‐phenylalanine (PCPA). Unexpectedly Lu 10‐171 did not change either the accumulation of 5‐HT or the decrease in 5‐HIAA after inhibition of MAO with pargyline. By and large the results are consistent with the proposed negative feed‐back regulation of 5‐HT neuronal firing rate due to the abundance of 5‐HT at postsynaptic receptors after inhibition of the reuptake mechanism.
Selenium Content of Whole Blood and Serum in Adults and Children of Different Ages from Different Parts of Finland
Authors: Westermarck Tuomas , Raunu Paavo , Kirjarinta Mikko , Lappalainen Leo
Published: July 2010

Abstract A low level of selenium (Se) in the blood and serum of Finns was demonstrated. Inhabitants in the central, eastern and southeastern districts of the country had particularly low levels selenium. However, the Se level of Lapps and the people of the Åland archipelago seemed to be significantly higher than the level of other Finns. In general, the Se levels in the serum were lower than the values for whole blood. Furthermore, the levels were lower in children than in adults. The significance of these findings in the pathogenesis of some human diseases is discussed.
The Effect of Calcium and Beat Interval on the Contractile Force and Refractoriness of the Isolated Rat Atrium in the Absence and Presence of Nifedipine: A Possible Mechanism for the Negative Staircase Phenomenon
Authors: Landmark Knud , Refsum Helge
Published: July 2010

AbstractAn increase in the calcium concentration of the Ringer solution increased the contractile force and reduced the effective refractory period of the isolated rat left atrium paced at a frequency of 60 per min. An increase in the frequency of stimulation decreased the contractile force (negative staircase) and reduced the effective refractory period; these effects being most pronounced at the highest calcium levels. A calcium‐antagonistic drug, nifedipine, decreased the contractile force and the effective refractory period. The effect of an increased frequency of stimulation on the contractile force at different calcium levels in the absence and presence of nifedipine paralleled its effect on the effective refractory period. This observation suggests that both these phenomena are caused by a decreased quantity of inflowing calcium ions during the period of excitation, and thus might explain the absence of positive staircase in the rat myocardium.
Studies on the Mechanism of Flush Induced by Nicotinic Acid
Authors: Andersson Rolf G. G. , Åberg Gunnar , Brattsand Ralph , Ericsson Elsa , Lundholm Lennart
Published: July 2010

AbstractFlush is a common side effect of nicotinic acid therapy in patients. The effect is present as long as the level of nicotinic acid increases in the plasma. The mechanism of flush after nicotinic acid has been studied in the ears of guinea‐pigsin vivo. The threshold dose of nicotinic acid (1‐3 mg/kg) to raise the skin temperature of the ears and to increase the cyclic AMP level of this tissue was similar. Indomethacin and acetylsalicylic acid which inhibit the synthesis of prostaglandins markedly reduced the duration and intensity of the flush. In isolated slices from guinea‐pig ears, nicotinic acid increased the level of cyclic AMP; this effect was inhibited by indomethacin. The stimulating action of prostaglandin E1on the cyclic AMP level of the ear slices was not inhibited by indomethacin. Since administration to man of both cyclic AMP and prostaglandin E1produces flush it is suggested that nicotinic acid may induce flush by the formation of some prostaglandin which then increases the formation of cyclic AMP.