Synthesis of ferrocenethiols containing oligo(phenylenevinylene) bridges and their characterization on gold electrodes.

Ferrocene-terminated oligo(phenylenevinylene) (OPV) methyl thiols have been prepared by orthogonal coupling of phenylene monomers. Ethoxy substituents on the phenyl rings improve the solubility of OPV, enabling the synthesis of longer oligomers. Self-assembled monolayers containing a mixture of a ferrocene OPV methyl thiol and a diluent alkanethiol were deposited on gold. A cyclic voltammetric study of monolayers containing oligomers of the same length with and without ethoxy solubilizing groups reveals that both solubilized and unsolubilized oligomers form well-packed self-assembled monolayers. Changing the position of the solubilizing groups on an oligomer chain does not preclude packing of the oligomer in the monolayer. Conventional chronoamperometry, which can be used to measure rate constants up to approximately 10(4) s(-1), is too slow to measure the electron-transfer rate through these oligomers over distances up to 35 A. OPV bridges are expected to be highly conjugated unlike oligo(phenyleneethynylene) bridges, which may be only partially conjugated because of rotation of the phenyl rings about the ethynylene bonds. Because of its high conjugation, OPV may prove useful as a molecular wire.

Rapid electron tunneling through oligophenylenevinylene bridges.

We measured rate constants of thermal, interfacial electron transfer through oligophenylenevinylene bridges between a gold electrode and a tethered redox species in contact with an aqueous electrolyte using the indirect laser-induced temperature jump technique. Analysis of the distance dependence indicates that, unlike other bridges studied to date, the rate constants are not limited by electronic coupling for bridges up to 28 angstroms long. The energy levels of the bridges relative to those of the redox species rule out hopping through the bridge. We conclude that, out to 28 angstroms, the transfer is limited by structural reorganization and that electron tunneling occurs in less than 20 picoseconds, suggesting that oligophenylenevinylene bridges could be useful for wiring molecular electronic elements.

Bioreactive self-assembled monolayers on hydrogen-passivated Si(111) as a new class of atomically flat substrates for biological scanning probe microscopy.

This is the first report of bioreactive self-assembled monolayers, covalently bound to atomically flat silicon surfaces and capable of binding biomolecules for investigation by scanning probe microscopy and other surface-related assays and sensing devices. These monolayers are stable under a wide range of conditions and allow tailor-made functionalization for many purposes. We describe the substrate preparation and present an STM and SFM characterization, partly performed with multiwalled carbon nanotubes as tapping-mode supertips. Furthermore, we present two strategies of introducing in situ reactive headgroup functionalities. One method entails a free radical chlorosulfonation process with subsequent sulfonamide formation. A second method employs singlet carbenemediated hydrogen-carbon insertion of a heterobifunctional, amino-reactive trifluoromethyl-diazirinyl crosslinker. We believe that this new substrate is advantageous to others, because it (i) is atomically flat over large areas and can be prepared in a few hours with standard equipment, (ii) is stable under most conditions, (iii) can be modified to adjust a certain degree of reactivity and hydrophobicity, which allows physical adsorption or covalent crosslinking of the biological specimen, (iv) builds the bridge between semiconductor microfabrication and organic/biological molecular systems, and (v) is accessible to nanopatterning and applications requiring conductive substrates.

Polar orientation of dyes in robust multilayers by zirconium phosphate-phosphonate interlayers.

Polar orientation of molecules in solids leads to materials with potentially useful properties such as nonlinear optical and electrooptical activity, electrochromism, and pyroelectricity. A simple self-assembly procedure for preparing such materials is introduced that yields multiple polar dye monolayers on solid surfaces joined by zirconium phosphate-phosphonate interlayers. Second harmonic generation (SHG) shows that the multilayers have polar order that does not decrease with increasing numbers (up to a large number) of monolayers in the film. The inorganic interlayers, as determined by SHG, impart excellent orientational stability to the dye molecules, with the onset of orientational randomization above 150 degrees C.

In situ scanning tunneling microscopy of corrosion of silver-gold alloys.

An in situ scanning tunneling microscope (STM) was used to observe the morphological changes accompanying the selective dissolution of Ag from low-Ag content Ag-Au alloys in dilute perchloric acid. This study was undertaken to explore the role of surface diffusion in alloy corrosion processes. These results are interpreted within the framework of the kink-ledge-terrace model of a crystal surface and a recent model of alloy corrosion based on a variant of percolation theory. The corrosion process leads to roughening of the surface by dissolution of Ag atoms from terrace sites. Annealing or smoothening of the surface occurs by vacancy migration through clusters and the subsequent annihilation of clusters at terrace ledges.

Free energy and temperature dependence of electron transfer at the metal-electrolyte interface.

The rate constant of the electron-transfer reaction between a gold electrode and an electroactive ferrocene group has been measured at a structurally well-defined metal-electrolyte interface at temperatures from 1 degrees to 47 degrees C and reaction free energies from -1.0 to +0.8 electron volts (eV). The ferrocene group was positioned a fixed distance from the gold surface by the self-assembly of a mixed thiol monolayer of (eta(5)C(5)H(5))Fe(eta(5)C(5)H(4))CO(2)(CH(2))(16)SH and CH(3)(CH(2))(15)SH. Rate constants from 1 per second (s(-1)) to 2 x 10(4) s(-1) in 1 molar HClO(4) are reasonably fit with a reorganization energy of 0.85 eV and a prefactor for electron tunneling of 7 x 10(4) s(-1) eV(-1). Such self-assembled monolayers can be used to systematically probe the dependence of electron-transfer rates on distance, medium, and spacer structure, and to provide an empirical basis for the construction of interfacial devices such as sensors and transducers that utilize macroscopically directional electron-transfer reactions.

Electroactive polymers and macromolecular electronics.

Electrodes can be coated with electrochemically reactive polymers in several microstructural formats called sandwich, array, bilayer, micro-, and ion-gate electrodes. These microstructures can be used to study the transport of electrons and ions through the polymers as a function of the polymer oxidation state, which is essential for understanding the conductivity properties of these new chemical materials. The microstructures also exhibit potentially useful electrical and optical responses, including current rectification, charge storage and amplification, electron-hole pair separation, and gates for ion flow.

Effect of magnetic fields on the triplet state lifetime in photosynthetic reaction centers: Evidence for thermal repopulation of the initial radical pair.

The lifetime of the molecular triplet state formed by recombination of the radical ion pair in quinonedepleted bacterial photosynthetic reaction centers is found to depend on applied magnetic field strength. It is suggested that this magnetic field effect results from thermally activated repopulation of the same radical ion pair that generates the triplet. Consistent with this hypothesis, the magnetic field effect on the triplet lifetime disappears at low temperature where the triplet state decays exclusively by ordinary intersystem crossing. This activated pathway for the decay of the triplet state can explain the strong temperature dependence of the triplet decay rate. A detailed theoretical treatment of the problem within a set of physically reasonable assumptions relates the observed temperature dependence of the triplet decay rate to the energy gap between the radical ion pair intermediate and the triplet state. This energy gap is estimated to be about 950 cm(-1) (0.12 eV). Combined with an estimate of the energy of the donor excited state, we obtain an energy gap between the excited singlet state of the donor and the radical ion pair of 2,250 cm(-1) (0.28 eV).

Anisotropic magnetic interactions in the primary radical ion-pair of photosynthetic reaction centers.

The quantum yield of triplets formed by ion-pair recombination in quinone-depleted photosynthetic reaction centers is found to depend on their orientation in a magnetic field. This new effect is expected to be a general property of radical pair reactions in the solid state. For 0 < H < 1,000 G, the quantum yield anisotropy is caused by anisotropic electron dipole-electron dipole or nuclear hyperfine interactions, or both. For high fields it is dominated by the anisotropy of the difference g-tensor in the radical ion-pair. The magnitude and sign of the contribution of each interaction depend not only on the values of the principal components of each anisotropic tensor but also on the geometric relationship of the principal axes of each tensor to the transition dipole moment used to detect the yield. A detailed formalism is presented relating these quantities to the observed yield anisotropy. The expected magnitude of each anisotropic parameter is discussed. It is demonstrated that the field dependence of the yield anisotropy is consistent with these values for certain reaction center geometries.

Inhibition of theophylline clearance by troleandomycin.

The effect of troleandomycin, a macrolide antibiotic, on theophylline elimination was examined in eight patients with chronic asthma. Clearance from serum was reduced by 50 +/- 6% (mean +/- SD) during administration of 250 mg troleandomycin four times daily. Reduction of clearance persisted to a lesser degree in one of these patients examined while receiving 250 mg troleandomycin daily. An increase in serum theophylline concentration can thus result from initiating troleandomycin in asthmatic patients receiving continuous treatment with theophylline. This may be at least a partial explanation for the apparent benefit of troleandomycin in chronic asthma and also suggests that possibility of inducing theophylline toxicity, including seizures, as was observed in one of the patients in this study.

Pharmacokinetic studies of quinidine in patients with arrhythmias.

The absorption and disposition of quinidine were measured in nine patients following single oral and intravenous dosing. A new specific chromatographic method was used to measure the drug in plasma and urine. After intravenous administration, the plasma half-life (t1/2beta) was 7.8+/-0.7 h, the volume of distribution (Vd) was 3.0+/-0.5 liters/kg, and the total body clearance was 4.8+/-0.8 ml/min/kg. After oral administration, 87+/-7% (mean+/-SEM) was available to the systemic circulation. Quinidine was removed primarily by hepatic metabolism, with the renal clearance averaging only 1.0+/-0.2 ml/min/kg. Mean quinidine concentrations were estimated in 42 patients on chronic therapy by averaging blood levels during a dosing interval. In patients without heart failure, these corresponded well to mean drug levels predicted from the pharmacokinetic parameters measured after a single intravenous dose, but in patients with heart failure, the values for mean quinidine concentrations were higher than predicted. This suggests that impaired elimination of the drug or a decreased volume of its distribution, or both, may develop in heart failure.

Minoxidil reduces pulmonary vascular resistance in dogs and cattle.

Minoxidil has a direct dilator effect on the systemic arterial smooth muscle. It is potentially an important drug in the treatment of systemic hypertension, especially when combined with beta blockade, which is used to control the associated tachycardia and increase in cardiac output. However, recent observations have suggested that minoxidil might cause pulmonary hypertension. Consequently, we examined the acute effect of monoxidil and propranolol, separately and in combination, on the pulmonary vasculature of the anesthetized dog and the awake calf during normoxia and hypoxia. In both species minoxidil reduced pulmonary vascular resistance. In the dogs this appeared to be the result of a direct action on the pulmonary vascular smooth muscle and in the cattle it was secondary to beta-receptor stimulation. Propranolol alone in the cattle increased the pulmonary pressor response to hypoxia. While we have not examined the possibility that chronic administration of minoxidil might cause pulmonary hypertension by some other mechanism, our acute studies suggest that it reduces, rather than increases, pulmonary vascular resistance. Furthermore, there seems to be a species difference in the mode of its action in dogs and cattle.

Intravenous aminophylline dosage. Use of serum theophylline measurement for guidance.

A practical method for monitoring serum theophylline concentrations has been used to investigate intravenous aminophylline dosage requirements. Initial serum theophylline concentrations were found to vary widely and correlate poorly with drug history. Aminophylline loading doses determined from these values more frequently resulted in drug concentrations in the therapeutic range (10 mug to 20 mug/ml) than when therapy was given without knowledge of serum theophylline concentrations. Continuous intravenous aminophylline therapy administered in a standardized dosage (0.9 mg/kg/hr in adults and 1.0 mg/kg/hr in children) produced variable and often excessive serum concentrations. This resulted from variable drug clearance rates, which in adults averaged 0.64 +/- 0.38 ml/kg/min (mean +/- SD), only half that previously reported. These observations suggest that it is not possible to achieve optimal therapeutic aminophylline dosage without monitoring serum theophylline concentrations.

The use of drug concentration measurements in studies of the therapeutic response to propranolol.

The dose of propranolol which produces the optimal therapeutic effect in patients with angina pectoris has been found to vary widely among patients. Because the plasma concentration of propranolol also differs markedly due to interpatient variability in absorption it seemed possible that this might be the reason for the wide range of effective doses in angina and that plasma propranolol might provide a useful guide to therapeutic response. To examine this possibility we selected ten patients with coronary artery disease complicated by angina and studied them at varying propranolol doses to a maximum of 320 mg/day. Exercise capacity was tested on a treadmill and plasma propranolol concentration was measured by gas liquid chromatography. In seven normal subjects beta-blockade was quantified precisely as inhibition of exercise tachycardia and was related to plasma propranolol levels at various doses. Maximal beta-blockade occurred at 100 ng/ml of plasma propranolol, but the dose response curve of blockade was relatively flat and the ED50 of plasma propranolol was 8+/-1 ng/ml. In the patients maximal therapeutic benefit from propranolol occurred at 30+/-7 ng/ml and at a dose of 144 mg/day. This resulted in an increase in exercise capacity from an estimated 12-7+/-0-8 ml/kg/min of oxygen consumption during control to 17-2+/-1-1 ml/kg/min on the drug. Thus, there was a wide variation of both dose and concentration among these patients at the maximum therapeutic response. However, when plasma propranolol was related to pharmacologic activity, the maximum therapeutic response was observed between 64 and 98% of total blockade. These studies indicated the extent of beta-blockade necessary to produce an effective therapeutic response in angina, but demonstrate that plasma drug levels provide no practical guide to therapy in patients with angina pectoris. A further study was conducted measuring plasma propranolol in twenty hypertensive patients to investigate the fall in blood pressure in relations to the change in plasma renin activity and the inhibition of cardiac adrenergic receptors. The inhibition of plasma renin closely resemble the response seen in heart rate inhibition in that the maximum response is seen at 100 ng/ml and the ED50 was 11 ng/ml. In contrast propranolol is shown only to begin to have a significant effect on blood pressure at a plasma level of 30 ng/ml and the effect becomes progressively greater as the plasma level increases. This suggests that the hypotensive effect of propranolol may be dissociated from the beta-blocking effects of cardiac and renin releasing receptors.

Correlation of plasma propranolol concentration with therapeutic response in patients with angina pectoris.

The therapeutic response to propranolol was evaluated in patients with documented coronary artery disease at doses varying from 40 to 320 mg/day. Therapeutic response was quantified by evaluating exercise performance on a treadmill and then related to plasma propranolol concentration. Plasma propranolol was defined in terms of beta-adrenergic blockade by comparison with dose (concentration) response curves in normal subjects. Individual therapeutic benefit occurred at doses which averaged 144 +/- 21 mg/day and at concentrations which averaged 30 +/- 7 ng/ml. There was a wide variation between both dose and concentration among the patients at maximum therapeutic response, but when the plasma propranolol was related to pharmacologic activity, the maximum therapeutic response was observed between 64 to 98% of total blockade. Despite the increased exercise performance in these patients, the double product of heart rate and systolic blood pressure was always less, suggesting either an alteration of the relation between myocardial oxygen consumption and the double product during propranolol or a reduction on oxygen delivery to the myocardium as the result of beta-adrenergic blockade of the coronary vasculature.

Studies of the absorption and removal of propranolol in hypertensive patients during therapy.

The variability of plasma propranolol concentrations has been determined in a large group of patients being treated with the drug. Although the average patient achieved a therapeutic plasma level with 160 mg/day, there was marked interpatient variation. This was found to be primarily the result of differences in effective absorption of the drug, which averaged 46% of the oral dose but ranged from 20 to 80%. Propranolol disappeared from plasma with a half-life of 4.7 hours and its removal appeared to follow dose independent kinetics with no evidence of saturation of hepatic metabolism. The derived pharmacokinetic values of volume of distribution and clearance rate have been used to provide guidelines for initiating propranolol therapy intravenously, and the schedule of 8 mg as a loading dose and 0.02 mg/min as a sustaining dose has been suggested.

Hypotensive and renin-suppressing activities of propranolol in hypertensive patients.

1. In patients with mild or moderate essential hypertension, oral propranolol, given in incremental doses, produced a moderate but significant lowering of blood pressure which was correlated with the concentration of propranolol in plasma. 2. Propranolol also reduced plasma renin activity (PRA) in the supine posture, on standing and after intravenous frusemide. However, 'supine' and 'frusemide' PRA values were markedly reduced at a plasma concentration of propranolol that had little effect on blood pressure. 3. On administration of propranolol there was little correlation between blood pressure decrease and PRA suppression, and even less between pretreatment PRA values and hypotensive response. 4. It is concluded that in patients with mild and moderate hypertension and low or normal plasma renin activity, suppression of PRA is not an important determinant of the hypotensive response to propranolol.

Rapid analysis for theophylline in serum by use of high-pressure cation-exchange chromatography.

We have developed a quantitative assay for serum theophylline by high-pressure cation-exchange chromatography. As little as 0.1-ml aliquots of serum were prepared for analysis simply by diluting them with a solution of the internal standard (8-chlorotheophylline). Theophylline and the internal standard were eluted in 17 and 27.5 min, respectively, and the peaks for them were distinct from those of other xanthines and uric acids. We encountered no interference when we used: (a) plasma obtained from blood anticoagulated with citrate; (b) hemolyzed, lipemic, or icteric serum; or (c) 52 samples from patients who were receiving various other medications. An analysis of calibration suggested that errors greater than plus or minus 2.6 mg/liter, a clinically acceptable range, were highly unlikely. Sensitivity was sufficient to identify less than 2.5 mg/liter. This assay was compared with the usual method involving solvent extraction and absorbance measurement in the ultraviolet and found to have similar accuracy, although it is easier, faster, requires less sample, and potentially is more specific.