The interpretation of gross left axis deviation in the electrocardiogram. In 94 patients with prominent left axis deviation, there was a marked disparity in the mean angles determined by the maximum magnitude of the deflections and that determined by areas. There was also considerable variation in the angle of the maximum vector in the frontal plane (frontal plane angle) and the angle of 50 msec vector in the frontal plane. Similar results were observed in 17 cases of ostium primum atrial septal defect. These differences contrasted with the findings in a normal group of 50 subjects where a close correlation was found. The initial vector was directed to the right in approximately 80% of normals and 60% of the patients with LAD indicative of conduction defects in the left anterior fascicular or its distal ramifications. We conclude that a rightward orientation of the 5--10 msec vector (i.e. causing a Q wave in lead 1) should not be required for diagnosis of left anterior fascicular block. The spatial orientation of the initial vector was always anterior in the control subjects. In these 'normals', as well as in the patients with left axis deviation, the initial vector varied markedly in its azimuth direction (right or left) when superiorly directed; but when inferiorly directed in the normal subjects it was virtually always directed rightward. From these data we were unable to construct rigid criteria which would reliably distinguish aberrant excitation patterns manifested by gross left axis deviation in the electrocardiograms of patients with established heart disease from subjects without defined heart disease. Old infarction patterns, anterior, inferior, and lateral were not obscured by the associated anterior fascicular block.


Anomalous origin of the left anterior descending coronary artery from the pulmonary trunk. An extremely rare congenital abnormality is reported in which the anterior descending branch of the left main coronary artery arises independently from the pulmonary trunk in a young patient who presented with unstable angina. Its clinical presentation, angiographic identification and surgical treatment are described. It appears to be a distinct entity with few of the features of the classical form of anomalous origin of the left main coronary artery.


Improved oral glucose tolerance following antiserotonin treatment in patients with chemical diabetes. The effects of short-term treatment with either placebo or two serotonin antagonists, cyproheptadine and metergoline, on oral glucose tolerance and insulin secretion have been evaluated in normal subjects and in patients with chemical diabetes. Placebo treatment was not associated with any significant change in the parameters examined. Glucose tolerance in chemical diabetics was significantly improved both after cyproheptadine and metergoline; fasting plasma glucose was also reduced by metergoline. Treatment with the latter drug was also associated with a significant decrease in incremental glucose area in healthy subjects, which was not affected by cyproheptadine. Basal and glucose-stimulated insulin secretion were not affected by either drug in any subjects. Cyproheptadine and metergoline improve glucose metabolism in chemical diabetes probably by reducing insulin resistance. This may depend either on decreased secretion of counter-regulatory hormones or on a direct pharmacological action of the drugs on glucose utilization, possibly mediated by their common antiserotoninergic properties.


Plasma theophylline level and effect on lung function after oral and rectal administration of aminophylline. Twelve patients with partly reversible, chronic airway obstruction, according to a double blind randomized cross-over design, received on three consecutive days oral aminophylline 500 mg, a 500 mg aminophylline suppository and a placebo. The effects on ventilatory function were studied and the plasma concentration of theophylline was measured. After rectal administration, the plasma concentration of theophylline rose to 5 to 10 microgram/ml, and after oral ingestion the plasma level in most patients exceeded 10 microgram/ml. Administration of the aminophylline suppository resulted in moderate improvement in ventilatory function, and although the improvement was less pronounced than after oral administration, the use of a suppository in the treatment of patients with chronic obstructive lung disease should not be rejected.


Biguanide-induced lactic acidosis in Finland. Twenty-four patients with biguanide-induced lactic acidosis were reported to the Adverse Drug Reaction Register of the Finnish National Board of Health from 1974-1977. Of them, 23 had been treated with phenformin and one with metformin. The mean age of the patients was 71 years, and all but one were more than 65 years of age. The mortality rate was 63%. One patient had cirrhosis of the liver and one was already known tohave had impaired renal function. Fourteen of the patients had a normal serum creatinine concentration either before or after the development of lactic acidosis. Thus, in most patients it had not been possible to prevent development of lactic acidosis by observing the contraindications to biguanide therapy. Most patients had some form of co-existing cardiovascular disease. Tetracycline therapy was a probable precipitating factor in three cases. Based on the statistics of biguanide consumption in Finland, the annual incidence of biguanide-induced lactic acidosis in 1976 and 1977 was between 1/2000 and 1/3000 and that of fatal lactic acidosis was 1/4000.


One hundred digitalis blood levels. A utilization review. One hundred consecutive digitalis serum level determination requests and results were analyzed to evaluate the rational of ordering the test and utilizing the results at his hospital. Sixty-six percent of the reasons given for ordering the test were categorized as "acceptable". As many as 25% of physicians requesting the test considered digitalis levels as "routine" diagnostic tests in a patient taking these drugs. There were 12 levels within the potentially toxic range, 19 below the usual therapeutic range. The physicians modified their therapeutic management in 38 patients as a result of their knowledge of the digitalis level in blood. It is concluded that digitalis level determinations at this hospital are reasonably well utilized and that knowledge of the digitalis levels improve the accuracy of digitalis utilization in at least one third of the patients in whom this test is done.


Absorption of boron after mouthwash treatment with Bocosept. Healthy volunteers and patients with gingivitis were treated locally with the boron-containing bacteriostatic agent, Bocosept. Blood levels and urinary excretion of boron were examined by a spectrophotometric method. Blood concentrations after a single mouthwash with Bocosept slightly exceeded those after intake of 200 g raisins or a bottle of red wine. The blood levels during a one-week course of treatment showed a low rate of boron accumulation. The highest concentration was about 0.3 microgram B/ml, a level which does not seem to involve any risk of boron poisoning. The small amount taken up after mouthwash treatment with Bocosept does not appear to represent absorption by the oral mucosa. It seems more likely that the uptake of boron takes place in the intestine after ingestion of residual amounts from the mouth.


Paracetamol metabolism in chronic liver disease. The plasma concentrations and urinary excretion of paracetamol and its glucuronide, sulphate, cysteine and mercapturic acid conjugates were measured in eight normal subjects, eight patients with mild liver disease and seven patients with severe liver disease following an oral dose of 1.5 g of paracetamol. The mean plasma paracetamol half-life was similar in normal subjects (2.43 h +/- 0.19) but was significantly prolonged in all patients with severe liver disease (4.25 h +/- 1.15:p = less than 0.001). Prolongation of the paracetamol half-life was related to reduced plasma albumin and increased prothrombin time. The mean ratios of plasma concentrations of unchanged paracetamol to paracetamol glucoronide and sulphate were significantly greater in patients with sever liver disease than the normal subjects. There were no significant differences in the overall 24-h urinary excretion of paracetamol and its glucuronide, sulphate, cysteine and mercapturic acid conjugates in the three groups. The glutathione conjugation of paracetamol did not seem to be impaired in patients with severe liver disease as evidence by the production of normal amounts of the cysteine and mercapturic acid conjugates. There is thus no evidence that they are at increased risk of hepatotoxicity when given a single therapeutic dose of paracetamol.


Placental transfer of atropine at the end of pregnancy. In a first study, 28 pregnant women received a fast intravenous injection of atropine sulphate 12.5 microgram/kg, as in a classical atropine test. Fetal tachycardia resulted. The maternal venous blood concentration of atropine, determined by bioassay on guinea pig ileum, decreased rapidly in the first 3--5 min and very slowly therafter. In a second study, 45 women in labour received the same dose i.v., and at birth atropine was measured both in maternal and cord blood. Placental transfer of atropine had occurred in every case and was highly variable, depending on the maternal blood concentration of the drug. This suggests that the atropine test is not mainly dependent on placental function.


Nocturnal inhibition of lipolysis in man by nicotinic acid and derivatives. The effect of nicotinic acid and several derivatives on the nocturnal level of free fatty acids was studied in 12 healthy young women and men. Free fatty acids are an important precursor of plasma triglycerides and their concentration is highest at night. The drugs used were nictinic acid, beta-pyridyl-carbinol, mesoinositol hexanicotinate and xantinol nicotinate. The highest plasma nicotinic acid level was observed with beta-pyridyl-carbinol, but significant reduction in free fatty acids during the entire night was only achieved with inositolhexanicotinate and xantinol nicotinate. There was no correlation between the plasm levels of free fatty acids and nicotinic acid at any sampling time. If prolonged reduction in free fatty acid concentration is desired in the therapy of hyperlipidemias, the inositol and xantinol esters of nicotinic acid appear to be superior to the other preparations.


Plasma and urinary levels of triamterene and certain metabolites after oral administration to man. The plasma and urinary levels of triamterene and two metabolites were measured using a specific method of analysis. Urinary excretion was completed after 48 h, which permitted a rough estimate of its half-life as longer than two hours. The areas under the curve were 672.5 +/- 160.3 and 1.311.3 +/- 399.1 micrograms/ml X h after the triamterene 150 mg and 300 mg p.o., respectively and correspondingly 4.2 +/- 1.4% and 3.7 +/- 0.6% of the dose were excreted as unchanged drug. The principal metabolite of triamterene found was the sulfate conjugate. The area under the curve of this metabolite amounted to 6.672 +/- 2.120 and 11.941 +/- 5.005 micrograms/ml X h after the of 150 mg and 300 mg triamterene doses, respectively. The urinary excretion of the metabolite varied between 25.0 +/- 4.0% and 17.5 +/- 3.5% of the dose after either dose. In healthy subjects an effect on sodium excretion was observed after a dose of 150 mg, whereas the potassium-retaining effect was observed only after the dose of 300 mg.


Absolute bioavailability of quinidine in two sustained release preparations. The bioavailability of quinidine in two sustained release preparations A and B has been compared in three females and three males with i.v. administration of quinidine. The initial rate of oral absorption did not differ between the two drug preparations; the peak concentration was observed after 4 h both for A and B, but was significantly higher after B. A slower decrease in plasma concentration was observed after preparation A than B. Absolute bioavailability did not differ significantly between A (median values 78.4%) and B (median 87.1%). Drug absorption in vivo was in good agreement with the results of in vitro dissolution tests on both preparations. The slower decrease in plasma concentration found for the new sustained release form of quinidine should be of clinical advantage.


Pharmacokinetics of cephacetrile in patients undergoing haemodialysis. The pharmacokinetics of cephacetrile were studied after its administration as a single i.v. bolus injection of 15 mg/kg body weight to 11 patients with terminal renal inpairment undergoing haemodialysis for 6 h. A two-compartment kinetic model was used to describe the biphasic decrease in plasma concentration. The quantities of antibiotic in the central and peripheral compartments, and the amounts eliminated, were calculated for different times. During haemodialysis sessions, the average pharmacokinetic parameters of cephacetrile determined at the dialyser input were: a = 5.03 h-1, beta = 0.458 h-1, K12 = 2.337 h-1, K21 = 1.996 h-1 K13 = 1.154 h-1, Vc = 5.5081, Vp = 6.4481, Vdss = 11.9561. As a function of the pharmacokinetic parameters of cephacetrile, a regimen of multiple doses was established for patients with terminal renal impairment, which will guarantee safe and effective concentrations of the antibiotic.


Pharmacokinetics of methadone during maintenance therapy: pulse labeling with deuterated methadone in the steady state. A technique is presented for study of steady state kinetics of methadone using pulse labeling with deuterated methadone (d3) and mass fragmentography to measure both unlabeled and labeled methadone in blood. Seven subjects maintained on methadone for at least 10 months were admitted to a closed metabolic ward. The daily dose of unlabeled methadone (d0) was substituted by one dose of methoadone-d3 and plasma levels of methadone-d0 and methadone-d3 were followed for 48 h using a precise (SD +/- 5%) and sensitive (30 pmol/ml) mass fragmentographic technique. Plasma half-lives (T1/2) for both methadone-do and methadone-d3 were calculated from samples obtained 8--24 H following the dose of methadone-d3. The t1/2 of oral methadone-d3 was shorter (22 +/- 2 h) than that of methadone-d0 (52 +/- 20 h). The same pattern was observed after intravenous administration. The results indicate multiple pools of methadone in the body.


Effect of verapamil on ionized calcium excretion in human parotid saliva. The effect of Verapamil on ionized calcium transport in the parotid gland and duct system was investigated in eight male volunteers. Transepithelial Ca++-transport was inhibited, as shown by markedly enhanced excretion of calcium in parotid saliva.


Pharmacokinetics of dihydroquinidine in congestive heart failure patients after intravenous quinidine administration. The pharmacokinetics of dihydroquinidine were studied in 8 patients with congestive heart failure following a 22 min intravenous infusion of a quinidine preparation that contained 5.9% dihydroquinidine as an impurity. Using a thin layer chromatography-fluorometric assay procedure for dihydroquinidine, the post-infusion plasma dihydroquinidine concentrations declined biexponentially. The half-life of the fast and slow dispositional processes was 4.42 +/- 1.81 min and 6.52 +/- 2.40 h, respectively. The central compartment volume for dihydroquinidine in these patients was 0.44 +/- 0.11 l/kg with an overall apparent volume of distribution of 1.14 +/- 0.38 l/kg. The computed values of total body plasma clearance of dihydroquinidine ranged from 1.29 to 2.69 ml/min/kg with a mean value of 1.94 +/- 0.60 ml/min/kg. In these patients, approximately 16% of the administered dihydroquinidine dose was excreted intact into the urine in 48 h. The estimated value of renal clearance was 0.314 +/- 0.129 ml/min/kg. When compared to control cardiac patients, the data showed that the apparent volume of distribution for dihydroquinidine is smaller in patients with congestive heart failure and as a result of this diminished volume, the clearance rate of dihydroquinidine was slower. The net effect of these differences was the production of higher plasma concentrations of dihydroquinidine in the heart failure group.


Absorption of quinidine from an enteric-coated preparation. The absorption of quinidine from single and multiple doses of an enteric-coated preparation (Systodin) was studied in seven healthy subjects, and was compared with the pharmacokinetics of intravenously administered quinidine and the results of in vitro dissolution tests of the tablets. Absorption of quinidine began after a variable delay, 2-8 h (mean 4.8) after fasting and 3-10 h (mean 6.1) after food. The rate of absorption varied both in and between individuals. It appeared to be lower when the drug was administered after food. Multiple doses after food gave a pattern of plasma concentration-time curves similar to that found on administration of single doses after food. The delay prior to absorption was prolonged at night. The ratio between the maximum and minimum concentration of quinidine during a dose interval varied from 1.3 to 3.2 (mean 2.0). Bioavailability of quinidine in fasting subjects ranged from 69 to 95% (mean 83); variation was greater when doses were administered after food. The release of quinidine from the enteric-coated preparation was pH dependent and was sustained at low pHs as may be found in the intestines. The results indicate that the absorption of quinidine from the enteric-coated formulation was dependent on the highly variable rate of gastric emptying and the pH of intestinal fluid, and it varied greatly both within and between individuals.


Enhancement of hepatic drug metabolism by glutethimide in patients with liver disease. A controlled study of the effects of glutethimide on antipyrine metabolism was performed to ascertain how patients with varying degrees of liver damage responded to microsomal enzyme inducing agents. The administration of 250mg glutethimide daily for one week resulted in significant enhancement of antipyrine metabolism in 4 patients with compensated cirrhosis and 5 patients with features of hepatic failure as well as 7 control subjects without liver disease. Even patients with very severe liver disease did undergo microsomal enzyme induction. Changes in antipyrine half-life after glutethimide were directly proportional to the original antipyrine half-life so that the greatest absolute alterations due to enzyme induction occurred in patients with the most severely impaired hepatic function. These results indicate that not only is antipyrine metabolism severely impaired in patients with liver failure, but elimination rates are markedly altered by enzyme inducing agents. Thus, although these results cannot be extrapolated to all inducers of hepatic microsomal enzymes nor to all drugs metabolized by microsomal oxidases, it is suggested that safe and effective management of drug therapy in these patients requires measurement of plasma levels.


Pharmacokinetics of cefoxitin in patients with normal or impaired renal function. The pharmacokinetics of cefoxitin have been determined after a single i.v. injection of 15 mg/kg body weight in 10 patients with normal renal function and 20 patients with varying degrees of renal impairment. The kinetics of the antibiotic followed an open two-compartment model. In patients with normal renal function the following pharmacokinetic parameters were found: alpha = 8.66 h-1 beta = 1.21 h-1 K12 = 3.47 h-1 K21 = 3.17 h-1 K13 = 3.15 h-1 Vc = 4.24 l. Vp = 4.87 l. Vdss = 9.11 l. In the patients with renal impairment there was a significant decrease in alpha, beta, K12, K21 and K13, and an increase in the apparent volume of distribution. The degree of plasma protein binding in patients with normal renal function was 73.6% and this was diminished in patients with renal impairment. A linear relationship between K13 of cefoxitin and creatinine clearance was demonstrated. The dosage regimen for patients with renal impairment should be adjusted by modifying the dosage interval whilst maintaining the amount administered.


Distribution of elimination of hydroflumethiazide in man. The pharmacokinetics of hydroflumethiazide (HFT) were investigated after intravenous and oral administration to healthy subjects. After intravenous infusion, HFT behaved according to a three-compartment model. Two distribution phases were observed, with mean half-lives of 0.26 and 0.85 h, reflecting distribution to red blood cells and tissues. Mean biological half-life (t 1/2 beta) after infusion was 5.2 h. Renal blood and plasma clearance of HFT, as well as the ratio renal blood clearance/renal plasma clearance of HFT, were lower after infusion than during the infusion, due to the distribution characteristics of HFT. After a single oral dose of 2 micronmol/kg, t 1/2 beta was significantly shorter in all subjects than after a single oral dose of 6 micronmol/kg, with mean t 1/2 beta of 8.7 and 17.9 h, respectively. Due to lack of a sufficiently sensitive method for determination of HFT in plasma, it could not be established whether the observed dose-dependent difference in biological half-life of HFT was caused by variation in renal clearance and/or the volume of distribution.


Pharmacokinetics of theophylline in young children with asthma: comparison of rectal enema and suppositories. Six children, aged 2 months - 4 years, received theophylline 5-6 mg/kg intravenously. Its disposition could be described by a two-compartment open model, the mean serum half life (t 1/2 beta) was 3.75 h, i.e., shorter than in adults, but there was a considerable interindividual variation (1.8-7.0 h, in one patient 13.3 h). Thirteen children (2 months - 4 years) received theophylline suppositories in a dose of 3.8-5.0 mg/kg, and ten (6 months - 4 years) in a dose of 8.4-14.5 mg/kg. Absorption was slow (mean half-time 43 min), incomplete and variable (biological availability 8-100%, mean 80%). Only four of the patients given the higher dose and none given the lower dose reached a therapeutic serum concentration (10-20 microgram/ml). Nine children (6 months - 4 years) received rectal enemas of theophylline 4.1-9.2 mg/kg. Absorbtion was rapid (mean half-time 5.5 min) and biological availability averaged 100%. Six patients reached a serum concentration within the therapeutic range. Using the mean values of the calculated pharmacokinetic parameters, rectal enemas providing a dose of theophylline of 6-8 mg/kg t.i.d. were computed to give serum concentrations between 8-20 microgram/ml, without producing too high a level during the absorption phase.


The effects of desmethylimipramine on the pharmacological actions of alpha methyldopa in man. The effect of pretreatment with the tricyclic antidepressant desmethylimipramine (DMI) 75 mg daily for 3 days on the action of oral methyldopa 750 mg was investigated in a double blind crossover design in volunteers. DMI pretreatment caused a small but not significant increase in supine systolic and diastolic blood pressure and heart rate. However, the effects of methyldopa on lying and standing blood pressure and heart rate were not markedly altered by pretreatment. In particular, the fall in standing blood pressure after methyldopa was present with and without DMI and the sedative action of methyldopa was similar. DMI alone reduced saliva production. No evidence was found that tricyclic antidepressant drugs significantly modify the hypotensive effect of methyldopa in man.


Dissociation of biochemical and hypotensive effects of debrisoquine in hypertensive patients. The 24 h urinary excretion of adrenaline, noradrenaline, metadrenaline, normetadrenaline and vanillylmandelic acid, plasma renin activity and plasma and urinary debrisoquine were measured before and during chronic treatment with oral debrisoquine in 14 in-patients with essential hypertension. There was a significant fall (mean +/- SD) in the 24 h urinary excretion of vanillylmandelic acid (15.3 +/- 2.8 to 6.7 +/- 1.9 micronmol) noradrenaline (199.0 +/- 105.8 to 125.2 +/- 43.3 nmol) and plasma renin activity (0.71 +/- 0.47 to 0.40 +/- 0.20 pmol Angio I ml-1 h-1) while the urinary normetadrenaline/noradrenaline ratio increased (10.4 +/- 6.1 to 17.1 +/- 5.1). No significant change was seen in the output of adrenaline or of O-methylated metabolites. Debrisoquine produces extensive noncompetitive inhibition of platelet monoamine oxidase in vivo at low therapeutic plasma concentrations. These changes support the view that treatment with debrisoquine produces intraneuronal inhibition of monoamine oxidase and post-ganglionic blockage. There was a significant correlation between the change in standing diastolic blood pressure and the daily dose (rs = -0.52), pre-dose plasma concentration (rs = -0.85) and mean daily urinary recovery (rs = -0.80), of debrisoquine. The full extent of the biochemical changes were seen at low dose and low plasma concentration and were not directly correlated with the fall in standing or supine blood pressure.


Sympathoneuronal and sympathoadrenal activation during ketamine anesthesia. The effects of ketamine anesthesia (3 mg/kg i.v.) on cardiovascular parameters and noradrenaline, adrenaline and dopamine-beta-hydroxylase (DBH) activity in plasma were studied in 12 patients. At 3, 6 and 10 min after induction of anesthesia, a pronounced increase in heart rate (+28%) and in systolic and diastolic blood pressure (+28% and 17% resp.) was observed. Concomitantly noradrenaline and adrenaline concentrations increased significantly from 187 to 415 ng/l and from 97 to 271 ng/l, respectively. DBH-activity in plasma remained almost unchanged. From these results it can be concluded that the well known cardiovascular stimulant effect of ketamine is due to greatly enhanced sympatho-neuronal and sympatho-adrenal activity, presumably brought about by a central mechanism of action of the drug. Furthermore, DBH-activity in plasma appeared not to be a reliable index of sympathetic activity in man.


Effect on paroxysmal re-entrant supraventricular tachycardia of a drug affecting calcium transport (Ro 11-1781). The effect of Ro 11-1781, a drug that affects calcium transport, in 10 patients with paroxysmal supraventricular tachycardia (PSVT), was studied by intracardiac recording and stimulation. The re-entry circuit involved an accessory pathway that conducted only in the ventriculo-atrial direction in 5 patients, and was confined to the A-V node in 5 cases. Prior to administration of Ro 11-1781 tachycardia could be initiated in all patients. An intravenous bolus of 2 mg/kg during PSVT terminated the tachycardia in all cases by blockade in the A-V node. Ro 11-1781 lengthened the A-V nodal conduction time as well as the functional and effective refractory period of the A-V node. The effective refractory period of the "fast" pathway was variably changed. After Ro 11-1781 the tachycardia zone was abolished in 3 cases, reduced in 3, increased in 3 and was converted to an echo zone in 1. The ability to sustain the PSVT was lost in one subject. The heart rate during PSVT was slowed following Ro 11-1781. Ro 11-1781 appears to be useful for the termination of PSVT, but its ability to prevent PSVT varies. Beneficial effects include abolition or narrowing of the tachycardia zone, loss of the ability to sustain PSVT and a reduction in heart rate during PSVT. The widening of the tachycardia zone may be harmful.


Standardized mental stress in healthy volunteers induced by delayed auditory feedback (DAF). Using delayed auditory feedback (delay 0.175 s) a standardized form of mental stress was investigated in 8 healthy male volunteers. After a resting period and a period of undelayed reading, the volunteers were exposed for 5 min to the DAF stress. During the DAF period heart rate increased by 10% and systolic and diastolic blood pressure increased by 9% and 18%, respectively. As a measure of acute sympathetic activation, plasma concentrations of norepinephrine and epinephrine rose by 68% and 49%, respectively. The activity od dopamine-beta-hydroxylase in plasma was increased by 25%. From these results it can be concluded that the DAF procedure provides a suitable method for inducing a standardized mental stress in normal subjects, which can be measured as changes in biochemical and cardiovascular variables.


Prazosin, pharmacokinetics and concentration effect. The pharmacokinetics and effects of prazosin have been studied after intravenous and oral dosing (1 mg) to 6 normal male volunteers. The mean terminal (beta) half-life was 2.9 h after intravenous and oral routes. Oral bioavailability was 56.9%. The effects of prazosin on blood pressure were more pronounced after intravenous than oral administration, and the hypotensive effect greater on erect blood pressure. There was a significant correlation (P less than 0.02) between the fall in blood pressure and the plasma drug concentration after intravenous prazosin.


Defective N-oxidation of sparteine in man: a new pharmacogenetic defect. Sparteine, an antiarrhythmic and oxytocic drug, is metabolised by N1-oxidation. The sparteine-N1-oxide rearranges with loss of water to 2- and 5-dehydrosparteine. 18 (i.e., 5%) out of 360 subjects were unable to metabolise the drug. These persons, who were designated as nonmetabolisers, excreted almost 100% of the administered dose in urine as unchanged drug. The defective metabolism of sparteine was found to have a genetic basis. Sparteine-N1-oxidation appears to be determined by two allelic genes at a single locus where nonmetabolisers are homozygous for an autosomal recessive gene.


Influence of the defective metabolism of sparteine on its pharmacokinetics. Sparteine is metabolized by N1-oxidation, which in some subjects is defective. The defect has a pronounced effect on the kinetics of the drug. In nonmetabolisers elimination of sparteine proceeds entirely via renal excretion by a capacity-limited process, 99,9% of the dose being excreted as unchanged drug. In metabolisers the drug is mainly eliminated by metabolic degradation. Pronounced differences in beta-phase half-life and total plasma clearance were observed between metabolisers (156 min; 535 ml . min-1) and nonmetabolisers (409 min; 180 ml . min-1).


Pharmacokinetics of metformin after intravenous and oral administration to man. The kinetics of 14C-metformin have been studied in five healthy subjects after oral and intravenous administration. The intravenous dose was distributed to a small central compartment of 9.9 +/- 1.61 (X +/- SE), from which its elimination could be described using three-compartment open model. The elimination half-life from plasma was 1.7 +/- 0.1 h. Urinary excretion data revealed a quantitatively minor terminal elimination phase with a half-life of 8.9 +/- 0.7 h. After the intravenous dose, metformin was completely excreted unchanged in urine with a renal clearance of 454 +/- 47 ml/min. Metformin was not bound to plasma proteins. The concentration of metformin in saliva was considerably lower than in plasma and declined more slowly. The bioavailability of metformin tablets averaged 50--60%. The rate of absorption was slower than that of elimination, which resulted in a plasma concentration profile of "flip-flop" type for oral metformin.


Relationship between plasma concentration and effect of dantrolene sodium in man. Dantrolen sodium is a muscle relaxant, which is used in the treatment of spasticity. Although it is given chronically, little is known about its pharmacokinetic behaviour. The relationship between the effect of a single oral dose of dantrolene sodium and its plasma concentration in healthy volunteers was studied by measuring the effect on the twitch tension, and in spastic patients on the decrease in muscle hypertonia. On the twitch tension dantrolene gave a depression of 49.1 +/- 9.4% (+/- DS) within 1.15 and 3.45 h after ingestion of 100 mg. The mean maximal plasma concentration was 1.24 +/- 0.32 microgram/ml (+/- SD). The effect and the plasma concentration were correlated. No relationship between the plasma concentration of dantrolene sodium and its effect could be established in patients, although definite activity in 6 out of 7 patients was observed after a single oral dose of 100 mg, and plasma concentration of dantrolene sodium greater than 0.3 microgram/ml were consistenly associated with better results than placebo treatment in 6 out of 7 patients.


Influence of milk products on fluoride bioavailability in man. The effect of milk products on the gastrointestinal absorption of fluoride from sodium fluoride tablets was studied in five healthy subjects. Two different diets were tested: (1) 250 ml standardized milk (3% fat) and (2) 500 ml of milk, 3 pieces of white bread with cheese and 150 ml of yoghurt. The 100% bioavailability of sodium fluoride tablets during fasting was greatly decreased by coadministration of milk products: with Diet 1 the absolute bioavailability calculated from combined plasma and urine data was in the range 50--79% and with Diet 2 it ranged from 50--71%. It is suggested that the decreased bioavailability produced by dairy products should be taken into account when establishing flouride dosage regimens for prophylaxis of caries.


Initiation of the blastogenic response of lymphocytes by hyperoptimal concentrations of concanavalin A. The blastogenic response of human lymphocytes in vitro to hyperoptimal concentrations of concanavalin A (Con A) has been studied by means of volume spectroscopy (measuring cellular and nuclear volume), flow cytofluorometry (measuring cellular DNA content) and incorporation of [3H]thymidine ([3H]dThd). The optimal Con A dose with respect to [3H]dThd incorporation was about 30 micrograms/ml. In cultures given hyperoptimal doses, e.g. 100 micrograms/ml, [3H]dThd incorporation was strongly inhibited, whereas the number of cells entering S-phase and significantly increasing their cellular and nuclear volume was considerably larger than with 30 micrograms/ml. With 200 micrograms/ml Con A, which induced negligible [3H]dThd incorporation, the percentage of responding cells was even larger. Hence, doses of Con A, which were hyperoptimal with regard to [3H]dThd incorporation, induced blastogenic response, including DNA synthesis, in a larger percentage of the cells than did the optimal dose. However, in cultures with hyperoptimal Con A doses, the progression of the cell cycle stagnated mainly during S- and G2-phase and few cells completed mitosis. Thus, the blocking effect of hyperoptimal doses was not confined to any particular point of the cell cycle. The reduced [3H]dTd incorporation, seen with hyperoptimal doses, is attributed partly to a failure of this assay under such conditions.


Identification of autoanti-Thi-1 antibody in the sera of BALB/c mice immune to P1798 lymphoma. The specificity was established for the anti-thymocyte autoantibody which appeared in BALB/c mice (BAA) during immunization to the P 1798 lymphoma. The results indicate that BAA is specific for the Thy-1 alloantigen of murine T cells. By immunoprecipitation of 125I-labeled A/J thymocyte surface antigens from freeze-thaw lysates and electrophoretic resolution of the immunoprecipitates on sodium dodecyl sulfate polyacrylamide gels, the BAA and congenic anti-Thy-1.1 or 1.2 were shown to be specific for determinants on the same antigens. Specificity of BAA for Thy-1.2 was shown also quantitative absorption studies. Coating P 1798 lymphoma cells with either BAA or anti-Thy-1.2 reduced the absorptive capacity of these cells for the same or the reciprocal antiserum. Coating P 1798 with an antiserum to P 1798 which was indifferent to the Thy-1.2 alloantigen did not diminish the absorptive capacity of these cells for either BAA or anti-Thy-1.2. These studies have provided firm evidence that BAA is specific for determinants on the Thy-1 alloantigen.


Investigation of the human macrophage. I. Collection and in vitro cultivation. By means of blister formation produced by cantharidin, a certain number of human macrophages could be readily obtained from the blister exudate. In the presence of 50% cell-free exudate, these cells were found to proliferate in vitro. The proliferating cells possessed the morphology and functional characteristics of macrophages.


Anti-idiotypic antibodies of IgM-type produced in carp (Cyprinus carpio L.). Carp synthesize highly specific anti-idiotypic antibodies of the IgM class. Ant-idiotypic antibodies could be elicited in these animals by a human IgM myeloma protein and were detected in a passive hemagglutination assay. The agglutination was completely inhibited by approximately 0.15 microgram homologous antigen, whereas a 100 000-fold excess of a heterologous IgM myeloma protein of the same L chain type did not produce any inhibition. A possible subgroup specificity of carp anti-idiotypic antisera can be excluded.


Sequential study of C 1 q-binding substances and of anti-DNA antibodies in (NZB X NZW)F1 mice: evidence for an acute phase of the lupus disease in 2-month-old mice. Longitudinal studies of C 1 q and DNA-binding substances were performed in sera from 38 (NZB X NZW)F1 female mice between days 39 and 150 of life. Results suggest a two-phase evolution of circulating immune complexes and anti-DNA antibodies in young (NZB X NZW)F1 mice and show the existence of an acute phase of the disease during the second month of life of these mice.


Monoclonal antibodies in cell-mediated cytotoxicity against human melanoma and colorectal carcinoma. Hybridoma-derived monoclonal anti-melanoma antibodies and anti-colorectal carcinoma antibodies were found to mediate in vitro antibody dependent cell-mediated cytotoxicity (ADCC) reactions against melanoma and colorectal carcinoma cells, respectively. The antigen(s) detected in ADCC on melanoma cells maintained for more than one hundred passages in tissue culture were also found on two recently established melanoma cell lines. These antigens were not detected on skin fibroblasts of the same patients from whom the melanomas were obtained. The ADCC reactivities of anti-melanoma and anti-colorectal carcinoma antibodies were found to be specific for melanoma cells and colorectal carcinoma cells, respectively.


Opioid activities of fragments of beta-endorphin and of its leucine65-analogue. Comparison of the binding properties of methionine- and leucine-enkephalin. For characterisation in vitro, four parallel assays were used: the guinea-pig ileum and mouse vas deferens as pharmacological models at 36 degrees C and the inhibition of binding of [3H]-naltrexone, [3H]-leucine-enkephalin and [3H]-methione-enkephalin at 0 degrees C. The Leu65-analogue of beta-andorphin and its fragments (61-65, 61-76 and 61-77) have a lower affinity to the [3H]-naltrexone binding site of mu-receptors than the corresponding Met65-peptides wereheas no such difference was found for the [3H]leucine-enkephalin binding sites or delta-receptors. When the binding of [3H]-methionine-enkephalin or [3H]-leucine-enkephalin was inhibited by cold ligands interacting with delta-, mu-, or kappa-receptors, no evidence was obtained for more than one type of delta-binding site.


Antinociceptive activity of clonidine and its potentiation of morphine analgesia. The activity of clonidine and its interaction with morphine was assessed in the mouse tail flick assay. In this assay, clonidine was found to be 10 times more potent than morphine. Clonidine potentiated morphine antinociceptive activity approximately five-fold and morphine potentiated clonidine activity four-fold. Clonidine's agonstic activity was not reversed by naloxone hydrochloride (10 mg/kg) while the potentiating effect of clonidine by morphine was. Tolerance to the antinociceptive effect of morphine was observed in morphine pellet-implanted mice but no cross tolerance was observed for clonidine. These data indicate that clonidine-induced analgesia is not a result of an interaction at morphine receptors; but rather, common pathway(s) are present which appear to complement the agonistic interaction of each.


Gastric emptying effect of d,1-tranylcypromine and its stereoisomers. The effect of d,1-, d- and 1-tranylcypromine (Tc) on gastric emptying of rats trained to eat once a day during a 2-h period under conditions of normal or depleted catecholamine stores was studied. d,1-Tc and d-Tc reduced gastric emptying intensely and almost similarly whereas 1-Tc produced a qualitatively less intense effect. Reserpine did not modify this effect of d,1-Tc. It is concluded that d,1-Tc is the most effective form for delaying gastric emptying, this effect being mainly due to the d-isomer. Catecholamines are not involved in the gastric inhibiting effect of these drugs.


Effects of pretreatment with 6-hydroxydopamine or noradrenergic receptor blockers on the clonidine-induced distruption of conditioned avoidance responding. The effects of clonidine were assessed on conditioned avoidance responses (CAR) in control, 6-hydroxy-dopamine (6-OHDA)- and vehicle-treated rats, using a shuttle box device. Clonidine (100--400 micrograms/kg) produced a significant decrease of CAR in control and vehicle-treated animals. On the other hand, avoidance responding was only slightly inhibited in the 6-OHDA-lesioned rats. Pretreatment with the alpha-adrenergic blocking drugs yohimbine or phentolamine (1--8 mg/kg) prevented the CAR disrupting effects of clonidine. When animals were pretreated with the beta-adrenergic blocking agent propranolol (1--8 mg/kg) the ensuing injection of clonidine caused a greater CAR depression. Our results further support the hypothesis relating the conditioned performance depression observed after clonidine to the activation of a presynaptic negative feedback mechanism mediated by alpha-adrenoceptors. It is also suggested that propranolol increases the clonidine inhibition through the blockade of a positive feedback mechanism dependent on the activation of presynaptic beta-receptors.


Effects of the unilateral nigral application of baclofen on dopamine release in the two caudate nuclei of the cat. "Encéphale isolé" cats were implanted with three push-pull cannulae. The two caudate nuclei (CN) were superfused continuously with 3H-tyrosine to measure the release of 3H-DA in serially collected fractions. Three hours after the beginning of the experiment, d,l-baclofen, d- or l-baclofen or gamma-hydroxybaclofen were introduced for 15 min in the medium used to superfuse the left substantia nigra. d,l-Baclofen (10(-6) M) stimulated 3H-DA release in the ipsilateral as well as in the contralateral CN but the effect was more pronounced in the ipsilateral CN. Similar effects were observed with l-baclofen. d-Baclofen and gamma-hydroxybaclofen were inactive. The results obtained are discussed in the light of effects previously observed during the nigral application of gamma-aminobutyric acid (GABA) and related compounds.


The effect of apamin on the smooth muscle cells of the guinea-pig taenia coli. The polypeptide apamin caused a small depolarization of the muscle cell membrane of the guinea-pig taenia coli accompanied by enhancement of spike activity and a concomitant muscle contration. The membrane hyperpolarization evoked by intramural stimulation of the non-adrenergic inhibitory nerves (inhibitory junction potential) was reduced by apamin; the antagonism being non-competitive in nature. The rebound depolarization and contraction following the inhibitory junction potential was enhanced by apamin. The membrane hyperpolarization induced by the purinergic compound ATP and by the sympathomimetic adrenaline was converted to a depolarization in the presence of apamin. This depolarization resulted in an increased spike activity and muscle contraction. This was followed by membrane hyperpolarization and muscle relaxation after washout of the drugs. These findings indicate that apamin is a non-competitive, non-specific antagonist of the non-adrenergic inhibitory transmitter and that the inhibitory junction potential and the rebound are mutually independent phenomena.


Analysis of the contractile responses of the ileal segment of the isolated blood-perfused small intestine of rats to adenosine triphosphate and related compounds. For close-arterial injection the isolated small intestine of the rat was perfused by a cross-circulation technique at a fixed flow rate through the superior mesenteric artery with arterial blood from a donor. Single intra-arterial injections of purine derivatives elicited a monophasic fast contraction of the ileum. In order to elucidate the mechanism of the fast contraction, adenosine triphosphate (ATP) was chosen for further investigations. The ileal response to ATP was abolished by tetrodotoxin, hexamethonium or morphine, but was resistant to blockade by atropine, methysergide or mepyramine. These results definitely indicate that ATP causes the fast contraction of the ileum by a stimulation of neuronal elements in the myenteric plexus involving cholinergic interneurons.


Action of parathyroid extract on arterial blood pressure and on contraction and 45Ca exchange in isolated aorta of the rat. The acute effects of parathyroid extract (PTE) on the cardiovascular system were the object of the study. PTE injected at concentrations of 10--100 U USP/kg into conscious rats induced a rapid, transitory fall in systolic blood pressure and a decrease in the total peripheral resistance. Since the cardiac output was unchanged, PTE must act on vascular smooth muscle. In vitro, PTE (2--16 U USP/ml) inhibited the tonic phase (which requires the presence of extracellular calcium) of the contraction of the thoracic aorta in response to phenylephrine or noradrenaline. 45Ca fluxes in the isolated aorta, measured by the lanthanum method, changed in the presence of a high concentration of PTE (1.0 U USP/ml). After 2 min, the influx was lowered and the efflux was enhanced. These effects may have been specific, since they did not appear when PTE had been previously inactivated. Our results suggest that the vasodilator effect of PTE in the rat is due to an action on Ca exchange in vascular smooth muscle.


Peripheral stimulation in mice induces short-duration analgesia preventable by naloxone. Peripheral stimulation was applied to mice by mild caudal electrostimulation, by mechanical pressure or by footshock for 30 sec, before testing on a 52 degrees C hot plate. Reaction times to paw lick and to escape from the hot plate were recorded. Analgesia could be elicited and measured by these procedures. It was of short duration, declining in a minute, and was antagonized by low doses of naloxone. The analgesia measured by the escape reaction time could be elicited after multiple caudal electrostimulation as well as in morphine-tolerant mice, and it could still be reversed by naloxone. An opioid link is thus involved in this phenomenon, which also supports the notion of more than one opioid pathway existing in the brain. The short period of analgesic cover afforded in the face of noxious stimuli would permit aversive action to be taken in nature and thus might represent the prime functional role of enkephalins in the brain.


Skeletal muscle sarcoplasmic reticulum in porcine malignant hyperthermia. To examine the function of sarcoplasmic reticulum (SR) in malignant hyperthermia, SR was isolated from semitendinosus muscle of normal and genetically susceptible Poland China swine. Determinations included rate of calcium binding (oxalate absent), rate and capacity of calcium uptake (oxalate present), and spontaneous calcium release (in the absence of ionic depolarization or calcium) with and without halothane, using the millipore filtration technique. Rate of calcium binding, and rate and capacity of calcium uptake were decreased, and spontaneous calcium release was greater in SR fragments from susceptible swine as compared to those from normal swine. Halothane 0.5% slightly increased the rate of calcium binding in susceptible and normal SR. Above 1%, halothane decreased calcium binding rate, and uptake rate and capacity, and increased calcium release similarly in susceptible and normal SR. These differences in SR function were insufficient to explain the etiology of malignant hyperthemia, nor did the effect of halothane account for its triggering action.


On the ability of choline and its analogues to interact with muscarinic cholinergic receptors in the rat brain. Choline displaced [3H]QNB binding from rat brain muscarinic receptors competitively, (Ki = 460 microM) but it was only 1/1000th as potent as ACh. Deanol was an extremely weak displacer of [3H]QNB binding while hemicholinium-3 was 50 times more potent than choline. Although brain levels of choline are well below its Ki value for muscarinic receptors, choline may directly interact with rat brain muscarinic receptors in some circumstances.


Relation of the centrally evoked pressor effect of angiotensin II to central noradrenaline in the rabbit. Experiments were performed in urethane-anaesthetized rabbits using ventriculo-cisternol perfusion. Central infusion of angiotensin II (50 ng/kg/min) induced a rise in blood pressure which was accompanied by an increase in the noradrenaline concentration of the cerebrospinal fluid. Both effects were highly correlated. Conversely, an i.v. infusion of noradrenaline (5 micrograms/kg/min) which caused a similar increase in arterial pressure did not affect the cerebrospinal fluid catecholamine levels. These results suggest that peripheral cardiovascular effects of centrally administered angiotensin II are related to the activation of noradrenaline structures in the brain.


Dihydralazine and catecholamine-synthesizing enzymes in spontaneous hypertension. Dihydralazine treatment which lowered blood pressure in young rats from the Lyon Hypertensive Strain (LHS), did not change phenylethanolamine-N-methyltransferase (PNMT) activity, but decreased tyrosine hydroxylase and dopamine-beta-hydroxylase activities in the C2 medullary region. These data suggest that the increase in PNMT activity, previously described for this strain, is not a consequence of the developing hypertension and that hypotensive treatment could inactivate some catecholaminergic neurons of the medulla oblongata.


Effects of prostaglandins on coronary flow rate and left ventricular work in isolated rat heart. In isolated rat hearts PGD2, PGE1, PGE2, PGF2 alpha and PGI2 increased coronary flow rate at concentrations of about 23, 1.4, 0.4, 2.5 and 0.6 nmol per l respectively. PGD2, PGE2, and PGI2 did not affect left ventricular work (W 1v). PGE1 (14 nmol/l) lowered W 1v (12% and PGF2 alpha (9 nmol/l) increased W 1v (10%). It is concluded that endogenously released PGI2 can probably affect coronary flow rate.


Responsiveness of cells in the cat's superior colliculus to textured visual stimuli. Responses to texture motion (visual noise) were investigated in the superior colliculus of paralysed cats, lightly anaesthetized with N2O/O2 supplemented with pentobarbitone or Althesin. Within the superficial layers two classes of texture-sensitive neurones were found: Type I units with weak responses to noise, often related to specific elements in the texture and Type II units which were driven independently of the texture structure, and tended to be recorded deep to the Type I units. Type III units recorded from the deep collicular layers were insensitive to texture. Anatomical bases for this differential sensitivity and the notion of two collicular subsystems are discussed.


Anisotropic receptive field structure of cat horizontal cells. Horizontal (H-)cells were recorded intracellularly in the retinae of optically intact feline eyes in vivo. A small light spot orbiting slowly around the receptive field centers was used to quantify the fine structure and diameter of the receptive fields. Receptive field diameters measured in this way were larger than those measured with centered spots of increasing diameter. All H-units studied showed clearly anisotropic receptive field structures. These results are summarized in polar plots representing the local response generating sites with their corresponding "response plus transport" latencies. It is shown that the anisotropic receptive field properties are not incompatible with the approximately homogenous spatial distribution of H-cell somata reported by Wässle and Rieman (1978) for the axonless type of horizontal cell. Finally it is concluded that each H-cell might be involved in many different locally specialized signal processing activities.


The placing reaction in the standing cat: a model for the study of posture and movement. By measuring the forces applied by each limb supporting the weight of the standing quadruped (cat), before and during elicitation of the placing reaction, it was possible to examine quantitatively and qualitatively the postural events which preceded and accompanied forelimb displacement. The findings are summarized as follows: 1. Postural adjustment consists of a shift from quadrupedal stance to a tripodal stance to permit withdrawal of weight from one forelimb without loss of equilibrium. The animal's weight is not equally distributed between the three supporting limbs but the majority of the weight is supported by the diagonally opposing limb pair. 2. During the isometric phase of the placing reaction, the animal's projected center of gravity moves contralaterally, across the diagonal line between the contralateral forepaw and the ipsilateral hindpaw, and comes to rest within the triangular zone outlined by the three supporting limbs. 3. The diagonal supporting stance is a maneuver of an anticipatory nature which precedes and accompanies the placing reaction. 4. The force changes exhibited by each limb to bring the animal to the stereotyped diagonal supporting stance illustrated that the way to achieve this is consistent within a given animal, but differs from one animal to another. The pattern in the same animal is generally symmetrical when lifting the right or left forepaw. 5. The data from the cat are compared to observations in other quadrupeds and man.


Smooth pursuit eye movements and optokinetic nystagmus elicited by intermittently illuminated stationary patterns. Stationary periodic visual patterns (row of equally spaced dots or black-white stripes) of the period Ps illuminated stroboscopically with a flash frequency fs induce an apparent movement perception (sigma-movement) when slow eye movements are performed across the periodic pattern. The movement appears in the direction of the eye movements when the angular speed VE of the eyes corresponds to the following condition: Ve = k . Ps . fs [deg . s-1] (1) k is a constant and equals 1 (or exceptionally 2 or 3). The sigma-movement induces a sigma-OKN with an average angular speed of its slow phases corresponding to Eq.(1). sigma-OKN can be elicited when identical foveal or identical extrafoveal stimulus patterns are applied from flash to flash. A considerable random variability of the flash sequence does not interrupt the sigma-movement and the sigma-OKN. Both phenomena can also be elicited by a stimulus pattern with its periodicity hidden in spatial noise and this periodic pattern only becomes visible during the eye movements. It is argued that the sigma-phenomena are caused by efference copy signals of the gaze control system, which interact with the afferent signals (displacement of visual stimuli on the retina) at different levels of the afferent visual system. One interaction is supposed at a cortical level where the extrapersonal visual space is represented.


Evidence that the different classes of relay cells of the cat's lateral geniculate nucleus terminate in different layers of the striate cortex. Small electrophoretic injections of horseradish peroxidase (HRP) were made with recording microelectrodes in different layers of area 17 of the cat. The sizes and locations of labeled relay cells in the lateral geniculate nucleus (LGNd) were then studied. Layer I was found to receive inputs mainly from small LGNd cells (13--21 micrometer). These cells were located in the parvocellular C laminae and the MIN. Layer II and the upper portion of layer III were not found to receive LGNd afferents. Lower layer III was found to receive inputs mainly from small to medium-sized relay cells. These cells were located in the A laminae and the parvocellular C laminae. Layer IVab and the layer III--IV border region were found to receive afferents from predominantly large LGNd neurons (greater than 20 micrometers). These cells were located in alminae A, A1, C, and the MIN. Layer IVc was found to receive inputs from mostly small to medium-sized cells (15--23 micrometer). Nearly all of these cells were in the A laminae although some small cells in laminae C were observed following layer IVc injections which involved the layer IV--V border region. Layer V, away from the layer IV--V border region, was not found to receive LGNd afferents. Finally, layer VI was found to receive inputs from both large and small relay cells. These cells were all located in the A laminae. In the light of previous findings, these results suggest that the terminals of W, X, and Y cell axons are segregated within the cat's striate cortex: W cells projecting to layer 1, the deeper portion of layer III and the layer IV--V border region; X cells projecting heavily to layer IVc with a minor projection to layer VI and possibly also to lower layer III; Y cells projecting heavily to layer IVab and the layer III-IV border region with a smaller projection to layer VI.


Development of inferior colliculus response properties in C57BL/6J mouse pups. Response properties of inferior colliculus (IC) neurons were studied in traquilized C57BL/6J mice during a period of rapid auditory system development between 12 and 17 days of age. In IC units of the youngest mice, spontaneous activity was absent, a disproportionate number of onset responses was observed, and many units were not securely driven by sound. Frequency response ranges were restricted to relatively low frequencies, sharpness of tuning was poor, and thresholds at best frequencies (BFs) were quite high. Dynamic intensity ranges were restricted, but nonmonotonic functions were observed. By 15--17 days of age, spontaneous activity was appreciable, incidences of response patterns were near adult proportions, and most units in the ventrolateral nucleus were securely driven by tones. Response ranges had expanded markedly to include high frequencies, sharpness of tuning increased, and thresholds had decreased. Dynamic intensity ranges and intensity functions were similar to those observed in adult mice.


Dendritic spikes in Purkinje cells of the guinea pig cerebellum studied in vitro. Extracellular spikes were recorded simultaneously from dendrites and somata of Purkinje cells in thin cerebellar sections. Spontaneously occurring dendritic spikes were biphasic with the initial phase positive. Triphasic dendritic spikes with a large negative phase appeared during electrophoretic application of glutamate. In media containing procaine, tetrodotoxin, or high concentrations of KCl, negative dendritic spikes occurred whereas soma spikes were abolished. The negative dendritic spikes were suppressed by CoCl2 or MnCl2. Electrical stimulation elicited climbing fibre responses in somata and large negative waves in dendrites. Spikes of dendritic origin were different from those reflecting electrotonic spread of soma spikes. The relation between soma spikes and active dendritic spikes is discussed.


On the function of recurrent inhibition in the spinal cord. Recurrent inhibition of alpha-motoneurons, via motor axon collaterals and Renshaw cells, obviously reduces the response (output) from a motor nucleus to a given synaptic input. It is proposed that the supraspinal covergence on Renshaw cells allows recurrent inhibition to serve as a variable gain regulator at motoneuronal level. This would allow for an optimal resolution in the force control during weak as well as strong contractions. Renshaw cells are not only inhibiting alpha-motoneurons but also gamma-motoneurons and IA inhibitory interneurons. It is argued that this distribution is meaningful since all these receptive neurons act together as a functional unit, forming an "output stage" of the motor system.


Chemical defense of crinoids by polyketide sulphates. The range of (presumed) polyketide constituents in comatalid crinoids has been extended to include bianthronyls, meso-naphthodianthrones and sulphate esters of various of the polyketides. Several species of fish are deterred from eating food by the inclusion in it of these sulphates at the concentration found in crinoids. Sodium 2-hydroxy-anthraquinone sulphate and anthraquinone-2-suphonate were also active as antifeedants for the species tested.


Cannabiripsol: a novel Cannabis constituent. Cannabiripsol [(-) (6aR, 9S, 10S, 10aR)9,10-dihydroxy-hexahydrocannabinol] (1), a new cannabinoid was isolated from a South African Cannabis variant. The structure was determined by spectral means and by synthesis.


Oxidation of synephrine by type A and type B monoamine oxidase. Synephrine (SP) was found to be a substrate for monoamine oxidase (MAO) in rat brain mitochondria, showing the Km and Vmax values of 250 microM and 32.6 nmoles/mg of protein/30 min respectively. The inhibition studies showed that the SP oxidation was carried out by both type A and type B MAO and a major part of the activity was due to type A MAO.


Brain adenylate cyclase activation in the jaundiced rat. Adenylate cyclase responses of brain cortex and neostriatum to noradrenaline and dopamine are increased in rats with jaundice in proportion to its severity. In comparing the situation with uraemia, the relevance of phenols has to be considered.


Occurrence of mitochondrial monoamine oxidase in human semen. Mitochondrial monoamine oxidase (MAO) was found in human semen, showing its Km and Vmax values of 91.7 microM and 290 pmoles/mg of protein/60 min, respectively, with kynuramine as substrate. A major part of the activity was due to type A MAO.


Female sex hormones and lysosomal stability in gingival polymorphonuclear leucocytes. In a group of 5 women taking oral contraceptives, the concentration of polymorphonuclear leucocytes along the gingival margin and the activities of cathepsin D, beta-glucuronidase and elastase were found to increase significantly during the intermenstrual phases.


Purification of 2-deoxy-2-dansylamido-D-glucose by affinity chromatography on a lectin-loaded agarose column. A method is demonstrated to purify 2-substituted derivatives of glucose and sterically related sugars by affinity chromatography on Con A-sepharose. The method seems to be of rather general applicability.


Inhibition of paraquat phytotoxicity by a novel copper chelate with superoxide dismutating activity. A chelate with superoxide dismutase activity, D-penicillamine copper complex, was shown to inhibit paraquat toxicity in flax cotyledons (Linum usitatissimum var. Reina). Paraquat-stimulated chlorophyll loss and ethane production were markedly reduced by this complex. The role of superoxide in the action of paraquat is briefly discussed.


Effect of insulin on lateral diffusion of pyrene in rat liver plasma membrane. The yield of excimer formation by pyrene molecules inserted in rat liver plasma membranes in sensibly decreased in the presence of 1 nM insulin. This effect can be interpreted as indicating a decrease of the value of the translational diffusion coefficient of the dye within the membrane.


Microorganisms seen by scanning and transmission electron microscopy in Legionnaires' disease from human lung. In addition to several anomalous structures, other general forms of definitely rod-shaped microorganisms have been found by scanning and transmission electron microscopy in the lung tissue taken at autopsy from a patient who succumbed to confirmed Legionnaires' disease with extensive necrotizing lobar pneumonia. The microorganisms were greatly varied in size and shape. They were micrographed in the act of fission. These forms have been found to some extent throughout the tissue. No nickel was demonstrated, either in the lung tissue or in the microorganisms.


Reassociation of eukaryotic ribosomal subunits by a factor from rat ascites hepatoma cytosol. Post-ribosomal supernatant extracts from Yoshida AH 130 ascites hepatoma cells promote the in vitro association of ribosomal subunits at low Mg2+ concentration. Comparable extracts from rat liver show, on the contrary, dissociation factor activity on ribosome monomers.


The effects of two neutral polymers on the geometry and deformability of the human erythrocyte. Polyvinylpyrrolidone and dextran decrease cellular deformability. Changes in volume do not wholly account for the changes which imply a stiffening of the plasma membrane. The effects differ from those induced by charged macromolecules.


Immunoglobulin synthesis by cord blood lymphocytes. The IgG, IgA and IgM synthesis by adult peripheral blood and cord blood lymphocytes incubated alone and with pokeweed mitogen was quantitated. The cord blood lymphocytes produced no immunoglobulin even with mitogen stimulation while the adult peripheral blood lymphocytes responded to the mitogen with a significant (p less than 0.04) increase in immunoglobulin production.


Gibberellins and the break of bud dormancy in virus-infected stem cuttings of Euphorbia pulcherrima. Break in bud dormancy in virus-infected stem cuttings of Euphorbia pulcherrima occurs because of the higher quantity of gibberellins present in them than in healthy cuttings in the dormant period of the plant.


Changes of X-prolyl dipeptidyl-aminopeptidase activity in developing rat brain. We found X-prolyl dipeptidyl-aminopeptidase activity in rat brain and examined the developmental changes at various ages. The total enzyme activity per brain increased until 4 weeks of age, and then decreased during maturation. Specific activity in young rat brain was higher than that in adult rat brain. The properties of the brain enzyme were different from those of pituitary and other tissues.


Registration of feeding behaviour in rats by recording food approach behaviour. A method is described in which food approach behaviour of rats is recorded to study feeding behaviour. Between rats, differences in food approach behaviour were observed. For each rat, food approach behaviour was constant over a long period of time. This allows conversion of approach behaviour data into quantified feeding behaviour. Examples of long-term feeding behaviour and of reproducibility of food intake are given.


Amylase secretion from rat parotid glands as dependent on co-operation between sympathetic and parasympathetic nerves. A slow, long-lasting 'degeneration secretion' from the parotid gland was brought about in anaesthetized rats by section of the auriculo-temporal nerve 16--19 h in advance. This parasympathetic background activity greatly increased the secretion of amylase elicited by sympathetic nerve stimulation.


Naloxone selectively blocks dopamine response of Br-type neuron in Helix pomatia L. The present study demonstrates that the potent opiate antagonist, naloxone can selectively block the DA induced inhibition of the bursting activity pattern of the RPal or Br-type neuron. The dopamine inhibitory affect can also be blocked by haloperidol, a established dopamine receptor blocker.


Central nervous system control of mucous gland secretion from frog skin. Surface electrical stimulation of the diencephalic roof of the frog. Rana berlandieri forreri, brain initiates integumental mucous gland secretion which is abolished by pithing.


Methods of analyzing dynamic responses of temperature-sensitive neurones. Methods are described for analyzing the dynamic responses of temperature-sensitive neurones or receptors using a computer facility. The methods allow correlation of impulse frequency with temperature changes or with the rate of temperature changes independent of the time course of the temperature change. Different types of dynamics responses and different thermal sensitivities could be distinguished.


A possible preferential inhibition of chemotaxis of polymorphonuclear neutrophils by a chemical modification. The modification of neutrophils with amino group blocking reagents of different chemical specificities showed that dansyl chloride caused inhibition of chemotaxis without suppression of random movement. Dansylated neutrophils, like control cells, ingested bacteria. Neither the stimulated cyanide-insensitive respiration, nor lactate production during phagocytosis, was affected significantly by dansylation as compared with the inhibition of directed movement.


Effect of adapting target size on the gain of the surround response mechanism in X- and Y-cells in cat retina. The adaptation field of the surround mechanism of X and Y retinal ganglion cells in the cat was assessed with variable size, unmodulated adapting spots. Both an on-inhibition measure and an off-discharge measure of surround gain was used. Results suggest that the surround mechanism in Y-cells is strongest in the receptive field middle but weak or nonexistent in the middle of X-cell receptive fields.


Recurrent inhibition of the monosynaptic reflex in the upper caudal cord of the cat. In spinal cats both ipsi- and contralateral antidromic volleys in the 3rd sacral ventral roots produce recurrent inhibition of the monosynaptic reflex evoked by stimulation of the 1st caudal dorsal root and recorded from the corresponding ventral root.


Cellularity and composition of epididymal adipose tissue from cold-acclimatized rats. Cold acclimatization induces morphological and compositional modifications of rat epididymal adipose tissue: a decrease in fat cell size, an increase of fat cell number per g of tissue, but no significant increase in total fat cell number in the tissue; finally, an increase in protein content and a decrease in triglyceride content.


Postnatal variations of extracellular free calcium levels in the rat. Influence of undernutrition. Ontogenetic changes in calcium activity were directly measured using an ion-selective micropipette in rat blood plasma and olfactory bulb extracellular fluid. Significant differences were observed according to the age and the nutritional state of the animal.


The interaction of warfarin with antacid constituents in the gut. A study was made of the effect of 4 constituents of antacid preparations on the absorption of the coumarin derivate warfarin sodium using an in vitro experimental model. The constituents tested were activated dimethiocone (a silicone) magnesium trisilicate, bismuth carbonate and the adsorbant, kaolin. Slight decreased intestinal absorption was shown by magnesium trisilicate (19%) and bismuth carbonate (7%), the other 2 components showing no effects.


Protective effect of selenite on nitrite toxicity. Selenite was found to decrease nitrite-induced mortality in a dose-dependent manner. Its effect seems to be due to its action in reducing methemoglobin formed by nitrite.


Reduction of acute toxicity of cyclophosphamide and X-rays by the new immunomodulating compound BM 12.531. BM 12.531, the 2-[2-cyanaziridinyl-(1)]-2-[2-carbamoylaziridinyl-(1)]-propane, (prop. INN Azimexon), reduces significantly the acute toxicity of cyclophosphamide and X-rays in rats and mice, respectively. The leucopenia induced by X-rays was partially compensated by BM 12.531 in rats.


Possible mutagenic activity of saccharin. A mutagenic effect of saccharin in Chinese hamsters, using the in vivo SCE test, was observed when massive overdoses were administered; cyclamate was not mutagenic.


50ppm MnBK subclinical neuropathy in rats. 40 rats were subjected daily for 6 months to an atmosphere containing 50ppm MnBK. 32 of the rats presented with demyelination of the sciatic nerve and 2 of these with axonal hypertrophy.


The principal toxin of Delphinium brownii Rydb., and its mode of action. Examination of D. brownii, a stock-poison of Western Canada, revealed that the principal toxin was methyllycaconitine: a potent neuromuscular blocking agent which appears to act competitively at nicotinic receptors.


A prostaglandin-like activity in small intestine and postirradiation gastrointestional syndrome. A correlation between the postirradiation increase of the small intestine motility and the prostaglandin-like activity in this organ during gastrointestional syndrome was observed. Indomethacin decreased the elevated motility of intestine and reduced the prostaglandin-like activity in this syndrome.


Effects of various media on tissular and cellular structures of the superior cervical ganglion of the rat. The superior cervical ganglia of the rat have been incubated in vitro for 1 h in basal medium Eagle (BME) with Hanks' salts, BME with Earle's salts, Kreb's solution and NCTC 109 medium. Comparison of the cell areas, established by a semi-automatic quantitative method, shows that the three former induce a 30--35% neuronal retraction, whereas NCTC 109 has no effect. Thus this latter medium seems the best one for studies using incubation of these cells.


Formation of lung colonies by mouse ascitic teratocarcinomas. Intravenous transplantation of teratocarcinomas resulted in the formation of colonies only in the lung. The lung colony system would be advantageous for the quantitative studies of differentiation of teratocarcinoma stem cells.


Histochemistry of some trout respiratory muscles. A histochemical study has been made of the main cranial muscles which produce ventilation movements of the rainbow trout. It is shown that a greater proportion of red(aerobic) fibres is present in those muscles known to be active during shallow ventilation than those which become active at greater ventilation volumes. An ordered recruitment of red, pink and white fibres within these muscles is also likely.


Differentiating abilities of avian somatopleural mesoderm. Quail-to-chick grafting experiments were performed on 2-day embryos in order to test the differentiating abilities of the somatopleure. After orthotopic and heterotopic transplatations of different parts of quail somatopleural mesoderm into chick embryos it is demonstrated that avian somatopleural cells differentiate into skeletal elements, smooth muscles, tendons and connective tissues. However, skeletal muscle fibres do not originate from somatopleural cells.


Cell division and cell death during regression of the chick embryo Müllerian ducts. In 9-day-old chick embryos, decreased DNA synthesis and enhanced necrosis were observed in a defined area of the right female Müllerian ducts, supporting the idea of the existence of a regression process in this organ. In the male ducts, decreased DNA synthesis and a low level of necrosis were present all over the studied portion of the organ.


Synapse-like profiles in regenerating sensory nerve fibres of Herbst corpuscles. During regeneration sequences of Herbst corpuscles, the synapse-like structures are described between pairs of non-myelinated sensory profiles. The probable significance of this unusual for sensory corpuscles finding is discussed.


Experimental desquamation of intestinal epithelium for in vivo studies of regeneration. Complete removal of villous as well as upper-crypt epithelium was achieved in vivo by vibration of an intestinal segment using tetraphenylboron sodium (TPB) as a disassociation agent.


The pattern of endothelial cell boundaries in regenerated aortae. The pattern of endothelial cell boundaries in the regenerated aorta was shown to differ greatly from that of control specimens as seen in silver stained preparations under the scanning electron microscope.


Sterilization of solanaceous hadda, Epilachna vigintioctopunctata F. by irradiating pupae using gamma radiation. Sterility in males and females was observed in the resulting adults when 3--4-day-old pupae of solanaceous hadda, Epilachna vigintioctopunctata F. were exposed to gamma radiation doses of 2000 rad and 2500 rad. However, at 2500 rad longevity of treated insects was adversely affected.


Ectopic human chorionic gonadotropin in breast carcinoma. Immunoreactive human chorionic gonadotropin (hCG) was found in 9 of 65 surgically removed malignant breast tumors. Concentrations ranged from 5 to greater than 500 mIU hCG/g tumor. hCG was measured by a beta-chain specific readiommunoassay. In further study of these specimens, an immunoperoxidase staining technique was used to stain for hCG in formalin-fixed sections. The hCG was shown to be localized within the cytoplasm and on the surface of the malignant cells.


Passive transfer of resistance in rabbits infested with adult Ixodes ricinus L: humoral factors influence feeding and egg laying. Parital immunity against the bites of female I. ricinus was transferred to normal rabbits by inoculating immune serum from resistant animals. Transferred humoral factors diminished the weight of the ticks' blood meal by 29% and increased the feeding period by about 1 day in comparison with ectoparasites engorged on controls. They provoked also the failure of egg laying by female I. ricinus. Only 55% of ticks fed on treated rabbits laid eggs (94% on controls). The immunological state of immune serum donors or recipients was studied and the IgG and homocytotropic specific anti-I. ricinus antibodies were identified. The immediate hypersensitivity of rabbits' skin was also controlled.


Structure specificity of some immunoadjuvant synthetic glycopeptides. The immunoadjuvant activity of muramyl dipeptide seems to be critically dependent on the type of substitution of the gamma-carboxyl group of the D-isoglutamine residue. Moreover the nonapeptide L-Ala-D-isoGlu-L-lys-D-Ala-(Gly)5-OME also shows a definite effect.


Dose-related enhancement of erythropoiesis by sulfhydryl compounds and its reversal with a thiol inhibitor. Erythropoietin-mediated erythrocyte development from bone marrow of hypertransfused rats was significantly greater when the culture medium contained an optimal dose of certain sulfhydryls. This stimulatory action was attributed to the presence of SH groups because erythroblast numbers fell to control levels when the culture contained the thiol inhibitor, p-hydroxymercuribenzoate.


Alterations in bone-marrow cellularity following thymectomy in rats. The number of nucleated marrow cells was decreased following neonatal thymectomy in rats, and was corrected by administration of syngeneic lymphoid cells, or by implantation of a syngeneic testis. These results suggest that, in the rat, as has been shown previously in the mouse, lymphoid cells exert parital control over bone marrow cellularity and this effect may be further modulated by sex steroids.


The adenohypophysial hormone content of the rat pars tuberalis. The pars tuberalis of the hypophysis was shown to contain LH, which increases after castration, TSH and a very low amount of PRL. FSH was found after castration.


Effect of removal of the Harderian glands on pineal melatonin concentrations in the Syrian hamster. Peak melatonin levels which are normally present in male Syrian hamsters at 8 h after the onset of darkness in animals maintained under a light:dark cycle of 14:10, were significantly decreased following the removal of the Harderian glands.


An immunohistochemical and ultrastructural comparison of the effects of 2-bromo-alpha-ergocryptine on intrasellar and transplanted rat pituitaries. Following 2 weeks of administration of 2-bromo-alpha-ergocryptine, a marked decrease was observed in prolactin immunoreactivity of the grafted pituitaries, whereas no reduction was noted in the intrasellar pituitaries. No evidence of crinophagy was revealed by electron microscopy in prolactin cells of 2-bromo-alpha-ergocryptine-treated rats.


Plasma testosterone concentration in control and testosterone-treated chick embryos. After testosterone propionate treatment (1 or 2 mg per embryo), plasma testosterone in chick embryos rises to 500 times higher than in control animals, and then progressively diminishes during the following days of incubation. These drastic changes in hormonal status after the TP treatment entails consequences that may be considered pharmacological rather than physiological.


Commercially available equipment suitable for post-implantation embryo culture. There is a need for commercially manufactured equipment for use in post-implantation embryo culture techniques. A simple, inexpensive modification to an existing device is described that enables such an apparatus to be used for the roller-tube technique.


[Role of serotoninergic mechanisms in realizing the influence of diazepam on the effect of self-stimulation]. It has been shown in experiments on rats that diazepam (I mg/kg) abolishes an inhibitory action of cytalopram, the serotonine reverse uptake inhibitor (10 mg/kg) on the self-stimulation effect. Activation of self-stimulation was observed during diazepam action and in the presence of a decrease in the activity of serotoninergic processes, that was achieved by parachloramphetamine administration in doses of 5 and 15 mg/kg. It is concluded that the activating effect of diazepam is not mediated through the serotoninergic systems of the brain.


[Dopaminergic component in the mechanism of action of gamma-aminobutyric acid derivatives and structural analogs]. In experiments on rats and male mice the GABA derivatives fenibut, fepiron and the organosilicon compound N-methyl (3-trimethylsilil)pyrrolidone (IA) antagonized apomorphine sterotypy and aggressiveness. Fenibut and IA potentiated haloperidol catalepsy. Fenibut, fepiron, sodium hydroxybutyrate and IA also antagonized the effects of phenamine. The biochemical investigations have shown that fenibut and IA produce acceleration of the intraneuronal synthesis and catabolism of DA. It is suggested that the behavioral effects of the GABA derivatives are partly relative to inhibition of the dopamin--ergic system.


[Morphine and promedol interaction with the plasma proteins of allergized rabbits]. It has been established that morphine interacts with albumins, alpha 2- and beta-globulins, while promedol with all globulin fractions and to a less measure with plasma albumins of the intact rabbit. Interaction of morphine and especially that of promedol with the same protein fractions of allergizated animals proceeds more actively and is characterized by a more pronounced formation of biological complexes with alpha 1-globulins. Decreased pharmacological activity of morphine and promedol coincides with intensification of their interaction with proteins.


[Attenuation of the action of morphine in rats immunized with a conjugated morphine-protein antigen]. The effect of immunization of rats with the conjugated antigen morphine-bovine serum albumin synthetized by the authors on the analgetic activity of morphine hydrochloride has been investigated. Morphine binding antibodies were shown to appear in the blood of rats during immunization. The spleen demonstrated mononuclear cells also capable of morphine binding. It has been established that immunization of rats with the above synthetic antigen makes them tolerate the pharmacological effects of the narcotic. Morphine at a dose of 5 mg/kg is not capable of inducing an inherent increase in the threshold of pain sensitivity in immunized rats. Immunization also slightly diminishes the morphine effect at a dose of 20 mg/kg on the EEC. Prolonged daily administration of morphine does not remove morphine tolerance due to immunization.


[Effect of etimizol on the noradrenaline content and energy metabolism in the rat central nervous system and myocardium]. It was shown in experiments on rats that ethimizol (25 mg/kg) produces the decreasing of noradrenaline in the brain tissue 20 min after intraperitoneal injection. The noradrenaline content is restored in 3 hours. The changes in the balance of tissue noradrenaline were accompanied by phosphorylase activation, decline of the glycogen level and by increasing of glucose and creatine phosphate concentrations. Ethimizol in the same dose did not produce any influence on the tested metabolic parameters in the myocardium of normal rats.


[Effect of dipidolor, seduxen, pipolphen and their combinations on the pain sensitivity of animals]. The analgetic activity of dipidolor and diazepam as well as absence of such an effect in pipolfen were established in experiments on 200 albino rats of both sexes. The combined action of the drugs is manifested in the form of potentiated sinergism shown by increased potency and duration of analgesia.


[Experimental hypolipidemic and antiatherosclerotic activity of bisanions]. Experiments on rabbits with experimental cholesterol atherosclerosis have shown bisanions :formula: see text.


[Antiheparin activity of polymers based on the alkaloid, lupinine]. Antiheparin activity and acute toxicity of a monomer and polymer quaternary ammonium salts obtained on the basis of the alkaloid lupinine were investigated. The monomer was shown to have no antiheparin activity even when administered in high doses. Lupinine polymetakryloyl iodoethylate is a selective heparin antagonist. This activity of polymers is relative to the extent of polymerization. A compound with a molecular weight of 20 000 turned out the most effective in the tested series of ready-made polymers. Acute toxicity of polycations is considerably less than that elicited by the monomer. The effect of heparin complete neutralization is accompanied by transitory thrombocytopenia.


[Toxicity and radioprotective properties of 1,3-oxazine and 1,3-thiazine derivatives]. Toxicity and radioprotective properties of 18 derivatives of oxazine and thiazine with a varying degree of the cycle saturation were studied in experiments on mice. Monotypic regularity in variations of their toxic properties relative to the chemical structure was noted. 4,4,6-Trimethyl-2-dimethylamino-4H-1,3-oxazine exerted a pronounced radioprotective action.


[Effect of the preliminary administration of dextran sulfate on the development of an acute radiation lesion]. Single intraperitoneal administration of dextran sulfate to noninbred mice at a dose of 60 mg/kg 3--24 and 48 hours prior to irradiation in lethal and sublethal doses exerts no radioprotective action. Administration of the drug 24 hours before irradiation increases the intensity of postradiation leukopenia. During irradiation of the animals in a dose of 650 rad dextran sulfate accelerates the recovery of hemopoiesis. With the dose of irradiation being increased up to 750 rad, the drug produces no effect on this parameter.


[Effect of preparations on the capacity of thyroxine to suppress compensatory thyroid hypertrophy in rats]. It has been shown in compensatory hypertrophy of the thyroid gland of male rats weighing 180--240 g that of 18 compounds tested five drugs (cyclic AMP, theophylline, phenformin, tryptophan and disulfiram) reduce an inhibitory effect of thyroxin and are likely to raise the threshold of homeostatic inhibition in the hypothalamohypophyseal and thyroid system.


[Poison content in the blood and tissues of mammals after the inhalational uptake of carbon monoxide and benzene and cyanide vapors]. The time of retention in the body of albino mice, hamsters, albino rats, guinea pigs, rabbits, cats and dogs of carbon oxide benzene and methylcyanide was analyzed. The amount of poison was determined by spectrophotometry and gas chromatography every 4 and 24 hours following inhalation. Conclusions are drawn about constancy of the poison half life for each animal species. Two phases of the poison elimination were determined: rapid (up to 5 hours) and slow (up to several days). The poison elimination rate directly correlated with the pulse rate, respiration and oxygen consumption per unit body weight in all animals, reverse dependence on the body weight being recorded only in albino mice, hamsters, albino rats and guinea pigs.


[Relationship of the antitumor action of cyclophosphamide and prednisolone to the sequence of their administration and to the intervals between administrations in methylcholanthrene carcinogenesis in mice]. The relationship of the antitumor action of cyclophosphamide combined with prednisolone and sequence of and intervals between administrations was studied in C57Bl/bj mice at methylcholanthrene cancerogenesis. Administrations of the drugs was started from the 50th day of cancerogenesis. The best results were obtained in an experiment where the first cycloion of prednisolone. Under these circumstances half of the animals did not develop tumours. Meanwhile the tumours that arose had low tempoes of the growth and tumour-bearing animals showed the longest life span. With an increase in the interval between prednisolone treatment onset and cyclophosphamide injection, the therapeutic effect of the combination declined that was manifested by all the parameters. An opposite effect was recorded in chronic administration of prednisolone following preliminary injections of cyclophosphamide. An increase in the interval between administration of the drugs enhanced therapeutic efficacy of the combination.


[Effect of pentazocine on the catecholamine content, phosphorylase activity and carbohydrate metabolism in tissues]. It was shown in experiments on white rats that pentazocin (3 mg/kg) reduces the adrenalin content in cardiac and hepatic tissues, the aerobic pathway of carbohydrate oxygenation being predominant. The action of pentazocin on the biochemical processes in tissues was compared to that of morphine and nalorphine in equianalgetic doses (3, 1 and 0.57 mg/kg, respectively).


[Pyrrolo(3,2-d)pyrimidines as potential antitumor agents]. Antibacterial and antitumor properties of pyrrolo (3,2-d) pyrimidines having diverse substituents in the second, fourth and sixth position were investigated. Forty-four compounds were examined in vitro and 20 in vivo. A number of the derivatives were shown to inhibit the growth of M. tuberculosis H37Rv and lactic acid bacteria Lactobacillus casei 7469. Antibacterial activity depends on the character of the substituents in positions 2, 4 and 6. The tested compounds when administered per os to mice with sarcoma 180 (a solid variety) proved several dozen times less toxic than 6-mercaptopurine. Some of them inhibited the tumour growth up to 50%. The data obtained in vitro experiments indicate that the mechanism of the antitumour action of pyrrolo (3,2-d) yrimidines from that of 6-mercaptopurine.


On knowledge, policy, practice, and fate. Knowledge of the nation's health and nutritional status is dated, uncertain, incomplete, and complex, whereas politicans demand simplicity and administrators, practicability, and everyone wants more and better information. Rational policy, the unicorn intellectuals hunt, should combine clarity, realism, and conviction, which calls for a touch of passion. Attempts to reconcile these contradictory elements can lead to dangerous political pressures on research; the simplification, exaggeration, and over-generalization of findings; and excessive expectations for humdrum programs that often bear little resemblance to their glorified goals. Inadequate knowledge can justify both action and inaction, which are merely different lays of meeting our fate. The ultimate goal of health and nutrition policy, it may be said, is a long and healthy life and a quick and happy death. That may be desirable, but is it attainable.


The use of government to protect and promote the health of the public through nutrition. There are broad requirements for translation of scientific knowledge in nutrition to public policy through the legislative process. First, it requires an ability to take highly objective, highly specific, scientifically derived facts--the stuff of scientific knowledge--and translate them into legislation based on highly subjective, quite general, broadly perceived values. Another requirement is to keep the level of uncertainty to tolerable levels during consideration of a legislative proposal. Finally, the governmental action proposed must conform to the perception held at that particular time of the role of government in carrying out the law. Three examples of the use of government to protect and promote the health of the public through nutrition are given. They illustrate very well the trials and tribulations of the untidy process of translating scientific knowledge in nutrition to public policy. Governmental action to improve the health of the general public through dietary means has been much a part of this country's policies. The augmentation of purchasing power of the poor, the distribution of surplus commodities to the indigent, the provision of meals to school children and the elderly, etc., are examples of govermental action. There will be further use of government to protect and promote the health of the public through nutrition. A basic requirement is further understanding of the relationship between nutrients and health through good scientific work.


Evidence and proof in making policy decisions. General dietary guidelines for the public are established to minimize risk. Recommended intakes of essential nutrients--the RDAs--are established at levels believed to be substantially above those required by most individuals in order to minimize the risk of deficiency of those with highest requirement. Such levels of intake do not benefit most individuals, cannot be proved to be correct since few individuals benefit, may mislead some individuals as to the benefits to be derived from such diets, but are defensible on the basis that they are probably helpful for a few and impose no health risk. They do impose unnecessary food selection for most people. Recommended intakes of fat, cholesterol, sugar, salt, toxic materials, etc.--food constituents that impose risks at higher intakes--must also be developed to minimize risk. No advantages are claimed for high intakes of the above. Abundant evidence, epidemiologic, clinical, and experimental, identifies high intakes as imposing substantial risk. The nature of chronic diseases associated with excessive intake, which may require 10-30 years before effects are manifest, precludes adequate experiments to definite the results associated with dietary change. The only rational position that can be taken is to recommend reduced intakes consistent with various practical restraints.


Science, senators, and uncertainty.

Science, senators, and uncertainty. Members of Congress consider value judgments and the likelihood of successful enactment as well as scientific facts in formulating policy. If scientists would provide a range of scientifically acceptable options at the same time as they recommend the scientifically optimal solutions, politicans could choose the best scientific option that is also politically acceptable. In the context of research funding Congress needs to be presented with more realistic expectations about the time it takes for different levels of research to result in practical applications, so as to provide better continuity in research funding.


Science, politics, and public policy: a legislator's perspective. Making judgments on priorities in funding is a politican's most difficult task. Scientific information is often necessary to make those judgments, so that good communication between scientist and politican is important. This is, however, difficult because the politician's usual training and working habits are different from those of the scientist. Messages to politicans must therefore be couched differently than in communications between scientists. These messages are more effective when they are concerned with the public need than when they plead for special interests. These messages are most effective when directed to those politicians serving on committees that must deal with the specified issue because Congress makes most political decisions through these committees. Committee members and committee staff members turn to scientists whom they know personally, so that getting to know the members of Congress and the key staff members of committees facilitates communication between science and public policy.


Circadian organization in Aplysia californica. Substantial progress has been made in unraveling the organization of the circadian system of Aplysia californica. There are at least three circadian pacemakers in Aplysia. One has been localized in each eye and a third lies outside the eyes. Removal of the eyes disrupts the free-running locomotor activity rhythm; however, an extraocular oscillator can mediate a free-running rhythm in some eyeless animals. Although photoreceptors sufficient for entrainment of the ocular oscillator have been localized in the retina, photoreceptors outside the eyes are capable of "driving" a diurnal rhythm of locomotor activity and may also influence entrainment of ocular pacemakers. Finally, attention has been focused on the optic nerve as a coupling pathway between various parts of the system. The evidence suggests that information transmitted in the optic nerves is involved in entrainment of the ocular pacemaker by light, and in ocular control of the locomotor activity rhythm.


Physiology of avian circadian pacemakers. The pineal gland plays a cental role in the circadian organization of birds, although it is clearly only one component in a system with other components that have not yet been positively identified. The relative importance of the pineal and other components may vary from one group of birds to another. In the most thoroughly studied species, the house sparrow, pineal removal abolishes circadian rhythmicity; rhythmicity is restored by transplantation of a donor bird's pineal and the restored rhythm has the phase of the donor. This, and other evidence, argues convincingly that the pineal is a pacemaker in the sparrow circadian system. The pineal of the chicken has circadian rhythms in several biochemical parameters that result in the rhythmic synthesis of melatonin. The activity of one enzyme in this pathway is rhythmic for at least two cycles in organ culture. In view of this result it is interesting that pineal removal does not abolish circadian rhythmicity in chickens. The fact that lesions of the suprachiasmatic nuclei abolish circadian rhythms in sparrows, several mammalian species, and perhaps Japanese quail and reptiles, suggests that vertebrate circadian organization may be based on differentially weighted interactions between the pineal, the suprachiasmatic nuclei, and perhaps other brain regions.