Molecular fingerprints in the electronic properties of crystalline organic semiconductors: from experiment to theory.

By comparing photoemission spectroscopy with a nonperturbative dynamical mean field theory extension to many-body ab initio calculations, we show in the prominent case of pentacene crystals that an excellent agreement with experiment for the bandwidth, dispersion, and lifetime of the hole carrier bands can be achieved in organic semiconductors, provided that one properly accounts for the coupling to molecular vibrational modes and the presence of disorder. Our findings rationalize the growing experimental evidence that even the best band structure theories based on a many-body treatment of electronic interactions cannot reproduce the experimental photoemission data in this important class of materials.

Large tunable Rashba spin splitting of a two-dimensional electron gas in Bi2Se3.

We report a Rashba spin splitting of a two-dimensional electron gas in the topological insulator Bi(2)Se(3) from angle-resolved photoemission spectroscopy. We further demonstrate its electrostatic control, and show that spin splittings can be achieved which are at least an order-of-magnitude larger than in other semiconductors. Together these results show promise for the miniaturization of spintronic devices to the nanoscale and their operation at room temperature.

Electron-phonon interaction at the Si(111)-7 x 7 surface.

It is shown that electron-phonon interaction provides a natural explanation for the unusual band dispersion of the metallic surface states at the Si(111)-(7 x 7) surface. Angle-resolved photoemission reveals a discontinuity of the adatom band at a binding energy close to the dominant surface phonon mode at h(omega0) = 70 meV. This mode has been assigned to adatom vibrations by molecular dynamics calculations. A calculation of the spectral function for electron-phonon interaction with this well-defined Einstein mode matches the data. Two independent determinations of the electron-phonon coupling parameter from the band dispersion and from the temperature-dependent phonon broadening yield similar values of lambda = 1.09 and lambda = 1.06.

Family strengths and the Kansas Marital Satisfaction Scale: a factor analytic study.

20 new items were developed to measure six concepts of family strengths and were administered, along with the Kansas Marital Satisfaction Scale, to over 266 married subjects as part of a larger survey of current and former members of the Christian Church (Disciples of Christ). A common factor analysis suggested that most of the items were associated with their expected factors, while reliability analyses indicated that most of the scales had acceptable estimates of internal consistency. The marital satisfaction items clearly were associated with their own factor and not other factors, providing support for the unidimensional nature of the Kansas Marital Satisfaction Scale and for its construct validity.

Seventy-eight-week dietary carcinogenicity study of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a novel drug for urinary frequency and incontinence, in mice.

The oncogenic potential of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a new drug for the treatment of urinary frequency and incontinence, was assessed when it was administered in the diet of Charles River B6C3F1 mice for 78 weeks in dosages of 0, 30, 100 and 300 mg/kg/day. No drug-related effects occurred on survival, appearance or behavior, or occurrence, location or number of palpable masses. Average food consumption, food efficiency and hematologic values also were apparently unaffected. Statistically significantly low body weights were observed in the 100 and 300 mg/kg/day mice. The plasma concentrations of NS-21 and its active metabolite, RCC-36, in the treated groups were increased in a dose-dependent manner. Histopathological examinations disclosed midzonal hepatocellular vacuolization compatible with lipid vacuoles in both sexes at the 300 mg/kg/day dose level. There were no test article-related effects on the incidence or type of neoplastic lesions. In conclusion, under the conditions of this study, no oncogenic effects were evident in B6C3F1 mice when NS-21 was administered in the diet in concentrations to produce an intake of up to 300 mg/kg/day for 78 weeks.

Two-year dietary carcinogenicity study of (+/-)-4-diethylamino-1, 1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a novel drug for urinary frequency and incontinence, in rats.

The oncogenic potential of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a new drug for the treatment of urinary frequency and incontinence, was assessed when it was administered in the diet of Charles River Fischer-344 rats for 2 years in dosages of 0, 10, 30 and 100 mg/kg/day. No drug-related effects occurred on survival, appearance or behavior, or occurrence, location or number of palpable masses. Food efficiency and hematologic values also were apparently unaffected. Statistically significantly low mean weekly body weights and average food consumption values were observed in the all dose groups. The plasma concentrations of NS-21 and its active metabolite, RCC-36, in the treated groups were increased in a dose-dependent manner. Histopathological examinations disclosed test article-related increases in the incidence of periportal hypertrophy and midzonal hepatocellular vacuolization in the livers of the 100 mg/kg/day animals. There were no test article-related effects on the incidence or type of neoplastic lesions. In conclusion, under the conditions of this study, no oncogenic effects were evident in Fischer-344 rats when NS-21 was administered in the diet in concentrations to produce an intake of up to 100 mg/kg/day for 2 years.

Serum progesterone and milk production and composition in dairy cows fed two concentrations of nitrate.

Forty clinically normal lactating Holstein cattle from a herd involved in a natural outbreak of chronic nitrate toxicosis were divided into 2 equal groups according to production, stage of lactation, age, and apparent pregnancy state (pregnant or nonpregnant). One group was fed a low-nitrate ration (average of 356 ppm on dry matter basis in concentrate; less than 400 ppm in free-choice hay for 1st 5 wks of study). The 2nd group was fed a high-nitrate (HN) ration (average of 1,600 ppm in protein concentrate-amemded corn silage; 4,000 ppm in free-choice hay for the 8-week study). At the end of the study, the 2 groups were classified according to their starting reproductive status: nonpregnant (open); early pregnant (less than 60 da); midpregnant (average of 105 da). Milk production, milk fat, and milk nitrate concentrations were similar for cows fed both rations. Serum progesterone concentration (SPC) was depressed (P less than 0.05) in cows fed the HN ration. This effect was prominent in open, luteal phase cows, less prominent but still apparent in early pregnant cows, and absent in midpregnant cows. The early reproductive problems of chronic nitrate toxicosis may be due to depression of SPC. A possible mechanism of inhibition of luteal progesterone synthesis by inhibition of cytochrome P-450 is presented.

Effects of various known and potential cyanide antagonists and a glutathione depletor on acute toxicity of cyanide in mice.

To compare the protective potencies of a large number of known and potential cyanide antagonists in one stock of mice, groups (N = 10) of male CF-1 Swiss-Webster mice were given a single maximal or near-maximal intraperitoneal injection of each substance. Ethyl maleate, a glutathione (GSH) depletor and potential enhancer of cyanide toxicity, was given to other groups. Thirty min later, the mice were given subcutaneous injections of graded doses of KCN. In untreated control mice, the 24-hr median lethal dose (LD50) of KCN was 11 mg/kg of body weight (potency ratio, PR = 1.0). In comparison, protective effects of traditional antagonists thiosulfate and nitrite produced PR values of 1.48 and 2.95, respectively. Tetrathionate, sulfate, dithionite, methionine, hydroxocobalamin, ascorbate, pyridoxal phosphate, alpha-ketoglutarate, alpha-ketobutyrate, GSH, GSH disulfide (GSSG) and selenite were similar in efficacy to thiosulfate (P less than 0.05; PR values 1.35-1.59). Cysteine, diethyldithiocarbamate (DEDC), and cobaltous chloride were more effective than thiosulfate (PR values 1.68, 1.69, and 1.85, respectively). Phentolamine and dicobalt EDTA were ineffective, whereas papaverine enhanced toxicity (PR 0.72). Agents with significant PR values (greater than or equal to 1.14) but which were less effective than thiosulfate included sulfite, dimercaptosuccinic acid, pyruvate, citrate, alpha-ketovalerate, naloxone, and corn oil. Ethyl maleate in corn oil markedly enhanced KCN lethality (PR 0.57 compared to corn oil alone), and caused prolonged illness in several mice. Vitamin E in corn oil had no effect. Dual mixtures of thiosulfate with other selected substances were also tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute intraperitoneal cholecalciferol (vitamin D3) toxicosis in mice: its nature and treatment with diverse substances.

To study the overt toxicosis of intraperitoneally (IP)-administered single doses of cholecalciferol (D3), groups of male CF-1 mice (N = 12) were given graded doses of D3 in corn oil and observed for 21 days. There was a 2- to 4-day onset of signs, including ocular squinting, reluctance to move, lethargy, weakness, anorexia, hunched posture, rough haircoat, and dehydration. This was followed by tremors, coma, and death (large doses) or gradual recovery. Deaths occurred 3 days (larger doses) to 21 days after D3 injection. The linear regression of mortality probits on log10 dose was Y = 7.332X-10.653. The median lethal dose (LD50) of D3 and 95% confidence limits were 135.4 mg/kg (112.2-157.4 mg/kg). To screen potential antidotes against acute D3 toxicosis, groups of mice (N = 12) were given subcutaneous (SC) injections of various substances beginning 2 days after IP injection of a large dose of D3 (300 mg/kg). Substances were given once or twice daily in constant volumes of saline solution (66.8 ml/kg) for 7 days. Two control groups were given D3 but no treatment. They both had 91.7% mortality; their mean (+/- SD) survival time (MST: censored to 21 days observation) was 6.8 +/- 4.7 days and 10.3 +/- 7.0 days. Mortality and MST were not affected significantly (P greater than 0.05) by once-daily injection of saline solution, saline containing dexamethasone (DEX), or saline containing the following substances with or without DEX: ascorbate; citrate; dimercaptosuccinic acid; oxytetracycline; ZnSO4; or MgCl2.(ABSTRACT TRUNCATED AT 250 WORDS)

Pathologic changes and tissue gentamicin concentrations after intravenous gentamicin administration in clinically normal and endotoxemic cats.

Hematologic and serum biochemical values, tissue gentamicin concentrations, and renal pathologic changes were determined in clinically normal and endotoxemic cats given 3 mg of gentamicin/kg of body weight, IV. Endotoxemia was induced by IV administration of 0.5 microgram of Escherichia coli endotoxin/kg of body weight. In experiment 1, 6 cats were given endotoxin. After rectal temperature increased at least 1 degree C, cats were given gentamicin. Blood samples were collected before and at 1 and 3 hours after administration of gentamicin. With the exception of severe leukopenia, other hematologic changes or changes in serum biochemical values were not observed. In experiment 2, 24 cats were allotted to 4 groups and were given gentamicin, endotoxin, gentamicin plus endotoxin, or neither substance. Three hours later, cats were euthanatized, and tissue and body fluid specimens were obtained and were assayed for gentamicin concentration. Kidney specimens were examined microscopically. Endotoxemic cats had more gentamicin in the renal medulla than did control cats, but none of the cats had detectable renal lesions. The possible nephrotoxic synergism between gentamicin and severe endotoxemia and the lack of major differences in gentamicin concentration in extrarenal tissues indicated that the dosage of gentamicin in endotoxemic cats does not have to exceed the dosage recommended for clinically normal cats. A single dose of gentamicin administered IV did not cause renal damage in mildly endotoxemic cats, but nephrotoxicity ascribed to multiple doses of gentamicin in more severely endotoxemic cats needs to be evaluated.

Pharmacokinetics of gentamicin in cats given Escherichia coli endotoxin.

Nineteen cats were given 3 mg of gentamicin sulfate/kg of body weight by rapid IV, SC, or IM injection for baseline values. Serum concentration of gentamicin vs time data were analyzed using a noncompartmental model based on statistical moment theory. One week later, each cat was given 0.5 microgram of Escherichia coli endotoxin/kg, IV. After cats had an increase in rectal temperature of at least 1 C, 3 mg of gentamicin/kg was administered by the same route used the previous week. Serum concentration of gentamicin vs time data were analyzed, and pharmacokinetic values were compared with base-line values. For IV studies, the half-life (t1/2) of gentamicin and the mean residence time were significantly different (P less than 0.05) compared with base line, whereas the total body clearance and apparent volume of distribution at steady state were not. The harmonic mean +/- pseudo SD for the t1/2 of gentamicin after IV administration was 76.8 +/- 12.6 minutes for base line and was 65.2 +/- 12.2 minutes in the same cats given endotoxin. The t1/2 of gentamicin after SC administration was 74.6 +/- 6.2 minutes for base line and was 65.2 +/- 13.6 minutes in the same cats given endotoxin. After IM administration, the t1/2 of gentamicin was 60.3 +/- 10 minutes for base line and was 59.7 +/- 13.6 minutes in the same cats given endotoxin. After IV administration of gentamicin, the arithmetic mean +/- SD for the mean residence time was 102.4 +/- 16.1 minutes for base line vs 79.2 +/- 18.4 minutes in the same cats given endotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of tobramycin in cats.

Tobramycin was administered to cats and its serum concentration vs time data were analyzed by use of a noncompartmental model. In the first experiment, 5 mg of tobramycin/kg of body weight was administered IV, IM, and then SC to 6 cats, 3 weeks apart. After IV administration, the mean +/- SD total body clearance of tobramycin was 2.21 +/- 0.59 ml/min/kg, and the apparent volume of distribution at steady state was 0.19 +/- 0.03 L/kg. The mean residence time was 90.5 +/- 16.2 minutes, with a harmonic mean serum half-life of 68.9 +/- 9.7 minutes. Blood urea nitrogen and serum creatinine concentrations were increased 3 weeks after the IV injection and also 3 weeks after the IM injection, which suggested possible renal damage. Moreover, large area under the curve values developed after IM and SC administrations, resulting in bioavailabilities of 159.5% and 189.9%, respectively, with no change in elimination rate. These results suggested a change in distribution, possibly caused by saturation of renal binding sites by residual tobramycin from the previous injection of 5 mg/kg. In experiment 2, 6 other cats were given 3 mg of tobramycin/kg by the same routes as before, but using a crossover design. Bioavailability after IM and SC administrations was 102.5% and 99.2%, respectively, indicating complete absorption of tobramycin. The BUN concentration increased in 3 cats, and serum creatinine concentration increased in 1 of these 3 cats.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative pharmacokinetics of yohimbine in steers, horses and dogs.

In steers, horses and dogs, the comparative pharmacokinetics of yohimbine were determined using model-independent analysis. The intravenous dose of yohimbine was 0.25 mg/kg of body weight in steers, 0.075 or 0.15 mg/kg in horses, and 0.4 mg/kg in dogs. The mean residence time (+/- SD) of yohimbine was 86.7 +/- 46.2 min in steers, 106.2 +/- 72.1 to 118.7 +/- 35.0 min in horses, and 163.6 +/- 49.7 min in dogs. The mean apparent volume of distribution of yohimbine at steady state was 4.9 +/- 1.4 L/kg for steers, 2.7 +/- 1.0 to 4.6 +/- 1.9 L/kg for horses, and 4.5 +/- 1.8 L/kg for dogs. The total body clearance of yohimbine was 69.6 +/- 35.1 mL/min/kg for steers, 34.0 +/- 19.4 to 39.6 +/- 16.6 mL/min/kg for horses, and 29.6 +/- 14.7 mL/min/kg for dogs. Between-species comparisons indicated that the mean area under the serum concentration versus time curve was significantly greater (P less than 0.05) in dogs than in horses. There were no significant differences (P greater than 0.05) between the means for the apparent volume of distribution, clearance, mean residence time, terminal rate constant, and area under the curve between horses given the two doses of yohimbine. The harmonic mean effective half-life (+/- pseudo standard deviation) of yohimbine was 46.7 +/- 24.4 min in steers, 52.8 +/- 27.8 to 76.1 +/- 23.1 min in horses, and 104.1 +/- 32.1 min in dogs. The data may explain why steers, horses, and dogs given certain sedatives and anesthetics do not relapse when aroused by an intravenous injection of yohimbine hydrochloride.

Pharmacokinetic and pathological evaluation of gentamicin in cats given a small intravenous dose repeatedly for five days.

Gentamicin was administered to six cats at a dosage of 3 mg/kg of body weight intravenously every 8 h for five days. Peak and trough serum gentamicin concentrations were measured after each injection. Gentamicin elimination rate and serum half-life were calculated. Serum urea nitrogen, creatinine, biochemistry profile, electrolyte, glucose, total protein, and albumin concentrations were measured daily. Urinalyses were performed before and after the five-day experimental period. The mean +/- SD peak serum gentamicin concentration was 7.19 +/- 1.10 micrograms/mL, and the trough concentration was 0.59 +/- 0.09 microgram/mL. These concentrations are known to be effective against most gentamicin-sensitive bacteria. The mean +/- SD gentamicin elimination rate was 0.0065 +/- 0.0004 min-1. The harmonic mean +/- pseudo standard deviation serum half-life of gentamicin was 107.21 +/- 12.79 min. There were no significant increases (P greater than 0.05) in clinicopathological variables. Microscopic examination of renal sections did not disclose pathological lesions. Signs of vestibular impairment were not observed. A dosage of 3 mg gentamicin/kg given intravenously every 8 h for five days was determined to be safe and to produce therapeutic blood levels in cats.

Pharmacokinetics of amikacin in cats.

Six mixed-breed adult cats were given 5 mg of amikacin sulfate/kg of body weight by rapid IV, IM, and SC routes of administration. The serum concentration-vs-time data were analyzed, using a noncompartmental model. The harmonic mean +/- pseudo-SD of the effective half-life of amikacin was 78.8 +/- 19.3 minutes after IV administration, 118.7 +/- 14.4 minutes after IM administration, and 117.7 +/- 12.8 minutes after SC administration. The arithmetic mean +/- SD of mean residence time was 118.3 +/- 21.7 minutes, 173.4 +/- 19.9 minutes, and 171.7 +/- 19.1 minutes after IV, IM, and SC drug administration, respectively. The mean apparent volume of distribution at steady state was 0.17 +/- 0.02 L/kg, and the mean total body clearance was 1.46 +/- 0.26 ml/min/kg. Mean bioavailability was 95 +/- 20% after IM administration and 123 +/- 33% after SC drug administration. A recommended dosage of 10 mg/kg, q 8 h can be expected to provide a therapeutic serum concentration of amikacin with a mean steady-state concentration of 14 micrograms/ml. The SC route of administration is preferred, because of rapid absorption, good bioavailability, and ease of administration.

Pharmacokinetics of gentamicin after intravenous, intramuscular, and subcutaneous administration in cats.

Six adult mixed breed cats were given 5 mg of gentamicin sulfate/kg of body weight by rapid IV, IM, or SC injection. The serum concentration vs time data were analyzed, using a noncompartmental model based on statistical moment theory. The mean +/- SD for the effective half-life after IV administration was 1.25 +/- 0.30 hours. Mean residence time was 1.80 +/- 0.43 hours. The apparent volume of distribution at steady state was 0.14 +/- 0.02 L/kg. Total body clearance was 1.38 +/- 0.35 ml/min/kg. Bioavailability was 67.8% after IM and 76.2% after SC administration. A recommended dosage of 3 mg of gentamicin/kg every 8 hours was calculated; this dosage would induce an average steady state serum gentamicin concentration of 4 micrograms/ml. The SC route of administration was preferred because of rapid absorption, good bioavailability, and ease of administration.

Effect of intravenously-administered putative and potential antagonists of ethanol on sleep time in ethanol-narcotized mice.

Groups of male CD-1 mice (n = 12/group) were injected intraperitoneally (IP) with 5 g ethanol/kg of body weight. After loss of righting reflex, they were given vehicle or one of 2-3 doses of reputed or potential antagonists of ethanol intravenously (IV). Sleep time was measured from loss to return of righting reflex. Mean sleep time (MST) was increased significantly (P less than 0.05) by a large dose of dl-amphetamine (24 mg/kg) and by 4-aminopyridine (1, 5 mg/kg). Significant (P less than 0.01) increases were also produced by small and large doses of aminophylline (25, 100 mg/kg) and by yohimbine (1, 5 mg/kg). MST was not altered significantly by small and medium doses of dl-amphetamine (6, 12 mg/kg), a medium dose of aminophylline (50 mg/kg), or by any doses of naloxone, thyrotropin-releasing hormone, propranolol, physostigmine, doxapram, or Ro 15-4513. When Ro 15-4513 was given IP 15 minutes before ethanol (n = 6/group), onset and duration of narcosis were not altered. None of the compounds tested was an effective IV antidote for deep ethanol narcosis because of drug side effects, toxicity, prolongation of MST, or insufficient shortening of MST.

Induced aflatoxicosis in rabbits: blood coagulation defects.

The effect of acute and subchronic experimental aflatoxicosis on blood clotting activity and platelets was evaluated. Male New Zealand White rabbits (weighing 2.4-3.2 kg each) were used. In Experiment 1, 19 rabbits were given orally 0.05 mg of aflatoxin B1 (AFB1)/kg of body weight daily from Day 0 through Day 23. Blood samples were collected before dosing and on Days 2, 5, 9, 12, 16, 19, and 23 of the experimental period. In Experiment 2, 40 rabbits were given a single dose of 0.4 mg of AFB1/kg of body weight. Blood samples were collected before dosing and at 12, 24, 36, and 48 hr after dosing. When compared to baseline and control animal values, one-stage prothrombin times and activated partial thromboplastin times of aflatoxin-dosed rabbits were lengthened, and there was a statistically significant decrease in fibrinogen, Factor IX, VIII, and V activities. Platelet counts were significantly increased in subacutely exposed rabbits, and platelet size was decreased in single high-dose treated groups. Factor deficiencies were attributed to a combination of decreased factor synthesis from hepatic insufficiency and consumptive coagulopathy or primary fibrinolysis.

Effect of clonidine, quipazine, and LY 53857 on the prolactin-suppressant action of bromocriptine in rats.

The alpha 2-adrenergic agonist clonidine hydrochloride, the serotonin agonist quipazine maleate, and the serotonin (5-HT2) antagonist LY 53857 were tested alone and in various combinations for their capabilities to increase mean serum prolactin (MSP) concentrations in rats given the synthetic ergot alkaloid CB-154 (2-bromo-alpha-ergocriptine), a known prolactin suppressor. The LY 53857 and the combination of clonidine, quipazine, and LY 53857 significantly decreased MSP concentrations. Quipazine given alone (10 mg/kg of body weight) was best able to increase MSP concentration and has potential to antagonize prolactin-depressant effects of ergot alkaloids.