Treatment of recurrent syndrome of inappropriate secretion of antidiuretic hormone with lithium.

The usual treatment for recurrent syndrome of inappropriate secretion of antidiuretic hormone has been fluid restriction. Recently White and Fetner described an adult with SIADH successfully managed with lithium carbonate. Described here is a child with recurrent SIADH who was diagnosed as having an acute hyponatremic episode and who then relapsed twice in a two-month period while chronic fluid restriction was attempted. He has now been maintained on 300 mg/day of lithium carbonate and is asymptomatic with normal serum sodium concentration and urine osmolalities. Lithium appears to be effective in the management of recurrent SIADH and may allow control in a patient who cannot comply with long-term fluid restriction.


Hypocalcemia, hyperphosphatemia, and dehydration following a single hypertonic phosphate enema.

Previous reports of hypocalcemia and hyperphosphatemia following use of phosphate enemas have either been in patients with renal disease or followed prolonged abuse of these products. The two patients described here had marked elevation of serum phosphate and concomitant lowering of serum calcium secondary to absorption of phosphate from a single administered enema. Associated moderate dehydration resulted in poor renal excretion of the absorbed phosphate and prolongation of hypocalcemia. Hydration was effective in permitting clearance of phosphate and restoration of normocalcemia.


Treatment of congenital virilizing adrenal hyperplasia patients with single and multiple daily doses of prednisone.

Six patients with congenital virilizing adrenal hyperplasia were evaluated on single- and multiple-dose prednisone schedules. Each of the treatment periods was for one month. Patients were evaluated by 24-hour urinary excretion of 17-ketosteroids and pregnanetriol, as well as 0900 plasma concentrations of 17-hydroxyprogesterone, progesterone, and testosterone. By the criteria of urinary excretion of KS and PNT appropriate for chronologic age, three of the six patients were adequately controlled on prednisone given once a day. Prednisone administered twice daily at 12-hourly intervals either in equally divided doses or with a larger dose in the evening, however, resulted in adequate suppression in all patients. Because of the marked diurnal variation of plasma 17-OHP, the time of day that the sample is drawn is critical. Afternoon samples are often misleadingly low. Plasma 17-OHP concentration may reflect escape from therapeutic control sooner than urinary KS and PNT excretion. There was no correlation between 17-OHP and P values. Plasma concentration of T was not a reliable indicator of good control, since T values were often at prepubertal levels when urinary KS and PNT were elevated.


Suppressibility of glucagon secretion by glucose in juvenile diabetes.

The suppressibility of plasma glucagon concentrations by glucose was investigated in normal and diabetic children. Fasting concentrations of plasma glucagon were similar in normal and in diabetic children despite the hyperglycemia of the latter. Infusion of glucose promptly suppressed glucagon values in the normal as well as in the diabetic children pretreated with half of their usual morning dose of insulin. Glucose alone, however, did not suppress plasma glucagon in diabetic patients, despite the attainment of significant hyperglycemia. Administration of insulin during an ongoing glucose infusion in the diabetic patients lowered their blood glucose concentration; the concentration of glucagon rose transiently when the glucose concentration fell. These data confirm the existence of relative hyperglucagonemia inappropriate for the degree of blood glucose concentration in diabetic children deprived of insulin. The data also suggest that this hyperglucagonemia is secondary to insulin deficiency and suppressibility of glucagon by glucose can be restored by insulin therapy.


Functional development of phagocytic activity of the spleen.

The improvement of phagocytic activity of organs was studied in rats by means of 99mTc sulfur colloid uptake. This function was measured in the newborn rat, 1-, 2-, 3-, and 4-week-old baby rats and in adult rats. Organ distribution of the 99mTc-S-colloid showed marked phagocytic activity of the liver in all age groups including the newborn period. Phagocytosis in bone marrow was markedly increased and that in spleen markedly decreased at the time of birth. However, rapid improvement of phagocytic activity with age was prominent in the spleen.


Argininemia.

The clinical features of argininemia in two cousins included hyperactivity, spasticity, ataxia, retardation, and repeated attacks of hyperammonemia. Study of a large kindred suggests that arginase-deficiency is transmitted as a Mendelian recessive. Treatment with an essential amino acid mixture with the total nitrogen intake limited to the requirement, controlled the hyperammonemia, reduced the plasma arginine level, and permitted a marked clinical improvement. There has been a significant increase in intelligence levels; the previously retarded children are now approaching the normal range of function.


Hyperargininemia.

A 7 1/2-year-old boy had progressive psychomotor retardation, behavior disturbance, and spasticity, and had growth arrest from age three. Plasma arginine on a self-selected protein-poor diet was increased (4.05 mg/dl; nl 0.4 to 2.6), whereas urinary amino acid excretion was normal. Red blood cell arginase was less than 1% of normal in the patient and was half normal in both parents, in two normal siblings, and in his paternal grandfather. Three hours after a meal providing 2 gm protein/kg body weight, the plasma arginine value rose to 13.2 mg/dl, dibasic aminoaciduria was seen clearly for the only time, but blood ammonia concentration remained normal. We conclude that arginase deficiency in the red blood cells and probably in the liver is inherited in an autosomal recessive manner and is responsible for the clinical syndrome in this patient.


The syndrome of inappropriate antidiuretic hormone secretion as a cause of hyponatremia in cystic fibrosis.

The syndrome of inappropriate secretion of antidiuretic hormone was observed in two patients with cystic fibrosis during acute exacerbation of chronic pulmonary disease. It was diagnosed by the accepted clinical and laboratory criteria and confirmed in one case by values for immunoreactive vasopressin that were inappropriately high for plasma osmolality. The severe hyponatremia was corrected by fluid restriction, alone or combined with intravenous treatment with diuretic and hypertonic saline solution. In addition, there was simultaneous therapy of the pulmonary disease. SIADH thus must be added to salt loss as a cause of hyponatremia in CF, and may be more common than realized in patients with CF and severe pulmonary disease.


Cystic fibrosis--related inhibition of mucociliary clearance in vivo in man.

Studies were performed to demonstrate possibly cystic fibrosis-related inhibition of mucociliary clearance in man. Topical application of normal serum or of CF serum did not inhibit in vivo nasal MCC. Induction of local inflammation by topical anti-IgE-reduced nasal MCC in CF subjects, but increased MCC in normal individuals. Furthermore, nasal MCC was inhibited in normal patients by CF serum but not normal serum, applied to the anti-IgE-treated nasal mucosa. These observations are consistent with the hypothesis that CF serum inhibits MCC in vivo in the inflamed mucosa.


Chronic idiopathic intestinal pseudo-obstruction syndrome in children--clinical characteristics and prognosis.

Eleven children with the diagnosis of chronic idiopathic intestinal pseudo-obstruction are presented. Four children, all siblings of a symptomatic patient, were asymptomatic and were diagnosed radiographically. The clinical course was characterized by intermittent episodes of abdominal distention, vomiting, abdominal pain, diarrhea, constipation, and malnutrition. Radiographic studies were most helpful in making the diagnosis. Findings on upper gastrointestinal series included abnormal esophageal motility, delayed gastric emptying, dilated loops of small bowel, and disorganized transit of barium. Half of the patients had abnormal evacuation patterns on barium enema. Manometric studies of esophageal motility were abnormal in seven of ten children. In those patients studied, small bowel and rectal biopsies contained ganglion cells. Treatment was directed at relieving symptoms, which in four patients became persistent and required total parenteral nutrition. CIIPS carries a poor long-term prognosis in children.


Long-term pulmonary sequelae of premature birth with and without idiopathic respiratory distress syndrome.

Seven children born prematurely who survived the respiratory distress syndrome, seven children born prematurely who had no neonatal lung disease, and seven normal children born at term were studied by comparison of flow volume curves obtained while breathing air to those obtained while breathing 80% helium and 20% oxygen. Expiratory flow rates in air both groups of prematurely born children were lower than flow rates of the children born at term, and the volumes of iso-flow were higher in the survivors of RDS than those of the children born at term. The differences in flow rates in air suggest an increase in large airway resistance in both groups of prematurely born children. It is speculated that this may be secondary to growth retardation related to prematurity. The elevated Viso V in the RDS group suggests an increase in small airway resistance secondary to the disease or to its therapy.


Dexamethasone levels in treated pregnant women and newborn infants.

Dexamethasone concentration was measured in plasma and amniotic fluid by radioimmunoassay using a rabbit antiserum raised against DX-hemisuccinate-albumin. Recoveries of added tracers averaged 70% after paper chromatography. The within- and between-assay coefficients of variation averaged 10%. The lower limit of detection was 0.2 mug/dl when 0.4 ml of plasma was assayed. Ten healthy pregnant women at term had cesarean sections 8 to 11 hours following administration of 8 mg of DX orally. DX levels in maternal vein, in umbilical vein and artery, and in amniotic fluid averaged 2.2, 2.9, 2.6, and 2.5 mug/dl, respectively. Although cortisol levels were markedly suppressed, the total relative glucocorticoid activity in blood of fetuses treated with DX far exceeded that of the untreated group.


Withdrawal symptoms in infants with the fetal alcohol syndrome.

Six infants with dysmorphic features of the fetal alcohol syndrome presented with symptoms of withdrawal from alcohol similar to those observed in adults and animals. Symptoms were characterized by irritability, tremors, spontaneous seizures, opisthotonos, and abdominal distention. A comparison of symptoms is made to animal and withdrawal from ethanol and to the neonatal narcotic withdrawal syndrome.


Asymptomatic gonorrhea: prevalence in a population of urban adolescents.

During a 12-month period, 2,672 sexually active youths, 12 to 16 years of age, had genital bacteriologic cultures for Neisseria gonorrhoeae. Anterior urethral cultures were obtained from 2,098 males of whom 2,064 had no symptoms or signs of genitourinary disease. Forty cultures (1.9%) were positive for gonorrhea. Of 574 females, 374 were asymptomatic and 26 (7.0%) had positive gonorrhea cultures from the cervix. Since adolescent boys are more likely to be sexual adventurers, the 1.9% carrier rate represents an important reservoir of gonorrhea and equal in importance to that found in the asymptomatic adolescent girl.


Adolescents who attempt suicide.

A suicide prevention program for teen-agers was established and at the completion of the first two years a review of the data was undertaken. A group of 65 adolescents who attempted suicide were identified in that time period. The median age group was 16 years, and 75% were girls. Ingestion was the predominant method used in these suicidal attempts. The major characteristics of these youngsters included long-term family disruption, social isolation, and academic difficulties. A subgroup of 25 adolescents received psychologic tests. When compared to a matched control group there was a significantly higher rate of minimal brain dysfunction for those adolescents who attempted suicide.


Hypothermic total body washout and intracranial pressure monitoring in Stage IV Reye syndrome.

The number of children in this report treated with either TBW or exchange transfusions is small. Case mortality rates among children with Reye syndrome in Stage IV coma tends to be exceedingly high, varying from 50 to 100%. Intracranial pressure monitoring with the subarachnoid screw may have been an additional factor in increasing our survival data in three patients in the TBW group, since it provided continuous monitoring of ICP and allowed judicious administration of mannitol intravenously. Survival of five of six patients without neurologic sequelae in the present series has encouraged us to coninue utilization of TBW in children with Stage IV Reye syndrome.


The displacement of bilirubin from albumin by furosemide.

Since furosemide, a sulfonamide diuretic, has been recommended for use in the newborn infant, a study was made of its effect on the bilirubin-binding capacity of albumin. Furosemide was compared to sulfisoxazole, a known displacer of bilirubin, by means of three methods. First, aliquots of whole blood from 20 icteric infants were diluted in phosphate buffer along with expected clinical concentrations of furosemide and sulfisoxazole. The red cells and globulins were then isolated and bilirubin concentrations were measured in these two fractions. The addition of Furosemide resulted in the displacement of bilirubin from albumin to red cells and globulins. Mole for mole, furosemide displaced bilirubin about as well as sulfisoxazole. Second, the hydroxybenzeneazobenzoic acid dye binding test of Porter and twaters was performed using the sera of eight jaundiced newborn infants. The mean dye binding capacity of the sera was significantly reduced with the addition of furosemide to a final concentration of 2 mug/ml. Third, the administration of furosemide (5 mg/kg) or sulfisoxazole (50 mg/kg) to adult Gunn rats resulted in a significant fall in mean serum bilirubin concentration compared to saline controls. Furosemide, like sulfisoxazole, is a potent displacer of bilirubin and should be used with caution in jaundiced infants.


Displacement of bilirubin from human albumin by three diuretics.

The interaction of three diuretics with bilirubin-albumin complexes was studied using the peroxidase assay, erythrocyte uptake, and sephadex gel filtration. On a molar basis, each diuretic was as potent or more potent than sulfisoxazole in displacing bilirubin from albumin. Furosemide and ethacrynic acid, when used at the recommended dosage (1 mg/kg), would probably not produce a significant increase in free bilirubin in most infants. Chlorothiazide could introduce a significant risk to jaundiced infants because of the higher dosage required.


Plastic flow during compression of directly compressible fillers and its effect on tablet strength.

The effects of the duration of the overall compression cycle and of the duration of the maximum compressive force on tablet strength were studied using an instrumented rotary tablet press. Various direct compression fillers were evaluated. Increasing the overall compression cycle duration to 10 sec resulted in significantly greater tablet tensile strengths with microcrystalline cellulose and compressible starch fillers but not with lactose or compressible sugar. Increasing the duration of the maximum compressive force to 20 sec significantly increased the tensile strength in all cases, but microcrystalline cellulose and compressible starch tablets were affected more than lactose or sugar tablets. The maximum compressive force decayed with time for all fillers but at a greater rate with microcrystalline cellulose and compressible starch. This behavior was attributed to differences in the extent of plastic flow. The decay curves were analyzed using the Maxwell model.


Zero-order drug delivery system: theory and preliminary testing.

A new approach to zero-order drug delivery that includes geometric factors is described. An experimental device based on the theory was tested by following the release of stearic acid into ethanol. Three separate trials indicated that the solid was released via a zero-order process in a reproducible manner.


Analysis of theoretical behavior of a proposed zero-order drug delivery system.

An analysis of the theoretical behavior of a proposed zero-order drug delivery system is presented. Equations describing drug release with time are developed using a physically realistic model. The theory agrees well with experimental data and indicates that drug release from the device is nearly, although not rigorously, zero order.


Effect of symmetrical tetraalkylammonium salts on cloud point on nonionic surfactants.

The salting in and salting out of the nonionic surfactant octoxynol NF by halides of ammonium and the four lowest symmetrical tetraalkylammonium cations were investigated by measuring their effect on the cloud point at various salt concentrations. The chloride anion tended to salt the surfactant out, lowering its cloud point. The iodide anion tended to salt it in, raising the cloud point, while the bromide ion had no pronounced effect. The ammonium and tetramethylammonium cations tended to lower the cloud point, the latter more extensively than the former. The tetraethylammonium cation had no pronounced effect, while the tetra-n-propylammonium and tetra-n-butylammonium cations tended to raise the cloud point, the latter more extensively than the former. The salt effect on the cloud point generally increased with increasing salt concentration. Tetramethylammonium chloride was the most efficient salt in lowering the cloud point (by 4 degrees at the 0.10-molal level and by 20 degrees at the 1.00-molal level), while tetrabutylammonium halides were the most efficient salts in raising the cloud point (by 18-19 degrees at the 0.10-molal level for chloride and bromide). Cloud point increased were attributed to the formation of mixed micelles or to hydrotropy. The salting-out efficiency of tetramethylammonium chloride and bromide was ascribed to their ability to increase the structure of water.


Stereochemistry of metabolism of amphetamines: use of (-)-alpha-methoxy-alpha-(trifluoromethyl)phenylacetyl chloride for GLC resolution of chiral amines.

Amphetamine and eight related compounds were reacted with the chiral acylating reagent (-)-alpha-methoxy-alpha-(trifluoromethyl)phenylacetyl chloride to obtain, in each case, two diastereomeric amide derivatives. GLC conditions were found for the separation of the diastereomers in seven of the nine cases studied. This procedure may be suitable for the resolution of amino acid enantiomers via the amide derivatives of the methyl esters. Secondary amines were not derivatized under the reaction conditions used. A correlation between absolute configuration and elution order of the diastereomeric amides was observed for five compounds. The chiral acylating reagent was used in the determination of the enantiomeric composition of 2,5-dimethoxy-4-methylamphetamine excreted in rat urine after intraperitoneal drug administration. The chiral acylating reagent is suitable for the determination of the optical composition of compounds extracted from biological fluids.


Interpretation of plasma concentration-time curves after oral dosing.

The pharmacokinetic information obtained after oral administration is examined using the two-compartment model. Data were obtained by simulation and experimentally by administering sulfisoxazole by an exponential infusion to rabbits. When the absorption rate constant is allowed to approach alpha, a typical two-compartment oral absorption curve is obtained, which is described by a triexponential equation. However, if the absorption rate constant approaches E2 (the sum of the elimination rate constants out of the peripheral compartment), the data are adequately fit by a one-compartment model, with the calculated absorption rate equal to alpha. The relative error in using a one-compartment model to calculate absorption rate constants for two-compartment data is also evaluated.


Quantitative estimation of particulate matter in pharmaceutical preparations intended for intravenous administration.

A fast, reproducible, economical, and dependable automated counter method is recommended for the quality control of pharmaceutical preparations intended for intravenous administration. The USP gives no specifications on the limitations of particulate matter in intravenous products, while the BP specifies limitations on intravenous solutions of more than 500-ml volume. Out of 15 different marketed products, few passed the BP specifications. The microscopically identifiable particles included starch, cellulose fibers, glass, rubber, lacquer flakes, carbon black, and metal shavings. The proposed quality control method introduces a modification to the BP specifications. The method includes a standard log-log plot obtainable from a least-squares line fit to the data of the marketed products showing minimal particle contamination. The standard plot is compared to the experimental data obtained from any other product and, accordingly, it is decided whether the product is acceptable or not.


Identification of nonpolar methotrimeprazine metabolites in plasma and urine by GLC-mass spectrometry.

Two metabolites of methotrimeprazine, the sulfoxide and the demethylated analog, were identified in extracts from patient plasma by combined GLC-mass spectrometry. Methotrimeprazine and its sulfoxide had similar mass spectra but different GLC retention times. In addition to the metabolites found in plasma, two other metabolites, the didesmethyl analog and the monodesmethyl sulfoxide, were identified in a urine extract.


High-performance liquid chromatographic determination of diethylpropion hydrochloride in tablets: isolation and identification of two decomposition products.

A rapid assay was developed for diethylpropion hydrochloride tablets using high-performance liquid chromatography (HPLC) with UV detection. This technique provided separation of the drug from other UV-absorbing components present as the result of decomposition. A major decomposition product detected by HPLC in extracts of tablets and of the cotton filler from a tablet bottle was collected from the column effluents. This product was subsequently identified as 1-phenyl-1,2-propanedione, a highly volatile compound. A second decomposition product, isolated from decomposed drug by distillation from alkaline solution, was identified as diethylamine, apparently present as the hydrochloride salt, GLC, UV, IR, NMR, and mass spectrometry were used to confirm the identity of the decomposition products. HPLC assay results compared favorably with results of the NF assay; the latter procedure separated the drug from 1-phenyl-1,2-propanedione via liquid-liquid extraction.


Kinetic spectrophotometric study of effect of triazolopyrazines on p-benzoquinone complexes.

The effect of adding triazolopyrazines to a p-benzoquinone-proline system and a p-benzoquinone-histamine system was studied by observing the kinetics of the spectral changes and analyzing the results using digital simulation methods. Below 35 degrees, the major effect was that the triazolopyrazine competed with the electron donors for the acceptors to form complexes. Above 35 degrees, there was predominantly a chemical interaction between the triazolopyrazine and the acceptors. A separate experiment showed that the triazolopyrazine interacted with p-benzoquinone to form a complex initially but that a chemical interaction took place later.


Protein binding of benz[a]anthracene and benzo[a]pyrene.

Fluorometric studies on the binding of benz[a]anthracene and benzo[a]pyrene to human serum albumin are described. The protein molecule appears to have one binding site for the hydrocarbons, but all of the sites on the protein are not fully occupied even in relatively large hydrocarbon concentrations. Equilibrium studies showed that both hydrocarbons bind to the protein to the same extent. Evidence for the energy transfer from the tryptophan residue of the protein to bound hydrocarbons is examined. By using Förster's theory, the mean distance between the tryptophan residue and bound ligand was found to be 15,2 A for benz[a]anthracene and 19.6 A for benzo[a]pyrene. It is concluded that the two hydrocarbons may bind to the same general area on the protein molecule near the tryptophan residue but at different sites. The structural differences of the hydrocarbons, which may greatly affect their orientations on the protein molecule, affect mainly the selection of the binding site rather than the binding equilibrium.


Rapid sensitive fluorometric analysis of cephalosporin antibiotics.

A rapid and sensitive fluorometric analysis for cephalosporins, which can also be applied to penicillins, is presented. The method involves reaction with 0.1 N sodium hydroxide at 100 degrees, producing stable fluorescent products. This method was applied to cephalexin and ampicillin with detection at concentrations as low as 0.01 mug/ml.


Aqueous chamber drug distribution volume measurement in rabbits.

A method was developed for aqueous chamber drug distribution volume measurement in the albino rabbit, and the apparent volume of distribution was determined for inulin, pilocarpine alkaloid, and 1-hexanoic acid. The method consists of injecting a suitable concentration of drug, in an appropriate volume of fluid, into the anterior chamber of the eye and monitoring the decline in drug concentration as a function of time by periodic sampling of the aqueous humor. Graphical analysis of the resulting data yields both the apparent volume of distribution and the turnover rate constant of the aqueous humor. The technique does traumatize the eye, causing formation of plasmoid aqueous, which does not interfere with the apparent drug distribution volume measurement or the determination of aqueous humor turnover. Inulin was used to determine the physiological aqueous volume, 287 mul, in good agreement with literature values. The turnover rate constant was 0.016 min-1, also in good agreement with literature values. The apparent volume of distribution for pilocarpine alkaloid was 575 mul in albino eyes and 760 mul in pigmented irides; for 1-hexanoic acid in albino eyes, it was 760 mul. For pilocarpine alkaloid, literature citations on the fraction of dose absorbed have been based on an assumed apparent volume of distribution of 250-300 mul. Therefore, a factor of two error has been introduced when using albino eyes and a factor of almost three has been introduced when using pigmented eyes. The implication of the apparent volume of distribution for pilocarpine in its ocular disposition is discussed, as is the unexpected observation that pilocarpine alkaloid apparently inhibits formation of plasmoid aqueous and follows one-compartment kinetics during these studies. Is is shown that the one-compartment kinetics for pilocarpine are due to its biological activity in the aqueous chamber.


Biological distribution of chemical analogs of fatty acids and long chain hydrocarbons containing a strong chelating agent.

The pharmaceutical preparation, chromatography, and biological distribution of a series of new chemical analogs of palmitic acid and diethylenetriaminepentaacetic acid, ethylenediaminetetraacetic acid, or diethylenetriamine are described. The biological distribution in rabbits 30 min after intravenous administration of these 99mTc-labeled and 57Co-labeled derivatives was compared to the biological distribution of the parent compound, 3H-palmitic acid. The average myocardial uptake for these compounds was 0.04%/g, compared to 0.15%/g for palmitic acid. The heart to blood ratio at 30 min reached a maximum of 3:1 for the best physiological analog of palmitic acid, compared to an average of 30:1 for palmitic acid. Although none of these analogs appears to be clinically useful, their production methods might be applicable to the synthesis of new compounds that might increase the specificity of radiopharmaceuticals.


Pharmacokinetics of beta-methyldigoxin in healthy humans I: intravenous studies.

The pharmacokinetics of intravenously administered solutions of 0.30-and 0.60-mg bolus doses of 3H-beta-methyldigoxin, labeled in the 12alpha-position, were dose independent. Individual radioactivities assignable to the parent drug and specifically identified metabolites after TLC separation were followed in the plasma, urine, and feces. A sum of four exponentials described the plasma beta-methyldigoxin data with apparent half-lives of 0.04, 0.33, 3.5, and 41 hr. beta-Methyldigoxin was 10% plasma protein bound and had a red blood cell-plasma water partition coefficient of 0.9. The only significant metabolite observed in plasma was digoxin, although glucuronides and sulfates of beta-methyldigoxin, digoxin and digoxigenin also were observed in urine. As much as 92 +/- 3% of the dose was excreted by all processes by 144 hr. Of this amount, renal excretion accounted for fractions that were 0.47 unchanged, 0.35 digoxin, and 0.058 water-soluble metabolites. The fraction in the feces was 0.13. The urine flow independent renal clearances of beta-methyldigoxin and derived digoxin were 59 and 206 ml/min, respectively. The metabolism was a relatively fast process. The terminal pseudo-steady-state elimination of beta-methyldigoxin with a half-life of 41 hr was reached 27 hr after drug administration and was primarily dependent on the slow release of sequestered or distributed drug drom the tissues into the central compartment. The drug and metabolite levels in plasma and urine were consistent with analog computer fitting to the proposed pharmacokinetic multicompartmental model.


Prediction of tableting problems such as capping and sticking: theoretical calculations.

Tabletability factors were developed through the use of an automated tabletability tester, and the applicability of these factors to actual manufacturing procedures was tested by the large-scale manufacturing of tablets. Use of this approach does not require knowledge of the tablet's physical properties, e.g., moisture content, porosity, particle size, fluidity, and angle of repose.


Indolizine derivatives with biological activity I: N'-substituted hydrazides of indolizine-2-carboxylic acid.

The synthesis and antimonoamine oxidase activity of some N'-substituted hydrazides of indolizine-2-carboxylic acid are described. They all inhibit monoamine oxidase and are more active than iproniazid. The structure-activity relationships also are discussed.


Synthesis and anticancer screening of 2-indolyl 5-(1,2,3,6-tetrahydropyridyl) ketones.

Several derivatives of 2-indolyl 5-(1,2,3,6-tetrahydropyridyl) ketone with various substituents on the pyridine nitrogen and with or without a benzenesulfonyl group on the indole nitrogen were synthesized and characterized by spectroscopic and analytical data. Only one showed erratic but confirmed activity in the P-388 screen. The other derivatives were inactive in the L-1210 leukemia screen.


Bioavailability of digoxin in a new soluble pharmaceutical formulation in capsules.

The in vitro dissolution and the bioavailability of two pharmaceutical formulations of digoxin were compared, one being a common commercial tablet form and the other a solution of the glycoside in soft gelatin capsules. Digoxin capsules dissolved more readily in vitro and showed higher bioavailability than digoxin tablets in both dogs and humans. In dogs, the capsules and tablets were compared with an elixir of digoxin, which possesses complete bioavailability. The better bioavailability of digoxin capsules as compared with tablets may be explained by the fact that this formulation contains the cardiac glycoside in a solution.


Cardiovascular and neuromuscular effects of dimethyl sulfoxide in anesthetized rabbits.

In rabbits anesthetized with pentobarbital, the carotid arterial blood pressure and bilateral contractions of the gastrocnemius muscles due to electrical stimulation of the sciatic nerves were recorded. Intravenous administration of up to 1 ml of dimethyl sulfoxide/kg caused profound hypotension and eventually failure of neuromuscular transmission. Caution must be used in considering dimethyl sulfoxide as a solvent for drug administration.


Biological disposition of rigid analogs of amphetamine.

Tissue levels of amphetamine and of amphetamine analogs with a rigid conformation (2-aminoindan, 2-aminotetralin, and 2-aminobenzocycloheptene) were measured in rats by a spectrofluorometric method involving the reaction of the primary amine group with fluorescamine. All drugs were concentrated in tissues, the order of distribution being lungs greater than kidneys greater than liver=spleen=brain greater than muscle greater than fat=heart greater than blood. In brain, amphetamine and 2-aminoindan were present mostly in the supernatant fraction after high speed centrifugation onbrain homogenates; the two higher molecular weight drugs were present at slightly greater concentrations in the particulate fraction. All four drugs disappeared from rat brain with half-lives of 1-2 hr. Iprindole pretreatment increased drug levels in brain and prolonged the half-lives by two- to threefold. The data suggest that the biological disposition of the rigid analogs resembles generally that of amphetamine and that all of the drugs are probably metabolized by ring hydroxilation in the rat.


Rapid acetylation of a dihydroxy compound by 4-(dimethylamino)pyridine catalysis: application to GLC determination of clindamycin palmitate hydrochloride.

The acetylation of clindamycin palmitate hydrochloride, preparatory to GLC assay, was accelerated greatly by the use of 4-(dimethylamino)pyridine as a catalyst. The reaction time was reduced from 2.5 hr at 100 degrees using pyridine and acetic anhydride to 30 min or less at ambient temperature upon addition of excess catalyst.


Tissue distribution of 3H-canrenoate potassium in rabbits.

Plasma and various organ concentrations of canrenone, canrenoate, and total 3H-activity were measured following single doses of 20 mg of 3H-canrenoate/kg iv to rabbits. Organs studied included heart, lungs, brain, kidneys, liver, adrenal glands, and spleen. Canrenoate was shown to be in rapid equilibrium with canrenone. Both were eliminated from plasma and other tissues with a half-life of about 1 hr. Plasma concentrations of both drugs were equal as early as 10 min after intravenous drug administration. Canrenone was concentrated about 10-fold in organ tissues when compared to plasma, while no such preferential uptake was found with canrenoate. Total 3H-activity declined slowly in all tissues with a half-life of approximately 15 hr, indicating extensive metabolism and metabolite retention in the rabbit.


Survival of pleomorphic sarcoma-37 transplanted virgin female DBA/2J mice: effects produced by high blood glucose levels alone and in combination with drugs.

Procedures for producing, monitoring, and maintaining 3-hr 400-500-mg% whole blood glucose levels in Sarcoma-37 (S-37) transplanted virgin female inbred DBA/2J mice are described. Aqueous infused 40% (w/v) dextrose was evaluated as a potential therapeutic factor. The effects of procedural variations on treatment survival and longevity are discussed. One hundred percent infusion safety and 25% increased longevity over nontreated transplanted mice were achieved. Doxorubicin and/or dacarbazine were also evaluated when administered prior to the dextrose infusion. Doxorubicin followed by intravenous dextrose increased survivor longevity by 37%, but this combination was unsafe at the drug dosages employed. A large dose of dacarbazine was safe and effective alone but unsafe when given prior to the infusion, although the survivors lived 29% longer than the untreated transplanted controls. Both drugs were marginally effective, but safe, when given together. When given together prior to the infusion, only 87% survived the treatment. The survivors lived 6 days longer than the controls.


New and simple method for determination of 2-(3-benzoylphenyl)propionic acid in body fluid.

A simple, fast, sensitive, and reliable method for the determination of 2-(3-benzoylphenyl)propionic acid in biological fluid is described. The method is based on a quantitative ether extraction of plasma samples followed by TLC separation, spot visualization and elution, and determination at 255 nm. The acid is detectable in amounts as low as 1 mug.


Water as a nonpolar partition medium.

Coacervates have been suggested as models for cytoplasm since cytoplasm is also essentially an aqueous phase of water-protein-colloid complexes. This study on partition coefficient properties made use of coacervate phases as the nonpolar phases in equilibrium with polar water phases. The partition coefficients of four barbiturates were obtained, and their values correlated with those reported in the literature for systems using organic solvents as the nonpolar medium. These values also correlated with reported values for the absorption ranking of the barbiturates in the rat colon. The partition coefficients of theobromine and theophylline in gelatin-benzalkonium chloride coacervate systems were also found to correlate with the partition values reported in the literature for heptane-water and chloroform-water systems. Is is suggested that coacervate systems form a more realistic model for studying and predicting the absorption characteristics of drugs than do conventional organic solvent-water systems.


Liquid chromatography in pharmaceutical analysis VI: determination of dantrolene sodium in a dosage form.

Operating conditions are described for the qualitative and quantitative determination of dantrolene sodium by high-pressure liquid chromatography. A 10-mum porous silica column was employed, using carbon tetrachloride-dimethylformamide (90:10) as the mobile phase. The flow rate was 2.0 ml/min (1800 psig), and the peaks were detected at 375 nm. The analysis of a dosage form can be carried out within 30 min with an accuracy of 3.1%. The results agree favorably with those obtained with a modified spectrophotofluorometric method.


Hydrazones of isoniazid for colorimetric analysis.

Two sensitive color reactions of isoniazid are described. They are based on the formation of hydrazone Schiff bases when isoniazid is reacted with 4-nitrobenzaldehyde or pyridoxal. Linear curves were obtained with both reagents when absorbance values were plotted against concentrations.


Rapid near IR spectrophotometric determination of meprobamate in pharmaceutical preparations.

A rapid near IR spectrophotometric method was developed for determining meprobamate in tablets, sustained-release capsules, suspensions, and injectables. The absorbance of a chloroform solution of the drug is obtained at about 1.96 mum for quantitation. Assay of nine commercial products from four different manufacturers gave results ranging from 97 to 104% of label claim. Coefficients of variation of 0.7 and 1.3% were obtained on the tablets and a sustained-release product, respectively.


9-nor-9beta-hydroxyhexahydrocannabinol, a cannabinoid with potent antinociceptive activity: comparisons with morphine.

The effects of (+/-)9-nor-9beta-hydroxyhexahydrocannabinol (beta-HHC) on tail-flick test activity and the accumulation of newly synthesized dopamine and norepinephrine were studied in the male albino mouse. The same parameters were also studied in naloxone-pretreated and morphine-tolerant mice. beta-HHC was about equipotent with morphine in the mouse tail-flick (ED50 = 7.12 mg/kg). The cannabinoid also produced dose-dependent increases in the accumulation of newly synthesized DA and NE. Pretreatment with 2 mg/kg of naloxone antagonized both the tail-flick activity and blocked the increases in catecholamine synthesis produced by beta-HHC. Cross-tolerance between beta-HHC and morphine did not exist in regard to either tail-flick activity or increased catecholamine synthesis. These studies suggest that beta-HHC may share some properties with the narcotic analgesics but that significant differences exist. Furthermore, these studies offer further evidence for the involvement of catecholamine containing neurons in the central mediation of the tail-flick response.


Application of principles of steady-state kinetics to the estimation of gamma-aminobutyric acid turnover rate in nuclei of rat brain.

13C-labeled glucose (50 mumol/kg/min) was infused into the rat tail vein for 10 minutes. The animals were killed by a microwave beam focused to the skull at various times after the infusion. In brain nuclei the concentrations of glutamate and gamma-aminobutyric acid (GABA) and their enrichment in 13C were measured by mass fragmentography. The results showed that in the five brain areas studied, substantia nigra contained the highest GABA concentration, followed by globus pallidus, N. accumbens, deep cerebellar nuclei, N. caudatus and cerebellar cortex. The concentrations of glutamate and GABA were comparable in some nuclei (substantia nigra and globus pallidus), but not in others. The glutamate content was 3 to 6 times greater than GABA content in cerebellum (cortex and nuclei) N. accumbens and N. caudatus. The turnover rates of GABA in substantia nigra, globus pallidus, N. caudatus and N. accumbens were calculated by applying principles of steady-state kinetics to the changes with time in the 13C enrichment of glutamic acid and GABA. In substantia nigra, N. accumbens and N. caudatus, the percentage of 13C incorporation into glutamic acid and GABA reached its maximum 10 to 15 minutes after the infusion. In N. caudatus and N. accumbens, the percentage of 13C incorporation into GABA was higher than that in substantia nigra and globus pallidus. The turnover rates of GABA were very similar in N. caudatus, N. accumbens, substantia nigra and globus pallidus (385-562 nmol/mg of protein per hr), but the turnover times were much faster in N. caudatus and N. accumbens. It must be kept in mind that in N. caudatus and N. accumbens the glutamate pool was several-fold greater than that of GABA. Since the data obtained indicate that the compartmentation is more complicated than in the model assumed for turnover estimations, this method should be used only for comparative purposes in drug studies. The validity of this method to obtain absolute measurements of GABA turnover remains to be documented.


Net uptake of gamma-aminobutyric acid by a high affinity synaptosomal transport system.

Reuptake of gamma-aminobutyric acid (GABA) by a high affinity transport system in nerve endings in the central nervous system is thought to terminate the action of this postulated neurotransmitter. This hypothesis has been challenged since the demonstration of exchange between synaptosomal and exogenous GABA (G. Levi and M. Raiteri, Nature 250: 735, 1974). In our studies, rat cortical synaptosomes were incubated (25 degrees C) in various media containing 10 muM 14C-GABA. After the synaptosomes were removed by centrifugation, 14C and total GABA (fluorometric assay) in the resulting supernatant were measured. Uptake of labeled GABA, detected by a decrease in medium radioactivity, is Na+- and K+-dependent. Net GABA uptake, however, does not parallel 14C-GABA translocation. Exchange accounts for 20 to 70% of radiolabeled GABA accumulation depending upon the experimental conditions. On the other hand, GABA-deficient synaptosomes (prepared by treatment with 56 mM KCl and 1 mM CaCl2) show equivalent net and radiolabeled GABA uptake in Ringer's solution containing 1 to 4 mM KCl and 60 to 150 mM NaCl (average 4.6 nmol of GABA accumulated per mg of synaptosomal protein). Net and 14C-GABA uptake by GABA-deficient synaptosomes are identical at various pH values (6.0-8.5), synaptosomal protein concentrations (0.4-3.5 mg/ml) and temperatures (5-37 degrees C). Although GABA homoexchange may contribute significantly to radiolabel accumulation by synaptosomes containing higher GABA levels (9.5-9.9 nmol/mg), homoexchange is limited in GABA-depleted synaptosomes. Our results are consistent with the proposal that presynaptic GABA capture by a high affinity system in vivo may terminate the action of this neuroactive amino acid.


The effects of acute and chronic botulinum toxin treatment on receptor number, receptor distribution and tissue sensitivity in rat diaphragm.

Tritiated alpha-bungarotoxin was used to determine the number and distribution of acetylcholine receptors in innervated, denervated and botulinum toxin-treated muscles. Innervated hemidiaphragms bound approximately 2.3 x 10(11) molecules of alpha-bungarotoxin; binding sites were restricted to the end-plate region. Neither acute denervation nor acute poisoning with botulinum toxin altered the number or distribution of alpha-bungarotoxin binding sites. In chronically denervated hemidiaphragms, there was an increase in alpha-bungarotoxin binding sites (maximum about 5.7 x 10(12); these sites were distributed across the muscle surface. In chronically poisoned hemidiaphragms, there was also an increase in the number (maximum about 4.7 x 10(12)) and distribution of binding sites. Chronic denervation and chronic botulinum toxin treatment both produced supersensitivity to acetylcholine. At maximal sensitivity, the respective ED50 values were: denervated muscle, 1.1 x 10(-6) M; botulinum toxin-treated muscle, 5.0 x 10(-6) M. The combination of denervation plus botulinum toxin treatment did not have additive or synergistic effects on alpha-bungarotoxin binding (4.9 x 10(12) molecules/hemidiaphragm) or on tissue sensitivity to acetylcholine (ED50 = 2.1 x 10(-6) M). It is concluded that denervation and botulinum toxin have rather similar effects on the number and distribution of acetylcholine receptors in rat hemidiaphragm.


Accelerated ventricular escapes induced in the intact dog by barium, strontium and calcium.

Accellerated ventricular escapes (AVE) were produced with infusion of BaCl2, SrCl2 and CaCl2. AVE demonstrated overdrive acceleration rather than overdrive suppression, i.e., faster pacing rates caused shorter escape intervals. BaCl2 (mean 20.2 mumol/kg) produced AVE in 18 of 23 dogs and a decrease in mean serum potassium (K+). SrCl2 alone (mean 2494 mumol/kg) did not produce AVE in 5 dogs and K+ was unchanged. When insulin and glucose were infused to lower K+ and SrCl2 was infused 30 minutes later, AVE was demonstrated in 7 of 10 dogs. CaCl2 alone (mean 1628 mumol/kg) produced AVE in 3 of 5 dogs and CaCl2 (mean 1733 mumol/kg) infused 30 minutes after insulin and glucose produced AVE in 4 of 4 dogs. This study demonstrates that AVE previously produced with cardiac glycosides can also be induced by infusion of barium, strontium and calcium.


Studies of the fate of tyramine in dogs: the effect of monoamine oxidase inhibition, portafemoral shunt and coronary artery ligation on the kinetics of tyramine.

Radioimmunoassay of tyramine (T) was used to investigate the kinetics of T in plasma of three groups of dogs (control, pretreated with monoamine oxidase inhibitor and those with portafemoral shunt). Furthermore, the influence of coronary artery ligation on the T content of the heart was studied. After i.v. administration of T-HCl (1.7mumol/kg, 0.3 mg/kg), there was a rapid initial decline in T plasma levels with an average T 1/2 of 4.3 minutes. Similar results were obtained in experiments in which the same dose of T-3H was used. There was a 10-fold difference between 3H and T concentrations. Pretreatment with a monoamine oxidase inhibitor resulted in a decrease in T metabolism as reflected by changes in pharmacokinetic parameters (estimated area under the curve AUC, 8166 vs. 1000 ng x min x ml-1, P less than .001; total body clearance, BC, 35.7 vs. 285 ml/min/kg. P less than .005). Similar results were obtained in dogs with portafemoral shunt. Coronary artery ligation resulted in an increase in the level of T in the infarction [1.2. +/- 0.3 (S.E.M.) ng/ml] compared to those of adult volunteers.


Disposition of 14C-mescaline by rabbit lung.

Metabolism of mescaline by several rabbit tissues was examined in vitro. Mescaline-oxidizing activity (micromoles per milligram of protein/15 min) of lung homogenates was 4 times greater than that of either liver or kidney. Brain and plasma each had comparatively little capacity to metabolize mescaline. Mescaline metabolism in vitro was sensitive to inhibition by semicarbazide. Removal of mescaline from the medium perfusing the isolated rabbit lung was explained by intrapulmonary metabolism. Semicarbazide (10(-3) M pargyline. Semicarbazide-treated lungs accumulated more mescaline than did untreated lungs. Mescaline efflux from lung was slower than that of its metabolite. These results indicate that the intact lung removes perfused mescaline and may be important in the disposition of circulating mescaline in vivo.


Prediction of hepatic extraction ratio from in vitro measurement of intrinsic clearance.

Under first-order conditions the activity of the hepatic drug-metabolizing enzymes may be closely approximated by the ratio of the in vitro kinetic constants Vmax and Km, which in turn is equivalent to the intrinsic clearance of the drug. In theory, after appropriate consideration for liver weight, blood flow and rug binding in the blood, the intrinsic clearance may be used to predict the extraction ratio for the total organ. This hypothesis was tested by comparing the predicted ratio based on a perfusion-limited model of hepatic elimination with that determined directly in the isolated perfused rat liver. Good agreement was obtained between the predicted and observed hepatic extraction ratios for antipyrine, carbamazepine, hexobarbital, phenytoin, propranolol, alprenolol and lidocaine, which span the extraction ratio from less than 0.1 to greater than 0.9.


Hepatic uptake of foreign compounds: influence of acute extrahepatic biliary obstruction.

Extrahepatic cholestasis produced by bile duct ligation decreased the net hepatic uptake of organic anions including sllfobromophthalein, sulfobromophthalein glutathione and phenol-3,6-dibromophthalein disulfonate, and the neutral organic compound, ouabain. The net hepatic uptake of procaine amide ethobromide, an organic cation was not similarly affected. Impairment of net hepatic uptake by bile duct ligation was demonstrated by reduced liver concentration and content of administered compound despite higher plasma concentration. Acute bile duct ligation did not alter the amount of hepatic cytoplasmic anion binding proteins. The impaired net hepatic uptake of sulfobromophthalein in bile duct-ligated rats was reversed by re-establishing bile flow. Deleterious effects of endogenous bile or bile constituents and specific alteration of membrane carrier proteins are considered possible contributing factors to the impaired net hepatic uptake process observed in bile duct-ligated rats.


Inhibition of carbonic anhydrases of rat liver by halides.

The hepatic carbonic anhydrases from male rat are known to differ from those of female rat in being resistant to inhibition by sulfonamides. In the present work the inhibition of carbonic anhydrases from livers of male and female rats by chloride and iodide was studied in the CO2 hydration reaction. The hepatic carbonic anhydrases from male rats were found to be more susceptible to inhibition by halides (I50 and Cl- = 7-15 mM, and I- = 0.7-1.5 mM). On the other hand, the hepatic carbonic anhydrases from female rats were less susceptible to inhibition by halides (I50 for Cl- = 150-250 mM and for I- = 3-10 mM). The presence of bicarbonate increased I50 of both Cl- and I- for liver isoenzymes of both male and female rats by about 2- to 20-fold. The differential susceptibility of carbonic anhydrases from livers of male and female rats to inhibition by halides was in contrast to their susceptibility to inhibition by sulfonamides.


Thioacetamide-induced hepatic necrosis. I. Involvement of the mixed-function oxidase enzyme system.

Metabolic activation of thioacetamide (CH3CSNH2) to a toxic metabolite which is responsible for its hepatotoxicity and/or its carcinogenicity has been proposed by a number of investigators. In this investigation thioacetamide and one of its metabolites, thioacetamide sulfine (CH3CSONH2), have been compared for their ability to inhibit hepatic mixed-function oxidase enzymes as well as their ability to induce hepatic necrosis. Thioacetamide sulfine was found to decrease aminopyrine N-demethylation and aniline hydroxylation at a lower dose and at an earlier time after administration than was the case with thioacetamide. In addition, at all doses examined, thioacetamide sulfine produced a more severe centrilobular hepatic necrosis than equivalent doses of thioacetamide. To determine whether the hepatic mixed-function oxidase enzyme system was involved in the biotransformation of thioacetamide and/or thioacetamide sulfine to a hepatotoxic compound(s), the severity of liver damage was examined after the administration of an inducer or inhibitors of hepatic mixed-function oxidase enzyme activity. Phenobarbital pretreatment potentiated the hepatic necrosis produced by both thioacetamide and thioacetamide sulfine. In contrast, pyrazole, SKF 525-A, and cobaltous chloride protected against the hepatic necrosis caused by thioacetamide and thioacetamide sulfine. These data suggest that both thioacetamide and thioacetamide sulfine are activated by hepatic mixed-function oxidase enzymes to a hepatotoxic compound(s). These data also suggest that the hepatotoxicity may be mediated by its metabolism to thioacetamide sulfine which, in turn, is metabolized to an ultimate toxic metabolite.


The effects of dopamine on human platelet aggregation, in vitro.

An unexpected inhibition of human platelet aggregation by dopamine -- the precursor of epinephrine and norepinephrine -- is presented. Human platelet-rich plasma was incubated in an aggregometer for 120 seconds at 37 degrees C, with either dopamine or saline control. Adenosine diphosphate, epinephrine or collagen was added as the aggregating agent. Dopamine inhibits induction of platelet aggregation by all three agents and causes platelet disaggregation. At low doses (400 mug/ml or less), dopamine induces platelet aggregation and enhances ADP-induced aggregation. In addition, a concentration of dopamine of 40 mug/ml induces aggregation, enhances ADP-induced aggregation and inhibits epinephrine aggregation. Phentolamine is able to block dopamine enhancement of ADP aggregation, but propranolol and haloperidol fail to prevent dopamine inhibition of epinephrine aggregation. These observations are explained neither by the currently known intracellular actions of dopamine which involve competition with serotonin nor by a single mediator such as cyclic adenosine 3':5'-monophosphate. It appears that dopamine may exert its effects via the platelet membrane.


Inhibition of spinocervical tract discharges from localized areas of the sensorimotor cortex in the cat.

1. Intracortical microstimualtion (ICMS) was applied within the sensorimotor cortex of cats anaesthetized with chloralose. 2. The effects of the ICMS were examined on the number of impulses in spinocervical tract (SCT) cells (recorded extracellularly in the contralateral lumbosacral spinal cord) evoked by peripheral stimulation. 3. Inhibition of SCT discharges was produced by ICMS in two distinct regions of the sensorimotor cortex. 4. One inhibitory regions was in part of cytoarchitectonic area 4 gamma in the upper bank of the cruciate sulcus. It sometimes extended caudally into area 4 delta, medially into area 3 alpha and/or rostrally into the part of area 4 gamma on the caudal lip of the cruciate sulcus. 5. The other inhibitory region was in the medial part of the posterior sigmoid gyrus and included parts of areas 3 alpha, 3 beta, 1, 5 alpha and 5 beta. 6. Most inhibitory sites were in cortical layers III, V and VI. 7. No regions were found in which ICMS consistently caused facilitation of SCT discharges.


A study of the ion selectivity and the kinetic properties of the calcium dependent slow inward current in mammalian cardiac muscle.

1. A voltage-clamp method combining a single surcose gap and two intracellular micro-electrodes was used to measure membrane currents in ventricullar myocardial fibres. 2. The adequacy of the voltage-clamp method is demonstrated by comparing the total current, It, across the gap with the voltage difference, delta V, between the two intracellular micro-electrodes, i.e. another independent way of measuring membrane currents. With both current measurements the slow inward current, Is, shows the same voltage- and time-dependences. 3. The sensitivity of the slow inward current to variation in external Ca and Na concentrations was investigated systematically. The reversal potential of the slow inward current was sensitive to variation of both ion species. 4. From the reversal potential measurements relative permeabilities of the conductance channels of the slow inward current were estimated as PCa/PNa approximately 1/0-01 and PCa/PK approximately 1/0-01 by means of the constant field equation. 5. The activation and inactivation kinetics of the slow inward current were explored in detail and related to the plateau of the action potential.


Drinking caused by exposing dogs to radiant heat.

1. Exposure to radiant heat caused dogs to pant and lose water by evaporation at rates of 40-70 g/hr. 2. When water was offered at intervals during the heating, the dogs drank at about half of the opportunities. The individual drinks were small but, by their repetition, loss of water by evaporation during heating was approximately matched by drinking. 3. Water given by stomach tube reduced drinking during a subsequent period of heating. 4. When water was offered more than 15 min after the end of a period of heating, after panting had ceased, drinking occurred only if the water loss exceeded 50-70 g, about 0-6% of the body water. This is regarded as drinking due to loss of water, beyond a threshold of dehydration necessary to stimulate drinking with the dog at rest. When water was offered during heating, drinking occurred with dehydration less than this threshold. 5. The drinking produced by heating was similar to that produced by running (O'Connor, 1975). When the animal ran under heat, panting was more severe and the water loss greater (85-150 g/hr); it was approximately matched by more drinking.


The effect of lowering external sodium on the intracellular sodium activity of crab muscle fibres.

1. Intracellular Na activity, aiNa, was continuously measured in crab (Carcinus maenas) muscle fibres using a recessed-tip Na+ -sensitive glass micro-electrode. Experiments could last up to several hours. AiNa remained stable during prolonged experiments. The mean resting aiNa was 8-4 +/- 0-02 mM (S.E. of mean for eighty-nine fibres) and the mean resting membrane potential was 65-3 mV +/- 0-3 (S.E. of mean for eighty-nine fibres). 2. Reducing [Na]o to 1/10 normal (maintaining ionic strength with equivalent amounts of either Li or Tris) caused a large and rapid fall of aiNa. There appeared to be two components of the effect, a fast and slow. The initial fast rate of decrease was about 3-5 m-mole/min decreasing to half this value in about 1 min. The rate of decrease of aiNa was not linearly related to aiNa. The size of the fast change of aiNa was related to the magnitude of the Na gradient across the membrane. 3. High concentrations (2 x 10-4m) of ouabain caused a very slow rise of aiNa by 1 or 2 mn/hr. This was equivalent to a net Na influx of between 1 and 10 p-mole/cmi. sec, depending on whether or not a correction was applied to account for the increased surface area of the fibre caused by the invaginating cleft system. 4. The response to low Nso was virtually insensitive to the removal of Ko or to prolonged reatment with high concentrations of ouabain (2 x 10-4 m; 100 min) and so could not readily be attributed to active Na/K pumping. 5. The response of aiNa to low Nao was reversibly inhibited by high concencentrations of Mn (50 mm) and by low concentrations of La (3-1 mm). La itself stimulated a rapid fall of aiNa in normal Nao.


The influence of immobilization and stretch on protein turnover of rat skeletal muscle.

1. Changes in muscle size have been studied as a function of time after immobilization and in relation to the functional length of the muscle. 2. When immobilized in a shortened position the soleus and extensor digitorum longus muscles underwent atrophy, showing net losses of tissue protein. This atrophy appears to be caused by decreases in protein synthesis and increases in protein break-down. Average rates of protein synthesis and degradation were measured in immobilized and unrestrained control muscles by sensitive in vitro methods. 3. When the two muscles were held in a lengthened position they grew compared with internal controls. This rapid growth was primarily due to increased rats of protein synthesis, which possibly arise from a more active involvement of ribosomes in translation. In keeping with these situations of growth, DNA synthesis, DNA and RNA concentrations were found to be higher in the immobilized tissues. 4. Passive stretch and the development of isometric tension via the stretch reflux are suggested as factors stimulating protein synthesis, and hence inducing the growth of muscles held in the lengthened state. Probably neither of these factors will be experienced appreciably in the shortened position of restraint, and the lower level of activity in these immobilized muscles leads to their atrophy.


The influence of activity on muscle size and protein turnover.

1. The effects of the loss of normal activity can be studied in muscles held in a shortened position by immobilizing the ankle in a plaster cast. Since the innervation remains intact with this procedure, removal of the restraining case allows normal activity to be restored. The soleus and plantaris muscles grew as a function of time after the return of normal activity and these changes in tissue size are explained by changes in the average rates of protein synthesis and protein break-down as measured by sensitive in vitro techniques. Activity stimulates protein synthesis and inhibits protein break-down of the soleus muscle, thus enabling the tissue to accumulate protein. Blockage of de novo synthesis of RNA, but not DNA, severely restricted the normal, rapid enhancement of protein synthesis after thr return of activity. 2. The return of isotonic activity to the extensor digitorum longus muscle after immobilization in a lengthened position failed to fully compensate for the loss of the growth-promoting influence of stretch and the tissue gradually returned to the size of the control muscle. During the recovery process the higher rate of protein turnover and RNA concentrations of the immobilized muscle returned to the lower values of the control.


The regulation of the calcium conductance of cardiac muscle by adrenaline.

1. The effect of adrenaline on the Ca-dependent slow inward current, Is, of mammalian cardiac muscle has been investigated by the voltage-clamp method. The mechanism of the increase in the conductance, gs, was analysed on the basis of a kinetic scheme (Hodgkin & Huxley, 1952) applicable to this system. 2. The rate constants alphad and betad, of activation of gs were not influenced by adrenaline, although the limiting conductance, gs, was greatly increased. 3. Reduction of [Ca]o from 1-8 to 0-2 mM decreased the amplitude of inward tail currents when gs was fully activated; however, the relative decrease of the current amplitude was the same with and without adrenaline. The reversal potential, ER, of Is was not changed by the drug. This indicates that the catecholamine has no influence on the selectivity of these conductance channels. 4. An increase in the number of functional conductance channels by adrenaline is discussed as a possible mechanism for the increase in Gs.


The influence of the lymph node on the protein concentration of efferent lymph leaving the node.

1. Experiments have been performed in sheep to determine the contribution of lymph formed within a lymph node to the total protein output in lymph leaving the node. 2. The lymphatic duct leaving the popliteal lymph node was cannulated and the protein and lymphocyte output in efferent lymph determined. The afferent lymph flow to the popliteal node was then diverted and lymph formed only within the lymph node collected from the efferent cannula. It appeared from the results that the popliteal lymph node forms lymph at the rate of approximately 1 ml. per hour and may contribute 30-50% of the protein output observed in efferent lymph. 3. The importance of lymph formation within the lymph node varied between nodes found in different regions of the body. This was due in part to the different protein concentrations in the afferent lymph to the different nodes. 4. A positive correlation was found between the protein and lymphocyte concentrations in efferent lymph from the popliteal lymph node in seven out of eleven sheep and in lymph formed within the popliteal lymph node in two out of three sheep. It is suggested that this relationship may be due to an increased transfer of plasma proteins through the post-capillary venules in the lymph node accompanying the continual traffic of lymphocytes across the wall of these vessels. The results indicated that the protein transfer across the post-capillary venules was not an indiscriminate transfer of plasma per se but a selective transport from the blood plasma compartment based on molecular size.


The actions of ouabain on intercellular coupling and conduction velocity in mammalian ventricular muscle.

1. The effects of ouabain on the electrical coupling between cells and the conduction velocity, theta, were studied in ventricular muscle preparations from calf and cow hearts using a silicon-oil-chamber. 2. After 90 min of exposure to 2 X 10(-6) M ouabain, an increase of the inside longitudinal resistance, Ri, from 420 omega cm to 1032 omega CM was observed. Assuming a constant myoplasmic resistivity this presumably reflects a reduced electrical coupling between myocardial cells. 3. Concomitantly, theta was decreased from 50-3 to 29-4 cm/sec. This change could be explained by the observed alterations in the maximal rate of rise of the action potential, (dV/dt)max, the amplitude of the action potential Vp, the membrane capacity Cf, and the sum, respectively, of the inside and outside longitudinal resistance per unit distance (ri + ro). Quantitatively, about 60% of the decrease of theta could be accounted for by the experimentally determined increase of Ri. 4. Time course studies revealed a biphasic action of ouabain on Ri. An early dose-dependent drop in Ri, equivalent to an improvement of the intercellular coupling, was followed by a delayed massive increase in Ri, whose onset and magnitude were also concentration-dependent. 5. The delayed increase in Ri was associated with an increase of the diastolic tension. Toxic ouabain doses (2 X 10(-6) M) produced irreversible changes on both parameters, whereas thereapeutic doses (less than 5 X 10(-7) M) affected neither of them. Reversible effects on both parameters were observed at an intermediate drug concentration (10(-6) M). 6. The strong correlation between decoupling and contracture is consistent with the idea that the intracellular Ca concentration, [Ca]i, is involved in the control of the nexal conductance. This is supported by the finding that increasing the extracellular Ca concentration, [Ca]o, accelerated the ouabain-induced decoupling, whereas reducing [Ca]o retarded it. 7. If anything, the contracture slightly preceded the increase in Ri. From this it is concluded that the threshold [Ca]i for the electrical decoupling between cells must be somewhat larger than the threshold level for the tension activation. 8. The delayed increase in Ri is compatible with an inhibition of the Na pump which according to the Na-lag hypothesis predicts an increase of [Ca]i secondary to a Na-accumulation. The early drop in Ri can either be explained by a stimulation of the Na pump, or by a non-monotonic relationship between Ri and [Ca]i.


Induction of compression in the re-established visual projections on to a rotated tectal reimplant that retains its original topographic polarity within the halved optic tectum of adult goldfish.

1. The topographic pattern of re-established retinotectal projections following various surgical manipulations of the optic tectum was studied in adult goldfish with neurophysiological mapping methods. 2. Immediately following excision of the caudal half of the tectum, a piece of the tectal tissue was dissected from the remaining rostral half-tectum, and then reimplanted to the same half-tectum after either 180 or 90 degrees anticlockwise rotation around the dorsoventral axis in the first experimental group. 3. A majority (twenty-one out of twenty-three) of these operated fish, in which the reimplanted tectal tissue degenerated, showed no sign of a field compression: only the nasal half of the visual field (with a localized partial scotoma corresponding to the area of the degenerated reimplant) projected on to the remaining intact area of the rostral half-tectum. 4. In seven fish, the re-established visual projections on to the 180 or 90 degrees rotated reimplants showed a corresponding localized 180 or 90 degrees rotation with reference to the other projections on to the surrounding intact area of the same half-tectum. Only one of these seven fish showed also a compression in the re-established projections from the entire visual field on to the operated half-tectum with the 90 degrees rotated reimplant. 5. When a field compression was induced first in the intact rostral half-tectum following excision of the caudal half, and then a piece of the 90 degrees rotated tectal tissue was reimplanted later within the rostral half-tectum, the previously induced field compression persisted, regardless of whether the reimplanted tissue degenerated or survived. In the latter case, the compression in the re-established visual projections on to the surviving reimplant occurred according to the original topographic polarity of the 90 degrees rotated tectal tissue. 6. A field compression could also be induced within a rotated tectal reimplant, which retained its original polarity, as follows. A piece of the tectal tissue was dissected from the central area of the whole tectum, and then reimplanted after either 180 or 90 degrees rotation. When the reimplanted tectal tissue became reinnervated later, the caudal half of the operated tectum (including the posterior half of the reimplant) was excised. The re-established visual projections on to the remaining part of the halved reimplant within the rostral half-tectum showed later a field compression in accordance with the original topographic polarity of the 180 or 90 degrees rotated tectal tissue. 7. These results provide direct evidence for the compatibility between the retention of original topographic polarity by a reimplanted tectal tissue and the capability of the same tectal tissue to readjust to a disparity in size. 8. Histological examination of the operated half-tectum with a reimplant, stained by a modified rapid Golai method, revealed that the reimplanted tectal tissues retained highly organized cytoarchitectonic structures...


The alteration by ouabain of calcium movements in human red cell ghosts.

1. The influence of ouabain on net Ca movements was studied in human erythrocyte ghosts by atomic absorption spectrophotometry. 2. Ouabain (10(-5) M) showed a dual effect, altering both entry and exit of Ca from K-rich ghosts incubated in a high-Na medium in the presence of 10 mM-Ca. 3. Stimulation of Ca entry was observed in the first 15 min at 37 degrees C, whereas during the subsequent 15 min incubation ouabain elicited Ca extrusion. This latter effect was eliminated when the ouabain concentration was raised to 1 mM. 4. Ouabain-dependent Ca movements were abolished by replacing both internal K and external Na with choline. They were also absent from ghosts prepared at a high lytic ratio (1 : 100) or obtained from ATP-depleted cells. 5. A moderate increase in cell ATP enhanced the effect of ouabain on Ca efflux whilst it was eliminated at higher ATP levels. 6. The actions of ouabain markedly depended on the initial ADP/ATP ratio in ghosts, being optimal at about 2-5. 7. The results suggest that the effects of ouabain on Ca movements are mediated through the Na pump. Reversal of this pump in Na-rich K-free medium may provide the energy for active Ca transport.


The effects of bilateral adrenalectomy or hypophysectomy of the foetal lamb in utero.

1. Foetal hypophysectomy or bilateral adrenalectomy, carried out in utero at about 100 or 125 days gestation respectively, increased the length of gestation in sheep. It was confirmed that pregnancy was not prolonged significantly if hypophysectomy or adrenalectomy was carried out on one of a pair of twins. The hypophysectomized foetus was, however, smaller and the adrenalectomized foetus larger, than the unoperated twin. 2. In about half of the previously operated foetuses intravascular catheters were inserted into both mother and foetus, either at about 125 days, for a comparison with normal catheterized foetuses, or during the post-mature period. Both adrenalectomized and hypophysectomized foetuses appeared to have little resistance to stress or infection and the majority survived only 1-2 weeks after the insertion of catheters. 3. Maternal peripheral plasma oestrogen, progesterone and corticosteroid concentrations did not appear to be altered by either foetal hypophysectomy or adrenalectomy and were maintained in the normal range during prolonged gestation. 4. Foetal plasma oestrogen concentrations were significantly lower after hypophysectomy or adrenalectomy than values found in control lambs. Plasma progesterone values were low in all three groups of foetuses. 5. Plasma corticosteroid concentrations after foetal hypophysectomy (12-6 ng/ml.) or adrenalectomy (14-7 ng/ml.) were in the same range as the values for control lambs before the pre-partum rise (14-6 ng/ml.). However, there was a small but significant maternal-to-foetal plasma corticosteroid gradient in the two operated groups whereas this difference was not found in the control animals. 6. Tissue glycogen concentrations were measured in non-catheterized adrenalectomized and hypophysectomized foetuses. In these two groups, whether examined before 149 days or after prolonged gestation, liver glycogen concentrations were 30-40% of those in non-catheterized control foetuses at term. In other respects there was little apparent difference between adrenalectomized and control foetuses. 7. Hypophysectomized foetuses had significantly higher glycogen concentrations in heart, skeletal muscle and lung compared with control or adrenalectomized lambs. Plasma glucose and fructose values were also low in this group compared with control foetuses.


Kinetics of the inhibition of the Na-K pump by external sodium.

1. When the ouabain-sensitive K influx or the ouabain-sensitive Cs influx is measured as a function of the extracellular concentration of K or Cs in Na-free solutions the resulting saturation curve at first rises more rapidly than a rectangular hyperbola, i.e. the curve is antisigmoid. 2. If the ouabain-sensitive K influx or the ouabain-sensitive Cs influx is measured in Na-free solutions at a fixed low concentration of K or Cs and at varying concentrations of Li, the influx decreases monotonically as the Li concentration rises and there is no evidence of competitive activation. 3. These findings can be accounted for by a model which proposes that there are two binding sites for K or Cs and that both the singly loaded and doubly loaded pump is capable of transport. 4. Extracellular Na changes the shape of both the K and the Cs saturation curve from antisigmoid to sigmoid. Dixon plots (1/ouabain-sensitive influx versus Na concentration at fixed K or Cs concentration) are linear at intermediate concentrations of K or Cs. 5. Na does not change the rate of K influx if the measurements are made at nearly saturating K concentrations using cells with nearly saturating internal Na concentrations. The effect of outside Na cannot therefore be explained by any mechanism which requires that Na alter the Vmax of the pump. 6. Measurement of the ouabain-sensitive Cs influx as a function of the external Cs concentration in solutions with different fixed Na concentrations results in curves which change from antisigmoid in Na-free solutions to sigmoid as the Na concentration rises. Dixon plots are linear at all but the lowest and highest Cs concentrations. 7. The resulting curves are best fit by equations which result from a model which proposes that Na acts both as a dead-end competitive inhibitor and as a heterotropic allosteric effector. Simpler models which propose either that Na acts solely as a dead-end competitive inhibitor or as a heterotropic allosteric effector do not fit as well as the more complicated model. 8. The combined competitive inhibition and allosteric effector model also describes adequately the relation between the ouabain-sensitive K influx and external K concentration measured at different external Na concentrations.


Kinetics of the inhibition of the Na-K pump by tetrapropylammonium chloride.

1. The tetrapropylammonium ion (TPA) acts as a mixed-type (with K) inhibitor of the Na-K pump. The kinetics of the process suggest that combination of the pump with a single TPA ion is sufficient for inhibition. 2. TPA inhibits the partial reactions of the Na-K pump (the uncoupled Na outflux, the Na-Na exchange, and K-K exchange). 3. TPA inhibits ouabain binding to the pump and this inhibitory effect is enhanced by external Na. The inhibitory effect of TPA on the pump rate is also promoted by external Na. 4. A Lineweaver-Burk plot of the reciprocal of the ouabain-sensitive K influx versus the reciprocal of the external K concentration is approximately a straight line if the measurements are made in Na-free solutions. TPA increases the apparent Michaelis constant (K 1/2) for K and the plot remains straight. 5. The Lineweaver-Burk plot is parabolic when the measurements are made in solutions which contain Na. TPA both increases the apparent K 1/2 for K and makes the curve more parabolic. 6. The characteristics of pump inhibition by TPA are similar to those for strophanthidin. In both cases the kinetic behaviour is consistent with a model in which the inhibitor binds: with greatest affinity to the pump form free of K; with less affinity to the pump form with a single bound K; and with least affinity to the pump form with two bound K.


The effect of ambient temperature upon the secretion of thyroxine in the young pig.

1. Fluctuations in the rate of secretion and metabolism of thyroxine in the pig were observed whilst the ambient temperature was reduced from 32 to 8 degrees C. The quantity of food supplied was either maintained constant or doubled when the animals were exposed to the lower temperature. 2. It was found that the rate of disappearance of [125I]thyroxine did not change when the animal was exposed to the cold, unless the animal's food intake was altered. 3. The secretion of thyroxine increased temporarily after exposure to the cold. This was shown by a rise in the concentration of thyroxine in the plasma and a simultaneously increased loss of 131I from the thyroid gland. The increase in secretion of thyroxine was not maintained throughout the exposure to cold when the food intake of the animal was kept constant.


The effect of preganglionic nerve stimulation on the accumulation of certain analogues of choline by a sympathetic ganglion.

1. Cat superior cervical ganglia were perfused with a Krebs solution containing 10(-6) M [3H]homocholine (2-hydroxypropyl-trimethylammonium) or 10(-5) M [14C]triethylcholine (2-hydroxyethyl-triethylammonium). Preganglionic nerve stimulation (20 Hz) increased the accumulation of homocholine (3-2-fold) and of triethylcholine (2-1-fold). This increased accumulation during stimulation was not the result of increased metabolism. 2. The increased accumulation of homocholine or triethylcholine induced by pregnaglionic nerve stimulation was not reduced by tubocurarine or by atropine, but it was blocked by choline and by hemicholinium. These results suggested that preganglionic nerve stimulation increased choline analogue accumulation into cholinergic nerve terminals. 3. The increased accumulation of homocholine or of triethylcholine induced by preganglionic nerve stimulation was reduced when the Ca2+ concentration was reduced and was abolished in the absence of Ca2+. However, changes in the Mg2+ concentration which depressed acetylcholine (ACh) release by amounts comparable to those induced by altered Ca2+ concentrations did not alter the uptake of homocholine or triethylcholine. It is concluded that the uptake of choline analogues is not regulated by transmitter release but that stimulation increases the uptake of the choline analogues by a Ca2+-dependent mechanism. 4. The accumulation of ACh by ganglia perfused with a Krebs solution containing choline and high MgSO4 (18 mM) was measured. The ACh content of these ganglia did not increase, although choline transport presumably exceeded that necessary for ACh synthesis to replace released ACh. It is concluded that choline transport does not limit ACh synthesis in ganglia.


The hepatocellular uptake of glucose, galactose and fructose in conscious sheep.

1. Surgical techniques for chronic catheterization of hepatic and portal veins in the sheep are described. These catheters remained usable for 2-6 months and did not alter hepatic morphology. 2. Hepatocellular uptake of monosaccharides was estimated from their ability to pass the boundaries of the sucrose space in a double indicator dilution procedure in conscious fed sheep. 3. A large proportion (81%) of D-glucose carried in the portal blood was found to enter an hepatic cellular compartment. 4. The radioactive label of D-glucose infused in the portal vein remained associated with D-glucose in hepatic venous blood samples during the experimental period. 5. A large proportion (74%) of an infused trace of D-galactose, a smaller proportion (33%) of D-fructose, and negligible amounts of L-glucose were taken up in a single passage through the liver. 6. Raised blood concentrations of sucrose or of methyl-alpha-D-glucoside (Me-alpha-DG) significantly diminished the proportional uptake of D-glucose. Raised blood concentrations of glucose, galactose or Me-alpha-DG diminished the proportional uptake of D-galactose. Raised blood concentrations of fructose diminished the proportional uptake of fructose. 7. Neither total hepatic blood flow changes nor competitive effects within the cell could account for these findings. 8. It is concluded that these monosaccharides enter the liver cell by facilitated diffusion, and share at least some of the membrane elements that mediate this process. It seems likely that only a proportion of the glucose-transporting apparatus is accessible to galactose.


Influence of medial preoptic-anterior hypothalamic area stimulation of the excitability of mediobasal hypothalamic neurones in the rat.

1. Extracellular action potentials recorded from 798 neurones in the mediobasal hypothalamus (MBH) of pentobarbitone anaesthetized male rats were analysed for a change in excitability following stimulation in the medial preoptic and anterior hypothalamic areas. 2. An increase in excitability characteristic of orthodromic excitation was observed from 11-5% (n=92) of MBH neurones. Latencies for excitation were shorter for cells tested with anterior hypothalamic area stimulation (n=42; mean 5-4 +/- 2-6 msec S.D.) than for cells tested with medial preoptic stimulation (n=50; mean 15-2 +/- 7-2 msec S.D.). With spontaneously active neurones, excitation was followed by a decrease in excitability lasting 150-250 msec. An initial decrease in excitability, suggestive of post-synaptic inhibition, over a wide latency range (4-30 msec) and with duration of 100-400 msec was observed from 3-6% of MBH neurones. 3. Features of antidromic invasion were observed from 149 MBH neurones. From the medial preoptic area, the latency range was 0-5-38 msec (mean 7-8 +/- 5-5); from the anterior hypothalamic area the latency range was 0-4-9-5 msec (mean 3-1 +/- 2-3). Occasionally an abrupt decrease in latency followed an increase in stimulus intensity. Most cells followed paired stimuli at frequencies up to 500 Hz. Axon conduction velocities were estimated to be under 2-0 m/sec. Antidromic invasion was usually followed by a decrease in excitability lasting approximately 100-150 msec. 4. Twenty MBH neurons displayed antidromic invasion from both the medial preoptic or anterio hypothalamic areas and one other stimulation site: the median eminence (five cells); the amygdala (six cells); the region of thalamic nucleus medialis dorsalis (three cells) and the midbrain periaqueductal gray (six cells). Interaction studies indicated that the axons of these cells branched close to the origin of the axon itself. 5. Antidromic invasion from the surface of the median eminence identified thirty-nine tuberoinfundibular neurones. Stimulation in the medial preoptic and anterior hypothalamic area produced orthodromic excitatory (n = 5) and inhibitory (n = 4) actions on HVM neurones, but was without an action on most other neurones (n = 30). Tuberoinfundibular neurones in the ventromedial nucleus also responded to stimulation in the amygdala, but usually at latencies greater than that for medial preoptic area evoked responses. 6. These observations indicate a close relationship between MBH neurones and cells located in both the amygdala and the medial preoptic-anterior hypothalamic area. The data for tuberoinfundibular neurones indicates that several extrahypothalamic areas may send fibres to these cells. These pathways may be important for the adaptive neuroendocrine responses reported in the literature.


Specific innervation of guinea-pig superior cervical ganglion cells by preganglionic fibres arising from different levels of the spinal cord.

1. The synaptic contribution of preganglionic nerve fibres arising from the last cervical (C8) and the first seven thoracic spinal cord segments (T1-T7) to neurones of the guinea-pig superior cervical ganglion has been studied by means of intracellular recording during ventral root stimulation in vitro. 2. The majority of neurones received innervation from the middle segments (T2 and T3) of the length of spinal cord from which preganglionic fibres derive; an intermediate number of ganglion cells were innervated by fibres from the segments adjacent to these (T1, T4, and T5), and relatively few neurones by fibres from the most rostral and caudal segments supplying innervation to the ganglion (C8, T6 and T7). 3. Each neurone received preganglionic terminals from multiple thoracic segments (range 1-7, mean = 4-0). The estimated minimum number of preganglionic fibres contacting each neurone was 10, on average. 4. As a rule, the spinal segments innervating a neurone were contiguous. Thus we rarely encountered neurones innervated by segments located both rostrally and caudally to a segment which failed to provide innervation. 5. Neurones tended to be innervated predominantly by axons arising from a single spinal segment, with adjacent segments contributing a synaptic influence that diminished as a function of their distance from the dominant segment. All segments provided dominant innervation to at least some neurones. 6. Stimulating the ventral roots of C8-T7 in vivo showed that the axons arising from each segment produced a characteristic pattern of peripheral effects. Thus different populations of neurones in the superior cervical ganglion of the guinea-pig are innervated by preganglionic axons from different levels of the spinal cord, as originally suggested by Langley (1892) for the cat, dog, and rabbit. 7. On the basis of our in vitro studies we conclude that underlying the specificity of innervation of neurones of the superior cervical ganglion that can be inferred from in vivo experiments is a tendency for individual neurones to be innervated in a systematically graded fashion by a contiguous subset of the eight spinal segments which provide innervation to the ganglion.


Interaction of air temperature and core temperatures in thermoregulation of the goat.

1. The interaction between air temperature, hypothalamus temperature, and spinal cord temperature in driving heat production and respiratory evaporative heat loss has been studied in conscious goats with chronically implanted thermodes. 2. Thermoregulatory heat production could be described as being approximately proportional to the sum of two linear drives determined by hypothalamus temperature and spinal cord temperature. This was found also for respiratory evaporative heat loss except that it was not influenced by spinal cord cooling. 3. Thermoregulatory heat production could be further described as being approximately proportional to a product of linear drives determined by hypothalamus and spinal cord temperature on one hand and air temperature on the other. Respiratory evaporative heat loss was approximately proportional to the sum of drives determined by spinal cord, hypothalamus and air temperatures. 4. Sensitivity to central cooling was found to undergo long-lasting but temporary changes which interfered with the immediate effects of air temperature on thermoregulation. 5. Central threshold temperatures for heat production and respiratory evaporative heat loss were found to be differently affected by air temperature. This indicates that integrating mechanisms for heat production and respiratory evaporative heat loss are to some extent functionally independent.


Innervation of the rabbit rectococcygeus muscle and the functional relationship of the muscle to the terminal large intestine.

1. The rectococcygeus muscle is supplied by cholinergic motor fibres from the parasympathetic division of the autonomic nervous system. 2. The histofluorescence technique reveals a sparse adrenergic innervation. 3. When a maintained state of partial contraction is induced by carbachol, stimulation of the extrinsic sympathetic nerves produces a relaxation of the muscle which is usually followed by contraction. 4. The rectococcygeus muscle may also receive nerves which are neither adrenergic nor cholinergic. 5. Ganglion cells have been found close to and, in some preparations, within the muscle; the role of these ganglion cells is not clear. 6. It would appear that the rectococcygeus muscle and the longitudinal muscle of the rectum are not linked by a myogenic mechanism. The rectococcygeus muscle would, however, appear to be linked by nerve fibres to neighbouring structures.


Dogmatism as a mediating influence on the perception of risk in consumer choice decisions.

The risk perceived by individual consumers when faced with an unfamiliar purchase situation was examined across three groups of females for three product categories. Group membership was determined on the basis of high, medium, and low scores on the Trodahl-Powell dogmatism instrument. Ss were 155 housewives of a medium size midwestern city in the United States surveyed as part of a two-tiered sampling process. The results of a multivariate analysis of variance procedure supported the hypothesis that consumers of a less dogmatic nature perceive lower levels of risk inherent within unfamiliar purchase situations than more dogmatic individuals. The implication for management is that the likelihood of obtaining successful new product introductions may be substantially enhanced through the process of risk reduction across dogmatic consumer segments by use of direct testimonial promotional themes stressing product acceptance in support of more traditional and informative advertising messages. The feasibility of this approach is based upon the premise that the behavior of dogmatic individuals is more frequently affected by pressures from peers and significant others than the behavior of individuals low in dogmatism which is generally based on more factual and relevant information.


Probability, personality, age, and risk taking.

Male and female college (n=22) and high school (n=18) students were presented information concerning probability and were also measured on the personality variables of independence of judgment, response set, Machiavellianism, and open-mindedness. An investigation of the risky shift phenomenon revealed that an understanding of probability did not vitiate the shift toward greater risk. Age was shown to be functionally related to risk taking, the teen years showing greater proclivity for risk than later years. Independence of judgment emerged as a powerful predictor of initial risk; Machiavelianism bore no relationship to risk taking. Both of these findings concerning personality variables were at odds with earlier work. An interpretation of contextual interaction was advanced as a possible explanation.


Family constellation and creativity: firstborn predominance among classical music composers.

Biographies of classical musci composers were examined for family constellation information. Usable data were found for 80 composers. Firstborns, especially only children, were found significantly more frequently than in a sample of creative writers studied by Bliss. Increased frequency of firstborns was also suggested in a study of musical performers by Raychaudhuri. Classical musci composition was seen as an ability more similar to usual academic pursuits than creative writing.


Reducing interracial aggression: inhibiting effects of victim's suffering and power to retaliate.

A 2 X 2 X 2 factorial experiment employing 64 white male university students investigated the aggression-inhibiting effects of three characteristics of a victim: his race, expression of pain, and potential to retaliate. As predicted, pain cues effectively inhibited aggression. A triple-order interaction effect extended previous findings by demonstrating that the expression of suffering reduced aggression (a) even if the victim had no power to retaliate and (b) even if the victim was a member of a racial minority. In contrast to the suppressive effect of suffering, potential retaliation was a relatively ineffective deterrent of physical attack. Additional factors limiting the aggression-inhibiting power of threatened retaliation were the victim's expression of suffering and expectations of weak counteragression.


Perceived self and ideal self ratings in relation to high and low levels of anxiety in college women.

The Cattell and Scheier IPAT Anxiety (Self Analysis) Questionnaire and the Corsini SAQS Chicago Q Sort were administered to 146 college women. Ss were divided into "high" and "low" anxiety groups on the basis of the IPAT anxiety scores. Those women with a high degree of anxiety were found to have a significantly greater discrepancy between their perceived self and ideal self concepts than did those women who had low levels of anxiety.


Effect of refraction on perceived locus of a target in the peripheral visual field.

A target of 44 min of arc with luminance of 1.03 log cd/m2 of 50 msec duration was presented to the loci along each of nasal, temporal, superior, and inferior half retinal meridians covering the eccentricity between 10 degrees and 50 degrees in steps of 10 degrees units. Two graduate students, serving as Ss, were instructed to point out the perceived locus where the target had appeared. The visual angles between the perceived and physical locus of the target were increased as a function of retinal eccentricity due to refraction.


Personality and attitude correlates of religiosity: a source of controversy.

The Allport-Vernon-Lindzey Study of Values and the Brown Modification of the Thouless Test of Religious Orthodoxy were administered to 120 male and female students in introductory psychology. Measures of anxiety, self-esteem, authoritarianism, and humanitarianism were also administered to the Ss in an effort to determine whether the two measures of religiosity would yield different personality and attitude profiles of the "religious" individual. A significant positive correlation was found between authoritarianism and the Thouless Test and between humanitarianism and the Study of Values religious measure. All other correlations involving the two measures of religiosity were found to be nonsignificant. These findings lend support to the notion that using two divergent measures of religiosity does result in the formation of different profiles of the "religious" individual.


The effect of interviewer bias on mental illness questionnaire responses.

The purpose of this study was to investigate how interviewer behavior affects information obtained from a respondent during an interview. The five factors of interviewer behavior that were studied were social reinforcement, interviewer disclosure, verbal modeling, interviewer dress, and seating arrangement. The dependent variable was the number of symptoms reported on the 22-item Mental Health Inventory. A total of 128 male and female adult patients under treatment for mental illness were interviewed under procedures using all combinations of the five factors. Control of patient sex, age, ethnicity, and education was effected through the use of a balanced design. The results demonstrated that the behavior of the interviewer influenced the respondent's report of psychiatric symptoms. The largest number of psychiatric symptoms were reported when the interviewer gave social reinforcement while wearing a lab coat and sitting across a desk from the respondent.