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1.  Comparison of on-site and photographic evaluations of the suppressive effects of cetirizine, loratadine, and fexofenadine on skin response to histamine lontophoresis: A double-blind, crossover study in healthy volunteers 
The standard method used to determine the potency of antihistaminesis to assess the degree of suppression of skin response to histamine challenge.
The aims of this study were to compare the efficacy of 3 antihistaminesusing a histamine challenge test and the usefulness of on-site evaluation with that of photographic evaluation of skin-test reactions.
In this prospective, double-blind, crossover study, healthy volunteerswere given cetirizine 5 mg (CTZ-5) and 10 mg (CTZ-10), loratadine 10 mg (LOR), fexofenadine 60 mg BID (FEX), and placebo (PLC), in a randomly assigned order, with an interval of at least 1 week between treatments. Before and 0.5 to 24 hours after administration, the areas of flare and wheal induced by histamine iontophoresis were measured directly (on site) by 1 evaluator and by another evaluator using photographic images on a computer monitor.
Ten healthy volunteers (6 men, 4 women; mean age, 28.2 years[range, 20–39 years]; mean weight, 60.7 kg [range, 41–81 kg]) were enrolled. The data from 9 subjects were analyzed; the data from 1 subject were omitted because the subject used an over-the-counter cold medication containing diphenhydramine several times during the study. By both methods, all antihistamines were shown to suppress flare significantly from 4 to 24 hours after administration. CTZ was most potent in suppressing both flare and wheal. For flare, the areas as measured using on-site evaluation were larger overall than those measured using photographic evaluation, but the shapes of the time-course graphs were similar for both. Overall, the flare area measurements started to decrease significantly from baseline values 4 hours after drug administration, reached a nadir at 10.5 hours, and remained significantly lower compared with baseline values at 24 hours. Comparisons between antihistamines showed significant differences in mean flare areas between the 2 doses of CTZ and LOR from 8 to 12 hours after administration in both evaluation methods. The wheal areas were significantly reduced from baseline values by most of the antihistamines 4 to 12 hours after drug administration, reached their lowest values at 10.5 hours, and returned to near-baseline values at 24 hours. Comparisons with PLC values at each time point, however, showed significant differences only for CTZ-5 and CTZ-10 from 4 to 12 hours after administration. Comparison between antihistamines showed significant differences in mean flare areas between the 2 doses of CTZ and LOR from 8 to 12 hours after administration in both evaluation methods. Although the flare areas measured by both methods correlated linearly (r = 0.90; P < 0.001), the correlation for wheal areas was weaker (r = 0.76; P < 0.001).
In this study in healthy volunteers, single doses of CTZ 5 mg and CTZ 10 mg were more potent compared with single-dose LOR 10 mg and FEX 60 mg BID in suppressing skin response. Although linear correlations were found between skin-response areas, as measured by on-site and photographic evaluation, it was difficult to differentiate between wheal and flare by photographic evaluation, especially when a typical wheal was suppressed to slightly edematous erythema by antihistamines.
PMCID: PMC3964551
antihistamine; histamine iontophoresis; histamine challenge test; ImageJ; fexofenadine; loratadine; cetirizine; wheal; flare
2.  Simultaneous transdermal extraction of glucose and lactate from human subjects by reverse iontophoresis 
This study investigated the possibility of simultaneously extracting glucose and lactate from human subjects, at the same skin location, using transdermal reverse iontophoresis. Transdermal monitoring using iontophoresis is made possible by the skin’s permeability to small molecules and the nanoporous and microporous nature of the structure of skin. The study was intended to provide information which could be used to develop a full, biosensor-based, monitoring system for multiple parameters from transdermal extraction. As a precursor to the human study, in vitro reverse iontophoresis experiments were performed in an artificial skin system to establish the optimum current waveforms to be applied during iontophoresis. In the human study, a bipolar DC current waveform (with reversal of the electrode current direction every 15 minutes) was applied to ten healthy volunteers via skin electrodes and utilized for simultaneous glucose and lactate transdermal extraction at an applied current density of 300 μA/cm2. Glucose and lactate were successfully extracted through each subject’s skin into the conducting gel that formed part of each iontophoresis electrode. The results suggest that it will be possible to noninvasively and simultaneously monitor glucose and lactate levels in patients using this approach and this could have future applications in diagnostic monitoring for a variety of medical conditions.
PMCID: PMC2527667  PMID: 18686780
transdermal; iontophoresis; glucose; lactate; diagnostic monitoring
The Journal of General Physiology  1952;35(5):703-710.
The effects of changes in electrolyte concentration on muscles which had been preserved in 50 per cent glycerol or washed in water were studied. The psoas preparation of Szent-Györgyi was generally used, but smooth and cardiac muscle gave the same results. If the preparations are immersed in 0.16 molar NaCl or KCl and if the electrolyte subsequently is washed out with distilled water, tension rises. This effect is not obtained if solutions of CaCl2 or MgCl2 are used, but it is restored by brief immersion in NaCl or KCl solutions. Changes in pH have no effect. It is concluded that divalent cations are bound more firmly than monovalent ions, but that divalent exchange with monovalent ions. After the application of ATP washing out electrolytes produces a much larger and more rapid rise in tension. This effect persists after ATP has been washed out and seems to be due to the removal of a substance which diminishes the dissociation of bound cations. Washing out electrolytes also causes a large increase in transparency and swelling. These effects are also enhanced by previous application of ATP and are abolished or diminished by divalent cations. The rise in tension and the swelling are explained as the result of an increase in the charge of the polar groups of the proteins. Because this mechanism produces only a small degree of shortening, it does not explain normal contraction, but it may be a part of this process. The significance of the phenomena described in relation to recent theories of the mechanism of muscular contraction is discussed. The observations show that increase in the charge of the contractile proteins causes contraction, not relaxation, as has been commonly assumed.
PMCID: PMC2147318  PMID: 14955614
4.  Neurophysiological and biophysical evidence on the mechanism of electric taste 
The phenomenon of electric taste was investigated by recording from the chorda tympani nerve of the rat in response to both electrical and chemical stimulations of the tongue with electrolytes in order to gain some insight into its mechanism on both a neurophysiological and biophysical basis. The maximum neural response levels were identical for an individual salt (LiCl, NaCl, KCl, or CaCl2), whether it was presented as a chemical solution or as an anodal stimulus through a subthreshold solution. These observations support the idea that stimulation occurs by iontophoresis of ions to the receptors at these current densities (less than 100 microA/cm2). Electric responses through dilute HCl were smaller than the chemically applied stimulations, but the integrated anodal responses appeared similar to chemical acid responses, as evidenced by an OFF response to both forms of stimuli. Hydrogen may be more permeant to the lingual epithelium and would thus be shunted away from the taste receptors during anodal stimulation. When the anion of electric taste was varied via subthreshold salt solutions, the response magnitude increased as the mobility of the anion decreased. The transport numbers of the salts involved adequately explains these differences. The physical aspects of ion migration occurring within the adapting fluid on the tongue are also discussed. Direct neural stimulation by the current appears to occur only at higher current densities (greater than 300 microA/cm2). If the taste cells of the tongue were inactivated with either iodoacetic acid (IAA) or N-ethyl maleimide (NEM), or removed with collagenase, then responses from the chorda tympani could be obtained only at these higher current densities. Latency measurements before and after IAA or NEM treatment corroborated these findings. The results are discussed in terms of several proposed mechanisms of electric taste and it is concluded that an ion accumulation mechanism can adequately explain the data.
PMCID: PMC2228775  PMID: 2993476
5.  Time-Dependent Electrical Properties of Human Nail Upon Hydration In Vivo 
The objectives of this study were to investigate the effects of hydration and solution ion concentration on the electrical properties of human nail in vivo and compare these in vivo results with those in vitro. In vivo electrical resistance measurements on the nail were conducted with a three-electrode system in phosphate buffered saline of 0.01–0.6 M. The effect of electric current on nail resistance and possible adverse effects were studied under 1.5- and 9-V iontophoresis in vivo. The electrical resistance of the nail plate was measured in vitro in side-by-side diffusion cells under the same conditions and compared with those in vivo. The in vivo electrical resistance decreased significantly upon 2-h nail hydration and then slowly decreased to a constant value, showing the same pattern as that in vitro. No significant effect of the applied voltage upon the nail electrical resistance was observed. Higher current densities caused moderate sensation and slight changes in nail appearance after iontophoresis. The observed decrease in nail resistance demonstrates the significance of nail hydration in transungual iontophoresis. The in vitro and in vivo correlation suggests that the in vitro nail plate can be a model in the research and development of transungual iontophoretic delivery.
PMCID: PMC2823477  PMID: 19462425
iontophoresis; human nail plate; constant voltage; hydration; electrical property
6.  Screening of Venlafaxine Hydrochloride for Transdermal Delivery: Passive Diffusion and Iontophoresis 
AAPS PharmSciTech  2008;9(3):791-797.
The objective of the study was to investigate in vitro transdermal delivery of venlafaxine hydrochloride across the pigskin by passive diffusion and iontophoresis. For passive diffusion, experiments were carried out in Franz diffusion cell whereas for iontophoretic permeation, the diffusion cell was modified to contain both the donor and return electrode on the same side of skin. Anodal iontophoresis was carried out using a current density of 0.5 mA/cm2. Donor concentrations used were 585.5 mg/ml (saturated solution) and 100 mg/ml. Experiments initially performed to determine the transport efficiency of venlafaxine ions showed promising results. Iontophoresis increased the permeation rate at both concentration levels over their passive counterparts (P < 0.01), but surprisingly higher steady-state flux was obtained from lower donor drug load (P < 0.01). The favorable pH of the unsaturated solutions is suggested to be the cause for this effect. Mild synergistic effect was observed when iontophoresis was carried out incorporating peppermint oil in the donor but the same was not found in passive diffusion. Highest steady-state flux obtained in the experiment was 3.279 μmol/cm2/h when peppermint oil (0.1%) was included in the donor. As the maintenance requirement of venlafaxine hydrochloride is approximately 9.956 μmol/h, the results suggested that the drug is a promising candidate for iontophoretic delivery.
PMCID: PMC2977036  PMID: 18592380
iontophoresis; menthol; peppermint oil; transdermal; venlafaxine hydrochloride
The Journal of General Physiology  1929;13(2):223-229.
The cells of Halicystis impaled on capillaries reach a steady P.D. of 60 to 80 millivolts across the protoplasm from sap to sea water. The outer surface of the protoplasm is positive in the electrometer to the inner surface. The P.D. is reduced by contact with sap and balanced NaCl-CaCl2 mixtures; it is abolished completely in solutions of NaCl, CaCl2, KCl, MgSO4, and MgCl2. There is prompt recovery of P.D. in sea water after these exposures.
PMCID: PMC2141029  PMID: 19872520
The Journal of General Physiology  1928;12(1):129-138.
1. Permeability to water in unfertilized eggs of the sea urchin, Arbacia punctulata, is found to be greater in hypotonic solutions of dextrose, saccharose and glycocoll than in sea water of the same osmotic pressure. 2. The addition to dextrose solution of small amounts of CaCl2 or MgCl2 restores the permeability approximately to the value obtained in sea water. 3. This effect of CaCl2 and MgCl2 is antagonized by the further addition of NaCl or KCl. 4. It is concluded that the NaCl and KCl tend to increase the permeability of the cell to water, CaCl2 and MgCl2 to decrease it. 5. The method here employed can be used for quantitative study of salt antagonism.
PMCID: PMC2323695  PMID: 19872441
9.  Phospholipid-Cholesterol Membrane Model  
The Journal of General Physiology  1962;45(5):989-1001.
A cephalin-cholesterol membrane model is described whose electrical resistance can be reversibly raised by CaCl2 or lowered by KCl or NaCl whether these ions are added to the membrane by mechanical immersion or are driven in electrically. Either KCl or NaCl acts antagonistically to CaCl2. Experiments with controlled pH indicate that the above effects depend somehow on combination of the cations with the phospholipid acidic groups. Also, they are correlated with decreased membrane hydration in CaCl2 solutions, and increased hydration in KCl or NaCl solutions. It is conjectured that cells may regulate their transsurface ion pathways and fluxes by K-Ca competition for negatively charged binding sites on plasma membrane phospholipid. It is regarded as a corollary to say that a fundamental event in excitation is displacement of membrane Ca from such a site by catelectrotonically propelled K.
PMCID: PMC2195221  PMID: 13921460
10.  Microdialysis and Delivery of Iontophoresis-Driven Lidocaine Into the Human Gastrocnemius Muscle 
Journal of Athletic Training  2011;46(3):270-276.
Iontophoresis is used frequently in physical medicine and rehabilitation, but many research techniques do not adequately measure it for depth of medicine delivery.
To determine if iontophoresis delivers lidocaine 5 mm under the surface of human skin.
Descriptive laboratory study.
Therapeutic modalities research laboratory.
Patients or Other Participants:
Eight men and 5 women volunteers (age range = 21 ± 2.3 years) who had less than 5 mm of adipose tissue in the area we measured participated in the study.
We inserted a microdialysis probe 5 mm under the skin of both legs and into the triceps surae muscle groups of 10 participants. Microdialysis was performed for 60 minutes to allow a recovery period for local skin blood flow to return to baseline. We then delivered 2 mL of 1% lidocaine to the treatment leg via iontophoresis at 40 mA/min. Next, microdialysis was performed continuously in both legs during the treatment and for 30 minutes posttreatment to collect the lidocaine samples. After we had gathered the samples, several saline solutions with various amounts of lidocaine (0.005%, 0.025%, 0.05%, and 0.1%) were prepared in vitro and analyzed. Although we did not intend to do so as a part of the original study, we also performed an identical follow-up study at 3 mm in 3 participants.
Main Outcome Measure(s):
Both in vitro and in vivo samples were analyzed via reverse-phase high-performance liquid chromatography (RP-HPLC). A protocol for detection and quantification of lidocaine using RP-HPLC was followed.
We did not detect any measurable levels or concentrations of lidocaine in the 10 control samples. According to the RP-HPLC analysis, the 10 treatment samples also were negative for the presence of lidocaine. However, when we performed the study at 3 mm, microdialysis detected lidocaine in the 3 participants at this depth in the treatment leg only.
Measurable levels of lidocaine were not detected at 5 mm but were found at 3 mm. More studies are needed to determine the efficacy of microdialysis in measuring iontophoresis-delivered compounds.
PMCID: PMC3419555  PMID: 21669096
drug delivery; electricity
The Journal of General Physiology  1929;12(6):783-792.
The pH of a 0.01 molar solution of glycine, half neutralized with NaOH, is 9.685. Addition of only one of the salts NaCl, KCl, MgCl2, or CaCl2 will lower the pH of the solution (at least up to 1 µ). If a given amount of KCl is added to a glycine solution, the subsequent addition of increasing amounts of NaCl will first raise the pH (up to 0.007 M NaCl). Further addition of NaCl (up to 0.035 M NaCl) will lower the pH, and further additions slightly raise the pH. The same type of curve is obtained by adding NaCl to glycine solution containing MgCl2 or CaCl2 except that the first and second breaks occur at 0.015 M and 0.085 M NaCl, respectively. Addition of CaCl2 to a glycine solution containing MgCl2 gives the same phenomena with breaks at 0.005 M and 0.025 M CaCl; or at ionic strengths of 0.015 µCaCl2 and 0.075 µCaCl2. This indicates that the effect is a function of the ionic strength of the added salt. These effects are sharp and unmistakable. They are almost identical with the effects produced by the same salt mixtures on the pH of gelatin solutions. They are very suggestive of physiological antagonisms, and at the same time cannot be attributed to colloidal phenomena.
PMCID: PMC2323746  PMID: 19872496
1. The ions of Ca and K condition general luminescence, and are therefore necessary to the conduction of the impulse. 2. In van't Hoff's solution from which Mg is omitted, Berœ shows hyperirritability with respect to luminescence. This is the result of the action of Ca and K ions unantagonized by Mg. 3. The luminescent material spread on filter paper does not show luminescence in sea water, NaCl, MgCl2, or saccharose solutions isotonic with sea water. In solutions of CaCl2, SrCl2, BaCl2, KCl, and K2SO4 the indicator paper glows with a bright luminescence. 4. In dark adapted Berœ, luminescence is inhibited by a certain quantity of light. This quantity has an average value of 57,285 meter-candle-minutes, which is twelve times the value given by Mnemiopsis.
PMCID: PMC2140713  PMID: 19872141
13.  A model study of factors involved in adhesion of Pseudomonas fluorescens to meat. 
A study was undertaken to investigate the factors involved in the adhesion of Pseudomonas fluorescens to model meat surfaces (tendon slices). Adhesion was fast (less than 2.5 min) and was not suppressed by killing the cells with UV, gamma rays, or heat, indicating that physiological activity was not required. In various salt solutions (NaCl, KCl, CaCl2, MgCl2), adhesion increased with increasing ionic strength up to 10 to 100 mM, suggesting that, at low ionic strengths, electrostatic interactions were involved in the adhesion process. At higher ionic strengths (greater than 10 to 100 mM) or in the presence of Al3+ ions, adhesion was sharply reduced. Selectively blocking of carboxyl or amino groups at the cell surface by chemical means did not affect adhesion. These groups are therefore not directly involved in an adhesive bond with tendon. Given a sufficient cell concentration (10(10) in the adhesion medium, the surface of tendon was almost entirely covered with adherent bacteria. This suggests that if the adhesion is specific, the attachment sites on the tendon surface must be located within collagen or proteoglycan molecules.
PMCID: PMC183008  PMID: 1444387
14.  Microporation and ‘Iron’ tophoresis for treating Iron deficiency anemia 
Pharmaceutical research  2012;30(3):889-898.
Iontophoretic mediated transdermal delivery of ferric pyrophosphate (FPP) in combination with microneedle pretreatment was investigated as a potential treatment for iron deficiency anemia (IDA).
In vitro transdermal delivery studies were performed using hairless rat skin and pharmacodynamic studies were performed in hairless anemic rat model. The hematological and biochemical parameters like hemoglobin, hematocrit and % serum transferrin were monitored in rats at healthy, anemic condition and post treatment. Micropores created by the microneedles were visualized in histological skin sections after staining with hemotoxylin and eosin. The recovery of micropores was investigated in vivo by measuring Transepidermal water loss (TEWL) at different time points.
The passive, microneedle and iontophoresis mediated delivery did not lead to significant improvement in hematological and biochemical parameters in anemic rats, when used individually. When iontophoresis (0.15 mA/cm2 for 4 hours) was combined with microneedle pretreatment (for 2 minutes), therapeutically adequate amount of FPP was delivered and there was significant recovery of rats from IDA.
Microneedle and iontophoresis mediated delivery of iron via transdermal route could be developed as a potential treatment for IDA. The transdermal controlled delivery of iron could become a potential, safe and effective alternative to parenteral iron therapy.
PMCID: PMC3578117  PMID: 23187864
Iron deficiency anemia; ferric pyrophosphate; iontophoresis; microneedle; hematology; oxidative stress; noninvasive
15.  Studies on the in vivo sensitivity of spindle microtubules to calcium ions and evidence for a vesicular calcium-sequestering system 
The Journal of Cell Biology  1981;88(3):604-617.
I microinjected calcium ions into echinoderm eggs during mitosis to determine the calcium sensitivity of microtubules (Mts) in vivo. Spindle birefringence (BR), a measure of the number of aligned Mts in the spindle, is locally, rapidly, and reversibly abolished by small volumes of microinjected CaCl2 (1 mM). Rapid return of BR is followed by anaphase, and subsequent divisions are normal. Similar doses of MgCl2, BaCl2, KCl, NaCl, pH buffers, distilled water, or vegetable oil have no effect on spindle BR, whereas large doses of such agents sometimes cause slow, uniform loss in BR over the course of a minute or more. Of the ions tested, only Sr++ causes effects comparable to Ca++. Ca-EGTA buffers, containing greater than micromolar free Ca++, abolishes BR in a manner similar to millimolar concentrations of injected CaCl2. Caffeine, a potent uncoupler of the Ca++-pump/ATPase of sarcoplasmic reticulum, causes a local, transient depression in spindle BR in the injected region. Finally, injection of potassium oxalate results in the formation of small, highly BR crystals, presumably CA- oxalate, in Triton-sensitive compartments in the cytoplasm. Taken together, these findings demonstrate that spindle Mts are sensitive to levels of free Ca++ in the physiological range, provide evidence for the existence of a strong cytoplasmic Ca++-sequestering system, and support the notion that Mt assembly and disassembly in local regions of the spindle may be orchestrated by local changes in the cytoplasmic free Ca++ concentration during mitosis. An appendix offers the design of a new chamber for immobilizing echinoderm eggs for injection, a new method for determining the volume of the injected solution, and a description of the microinjection technique, which was designed, but never fully described, by Hiramoto (Y. Hiramoto, Exp. Cell. Res., 1962, 27:416-426.).
PMCID: PMC2112760  PMID: 7194345
16.  Effects of Alternating Current Frequency and Permeation Enhancers upon Human Epidermal Membrane 
Previous studies have demonstrated the ability of AC iontophoresis to control skin resistance in different transdermal iontophoresis applications. The objectives of the present study were to (a) identify the alternating current (AC) frequency for the optimization of AC pore induction of human epidermal membrane (HEM) and (b) determine the effects of chemical permeation enhancers upon the extent of pore induction under AC conditions. Experiments with a synthetic membrane system were first conducted as the control. In these synthetic membrane experiments, the electrical resistance of the membrane remained essentially constant, suggesting constant electromobility of the background electrolyte ions under the AC conditions studied. In the HEM experiments, the electrical resistance data showed that higher applied voltages were required to induce the same extent of pore induction in HEM at AC frequency of 1 kHz compared with those at 30 Hz. Even higher voltages were needed at AC frequencies of 10 kHz and higher. AC frequency also influenced the recovery of HEM electrical resistance after AC iontophoresis application. An optimal AC frequency region for effective pore induction and least sensation was proposed. Permeation enhancers were shown to enhance pore induction in HEM during AC iontophoresis. The enhancers reversibly reduced the AC voltage required to sustain a constant state of pore induction in HEM during AC iontophoresis, consistent with the mechanism of lipid lamellae electroporation in the stratum corneum.
PMCID: PMC2723720  PMID: 19166921
Constant skin resistance AC iontophoresis; AC; human epidermal membrane; skin electrical resistance; permeation enhancer
The Journal of General Physiology  1928;11(5):539-545.
The quiescence, rounding, sinking of the granules, and paling of the nucleus are similar to the effects seen after the injection of potassium and sodium chloride (11). Since the sodium salts of the anions were used, it might be inferred that the sodium is the active agent in the injected solutions. This is not entirely the case, however, for the effective concentrations of NaCl required are many times greater than those required in the case of the sodium salts of the calcium-precipitating anions. The fact that practically the same effects can be obtained in both cases leads one to suspect that there is a relation between the results of an increase in sodium ions and a decrease in calcium ions. It has been shown that a M/416 CaCl2 solution will antagonize a M/1 NaCl solution and even a more concentrated solution of KCl inside the ameba (12). Therefore the reduction in amount of calcium may leave a comparatively high concentration of unantagonized sodium and potassium. The fine, purplish red granules resulting from the injection of the alizarin are, no doubt, the insoluble calcium alizarinate. Recovery of an ameba from such an injection may be explained by the postulate that the free calcium ions in the living ameba are in equilibrium with a reserve supply of unionized calcium. The equilibrium is upset when the free calcium is removed by precipitation or by other means, and the system may possibly react in such a way as to counteract the effect of the change imposed. By mobilization of the calcium from a reserve supply the ameba can therefore gradually resume its normal activity. The time required for the recovery depends on the amount of alizarin injected. The diffuse red color which is seen immediately following the injection of alizarin probably represents that extra amount of dye which was not used in precipitating the immediately available calcium. Then, as the calcium is being liberated from the reserve, it is taken up by this surplus alizarin, resulting in a gradual loss of the diffuse coloration and an increase in the number of purplish See PDF for Structure red calcium alizarinate granules. Only when all of the injected dye has been precipitated can the mobilized calcium be used to carry on the normal physiological processes of the organism. The need of calcium to effect ameboid movement has been shown by Pantin (13) in a series of immersion experiments. This fact is quite suggestive, because the first effect of the injection of any of the calcium precipitants is absolute quiescence. Furthermore, there is no return to normal movement until the calcium apparently becomes available to the protoplasm. In support of the conception of a reserve supply of calcium is the presence of the large crystals which give a positive reaction with alizarin for calcium on the death of the ameba. Schewiakoff (14), from crystallographic studies, claims that they are calcium phosphate. The effect of the injection of the calcium-precipitating anions on the calcium of the protoplasm may be shown in another way. In determining the relative toxicity of these salts an arbitrarily standardized injection, about one-fourth of the volume of an ameba, was used. This was introduced because of the necessity to avoid effects due to variable amounts of the solvent, viz., water.. Thus the water effect was kept constant, and the variations in actual amount of salt injected were obtained by using a graded series of concentrations. Arranging the sodium salts of these anions in order of increasing toxicity in one column, and the in vitro solubility products of the corresponding calcium salts in another column, it is seen that as the toxicity increases, the solubility product decreases (Table 1). This fact strongly suggests that the toxicity depends on the ability of the salt to remove calcium ions from the protoplasm. The apparent deviation of the carbonate from the rule can be explained by the specific effect of 002 (10) which is always present from the hydrolysis of the carbonate.
PMCID: PMC2141006  PMID: 19872419
The Journal of General Physiology  1935;19(2):239-247.
1. The question of the critical pore diameter for streaming potential is discussed. 2. The surface charge is calculated for cellulose in contact with solutions of K3PO4, K2CO3, K2SO4, KCl, and ThCl4. 3. The surface charge of cellulose in contact with a solution of 2 x 10–4 N NaCl is calculated as a function of temperature and is found to show a sharp break at 39°. This is interpreted in terms of the change of the specific heat of water. 4. A marked ion antagonism is found in NaCl:KCl, KCl:MgCl2, NaCl:MgCl2, NaCl:CaCl2, KCl:CaCl2, CaCl2:MgCl2 mixtures when the surface charge is calculated as a function of concentration.
PMCID: PMC2141426  PMID: 19872923
19.  Change in the Absorbancy of Bacterial Suspensions Before Initiation of Growth 
Journal of Bacteriology  1969;97(3):1062-1068.
The apparent absorbancy of suspensions of stationary-phase cells of Streptococcus lactis strain 354/07 decreased immediately after being placed in fresh media. This optical effect also occurred in defined mixtures of buffer glucose and KCl. CaCl2 caused the absorbancy to increase. CaCl2 and KCl together had about the same effect as KCl alone. SrCl2 could replace CaCl2, but it was less effective by a factor of 102. MnCl2, MgCl2, and NaCl were without effect. The absorbancy did not change when cells were first killed by p-chloromercuribenzoate or when the reaction was carried out at 0 C. The rate of the reaction was dependent on temperature and concentration of glucose and salts. Gradient centrifugation suggests that this optical effect was caused by change in the refractive index of the test organism rather than by change in volume. Nine other organisms representing four additional genera gave the same optical effect as S. lactis 354/07. Two other organisms reacted feebly whereas another strain of S. lactis reacted in the opposite way, the absorbancy of the suspension increasing instead of decreasing. Spores of Bacillus cereus did not respond.
PMCID: PMC249815  PMID: 4975744
The Journal of General Physiology  1952;35(5):781-796.
1. The effects of morganic ions, electrolyte concentration, and pH on the appearance and volume of the isolated rat liver nucleus have been studied. Nuclei were isolated by differential centrifugation in a buffered salt-sucrose mixture at pH 7.1. Nuclear volumes were determined photographically. 2. In solutions of NaCl, of KCl, and in potassium phosphate buffers the nuclear volume decreased markedly with an increase in concentration from 0.001 M to 0.05 M but remained essentially constant with further increase in concentration to 1.0 M. The effects of CaCl2 and MgCl2 differed from those of NaCl and KCl in that a smaller volume was obtained in concentrations less than 0.15 M, and in the case of CaCl2 an increase in volume was obtained in more concentrated solutions. The volume changes are considered to be due primarily to ionic effects on the nuclear colloids rather than to osmotic behavior. 3. Treatment of nuclei with DNAase prevented the characteristic volume changes resulting from ion effects, suggesting the importance of DNA in nuclear volume changes. 4. The optical changes in isolated nuclei in various concentrations of KCl, NaCl, CaCl2, MgCl2, and in potassium phosphate buffers as observed under phase contrast illumination are described. CaCl2 gave the most marked nuclear changes from the conditions in the uninjured cell and caused shrinkage and granulation in 0.001 M concentration. The effects of CaCl2 were also manifested in 0.88 M sucrose, in mixtures with monovalent salts, and in serum. Changes in nuclear volume and optical appearance which occurred in salt solutions and in 0.1 N HCl were readily reversible. 5. Nuclear volume remained constant between pH 8.91 and 5.12 and decreased in more acid solutions. 6. Sucrose had no appreciable osmotic effect, and in hyperosmotic solution. (0.88 M) nuclei showed swelling and rupture comparable to that in distilled water. 7. The results are considered in relation to the requirements of nuclear isolation media. 8. Rat liver nuclei isolated in a buffered salt-sucrose medium by differential centrifugation exhibited a pattern of size distribution similar to that of fixed nuclei but were of considerably larger volume. The ratio of the volumes of the peak frequencies of the two chief size groups was 1:1.9.
PMCID: PMC2147317  PMID: 14955619
21.  Transungual Iontophoretic Transport of Polar Neutral and Positively Charged Model Permeants: Effects of Electrophoresis and Electroosmosis 
Transungual iontophoretic transport of model neutral permeants mannitol (MA), urea (UR), and positively charged permeant tetraethylammonium ion (TEA) across fully hydrated human nail plates at pH 7.4 were investigated in vitro. Four protocols were involved in the transport experiments with each protocol divided into stages including passive and iontophoresis transport of 0.1 and 0.3 mA. Water and permeant uptake experiments of nail clippings were also conducted to characterize the hydration and binding effects of the permeants to the nails. Iontophoresis enhanced the transport of MA and UR from anode to cathode, but this effect (electroosmosis) was marginal. The transport of TEA was significantly enhanced by anodal iontophoresis and the experimental enhancement factors were consistent with the Nernst–Planck theory predictions. Hindered transport was also observed and believed to be critical in transungual delivery. The barrier of the nail plates was stable over the time course of the study, and no significant electric field-induced alteration of the barrier was observed. The present results with hydrated nail plates are consistent with electrophoresis-dominant (the direct field effect) transungual iontophoretic transport of small ionic permeants with small contribution from electroosmosis.
PMCID: PMC2556258  PMID: 17683062
transungual; iontophoresis; human nail plate; electroosmosis; electrophoresis
22.  Structural transition in chromatin induced by ions in solution 
Nucleic Acids Research  1977;4(11):3839-3854.
Structural transition in chromatin was measured as a function of counter ions in solution (NaCl or MgCl2) and of histones bound on the DNA. The addition of counter ions to aqueous solutions of chromatin, partially dehistonized chromatin, and DNA caused a drastic reduction in viscosity and a significant increase in sedimentation coefficient. Transitions occurred primarily at about 2 × 10−3 M NaCl and 1 × 10−5 M MgCl2 and are interpreted as a change in structure of chromatin induced by tight binding of cations (Na+ or Mg++) to DNA, either free or bound by histones, and is an intrinsic property of DNA rather than of the type of histone bound. At a given ionic condition, removal of histone H1 from chromatin had only a minor effect on the hydrodynamic properties of chromatin while removal of other histones caused a drastic change in these properties. An increase in the sedimentation coefficient of DNA was observed also for protamine. DNA complexes wherein the bound protein contains only unordered coil rather than the α-helices found in histones.
PMCID: PMC343204  PMID: 593889
23.  Iontophoresis of Endothelin Receptor Antagonists in Rats and Men 
PLoS ONE  2012;7(7):e40792.
The treatment of scleroderma-related digital ulcers is challenging. The oral endothelin receptor antagonist (ERA) bosentan has been approved but it may induce liver toxicity. The objective of this study was to test whether ERAs bosentan and sitaxentan could be locally delivered using iontophoresis.
Cathodal and anodal iontophoresis of bosentan and sitaxentan were performed on anaesthetized rat hindquarters without and during endothelin-1 infusion. Skin blood flow was quantified using laser-Doppler imaging and cutaneous tolerability was assessed. Iontophoresis of sitaxentan (20 min, 20 or 100 µA) was subsequently performed on the forearm skin of healthy men (n = 5).
In rats neither bosentan nor sitaxentan increased skin blood flux compared to NaCl. When simultaneously infusing endothelin-1, cathodal iontophoresis of sitaxentan increased skin blood flux compared to NaCl (AUC0–20 were 44032.2±12277 and 14957.5±23818.8 %BL.s, respectively; P = 0.01). In humans, sitaxentan did not significantly increase skin blood flux as compared to NaCl. Iontophoresis of ERAs was well tolerated both in animals and humans.
This study shows that cathodal iontophoresis of sitaxentan but not bosentan partially reverses endothelin-induced skin vasoconstriction in rats, suggesting that sitaxentan diffuses into the dermis. However, sitaxentan does not influence basal skin microvascular tone in rats or in humans.
PMCID: PMC3396598  PMID: 22808263
The Journal of General Physiology  1928;11(3):221-232.
I. The Plasmalemma. 1. On the plasmalemma of amebæ CaCl2 antagonizes the toxic action of LiCl better than it does NaCl, and still better than it does KCl. MgCl2 antagonizes the toxic action of NaCl better than it does LiCl and still better than it does KCl. 2. CaCl2 antagonizes the toxic action of LiCl and of KCl better than does MgCl2: MgCl2 antagonizes NaCl better than does CaCl2. II. The Internal Protoplasm. 3. The antagonizing efficiency of CaCl2 and of MgCl2 are highest against the toxic action of KCl on the internal protoplasm, less against that of NaCl, and least against that of LiCl. 4. CaCl2 antagonizes the toxic action of LiCl better than does MgCl2: MgCl2 antagonizes the toxic action of NaCl and of KCl better than does CaCl2. 5. LiCl antagonizes the toxic action of MgCl2 on the internal protoplasm more effectively than do NaCl or KCl, which have an equal antagonizing effect on the MgCl2 action. III. The Nature of Antagonism. 6. When the concentration of an antagonizing salt is increased to a toxic value, it acts synergistically with a toxic salt. 7. No case was found in which a potentially antagonistic salt abolishes the toxic action of a salt unless it is present at the site (surface or interior) of toxic action. 8. Antagonistic actions of the salts used in these experiments are of differing effectiveness on the internal protoplasm and on the surface membrane.
PMCID: PMC2140974  PMID: 19872392
25.  Quantitative structure-permeation relationship for iontophoretic transport across the skin 
The objective was to relate the efficiency of a charged drug to carry current across the skin during iontophoresis to its structural and/or physicochemical properties. The corollary was the establishment of a predictive relationship useful to predict the feasibility of iontophoretic drug delivery, and for the selection and optimization of drug candidates for this route of administration. A dataset of 16 cations, for which iontophoretic fluxes have been measured under identical conditions, with no competition from exogenous co-ions, was compiled. Maximum transport numbers correlated with ion mobilities and decreased with ionic size, the dependence indicating that the electromigration mechanism of iontophoresis would become negligible for drugs of hydrodynamic radius greater than about 8Å. Validation of the model was demonstrated by successfully predicting the transport numbers of three structurally distinct dipeptides, the iontophoretic data for which had been determined under distinctly different experimental conditions. Finally, for the “training” set of cations, a strong linear dependence between their transport numbers in skin and those in aqueous solution was demonstrated; the former were larger by approximately a factor of 1.4 consistent with skin’s cation permselectivity. In conclusion, this research offers a practical contribution to the development of a predictive structure-transport model of iontophoresis.
PMCID: PMC2082109  PMID: 17707106
iontophoresis; skin; transport number; conductivity; structure-transport relationship

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