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Box-Behnken experimental design in the development of a nasal drug delivery system of model drug hydroxyurea: characterization of viscosity, in vitro drug release, droplet size, and dynamic surface tension.

The purpose of the research was to investigate the changes in physicochemical properties and their influence on nasal formulation performance using 5-factor, 3-level Box-Behnken experimental design on the combined responses of viscosity, droplet size distribution (DSD), and drug release. Gel formulations of hydroxyurea (HU) with surface-active polymers (hydroxyethylcellulose [HEC] and polyethylene-oxide [PEO]) and ionic excipients (sodium chloride and calcium chloride) were prepared using Box-Behnken experimental design. The rheology and dynamic surface tension (DST) of the test formulations was investigated using LV-DV-III Brookfield rheometer and T60 SITA tensiometer, respectively. Droplet size analysis of nasal aerosols was determined by laser diffraction using the Malvern Spraytec with the InnovaSystems actuator. In vitro drug release studies were conducted on Franz diffusion cells. With PEO gel, calcium chloride increased the viscosity and DSD and retarded drug release, while sodium chloride decreased the viscosity, DST, and DSD and accelerated the release of HU. With HEC gel, the addition of the above salts resulted in less significant changes in viscosity, DSD, and DST, but both salts significantly increased the release of HU. Droplet size data obtained from a high viscosity nasal pump was dependent on type of polymer, polymer-excipient interactions, and solvent properties. The applications of Box-Behnken experimental design facilitated the prediction and identified major excipient influences on viscosity, DSD, and in vitro drug release.

Administration, Intranasal↗

Effect of calcium ions on the solubility of muscular collagen and tenderness of beef meat.

The aim of the present study was to determine the effect of aqueous solutions of calcium chloride and calcium lactate on the solubility of beef collagen in raw and cooked meat. The content of total collagen, water- and acetic acid-soluble collagen and insoluble collagen was determined in beef samples. Shearing force was measured after heat treatment. It was found that calcium ions had no significant effect on the solubility of muscular collagen. An improvement in beef tenderness (27%-34%) caused by calcium ions did not result from breaking of the native structure of muscular collagen.

Animals↗

Differential effects of ADH on sodium, chloride, potassium, calcium and magnesium transport in cortical and medullary thick ascending limbs of mouse nephron.

The effect of antidiuretic hormone (arginine vasopressin, AVP) on transepithelial Na+, Cl-, K+, Ca2+ and Mg2+ net transports was investigated in medullary (mTAL) and cortical (cTAL) segments of the thick ascending limb (TAL) of mouse nephron, perfused in vitro. Transepithelial net fluxes (JNa+, JCl-, JK+, JCa2+, JMg2+) were determined by electron probe analysis of the collected tubular fluid. Transepithelial potential difference (PDte) and transepithelial resistance (Rte) were measured simultaneously. cTAL segments were bathed and perfused with isoosmolal, HCO3- containing Ringer solutions, mTAL segments were bathed and perfused with isoosmolal HCO3- free Ringer solutions. In cTAL segments, AVP (10(-10) mol.l-1) significantly increased JMg2+ and JCa2+ from 0.39 +/- 0.08 to 0.58 +/- 0.10 and from 0.86 +/- 0.13 to 1.19 +/- 0.15 pmol.min-1 mm-1 respectively. Neither JNa+ nor JCl-, (JNa+: 213 +/- 30 versus 221 +/- 28 pmol.min-1 mm-1, JCl-: 206 +/- 30 versus 220 +/- 23 pmol.min-1 mm-1) nor PDte (13.4 +/- 1.3 mV versus 14.1 +/- 1.9 mV) or Rte (24.6 +/- 6.5 omega cm2 versus 22.6 +/- 6.4 omega cm2) were significantly changed by AVP. No significant effect of AVP on net K+ transport was observed. In mTAL segments, Mg2+ and Ca2+ net transports were close to zero and AVP (10(-10) mol.l-1) elicited no effect. However NaCl net reabsorption was significantly stimulated by the hormone, JNa+ increased from 107 +/- 33 to 148 +/- 30 and JCl- from 121 +/- 33 to 165 +/- 32 pmol.min-1 mm-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Chloride and calcium ions separate L-glutamate receptor populations in synaptic membranes.

Cl-/Ca2+-dependent and Cl-/Ca2+-independent L-[3H]glutamate binding sites in rat brain synaptic membranes showed marked differences in their pharmacological properties. One site resembled L-2-amino-4-phosphonobutyrate (L-APB)-sensitive receptors and the other N-methyl-D-aspartate (NMDA) receptors. Inhibition studies demonstrated that L-aspartate was more potent at Cl-/Ca2+-independent than at Cl-/Ca2+-dependent sites although L-glutamate was of similar potency at both sites; the D-isomers of aspartate, glutamate and alpha-aminoadipate exhibited the opposite trend. Quisqualate and ibotenate showed high and low affinity inhibition components in the presence of Cl- and Ca2+, and only low affinity inhibition at Cl-/Ca2+-independent sites. For a series of alpha-amino-omega-phosphono carboxylic acids (propionate-heptanoate), peaks of inhibitory activity in the presence of Cl- and Ca2+ were shifted to l-carbon shorter homologues than in the absence of these ions. These data indicate that the ionic environment is of critical importance for the activity of different physiological receptor populations in vitro.

Amino Acids, Dicarboxylic↗

Digital hydrofluoric acid burns: treatment with intraarterial calcium infusion.

Hydrofluoric acid (HF) produces a unique chemical burn due to tissue penetration by fluoride ion. Fluoride ion interferes with calcium activity in a variety of cell membranes and calcium-dependent processes, resulting in severe pain and deep tissue destruction. The currently accepted methods of treating HF burns include application of topical soaks or ointments with calcium or magnesium salts for minor burns and local injection of calcium gluconate for more severe burns. Digital burns also may require nail removal and direct injection into the nail bed. We present the cases of a series of patients with moderate to severe HF burns involving one or more fingers who were treated with selective intraarterial calcium infusion of dilute (1.66%) calcium salts. All patients had excellent relief of symptoms and marked improvement of the burn lesions following one to three four-hour infusions of calcium chloride or calcium gluconate. One patient required subsequent surgical intervention for grafting of a full-thickness burn, and one patient developed transient spasm at the site of percutaneous arterial line insertion. Intraarterial calcium infusion for the treatment of HF burns of the fingers provides many therapeutic advantages, including elimination of painful calcium injection directly into fingertips, avoidance of debilitating procedures such as fingernail removal, and assurance that all affected cells are receiving adequate amounts of calcium to replenish depleted stores and to complex with remaining free fluoride ion.

Adult↗

Sodium, potassium, chloride and calcium concentrations measured in pigeon perilymph and endolymph.

According to Davis' (1965) model of the inner ear, a potential difference between the endocochlear potential and the hair cell resting potential drives the transduction current across the apical hair cell membrane. It is assumed that the endocochlear potential (EP) consists of two components. The first is a diffusion potential, which depends on the ionic composition of endolymph and perilymph and on the permeability of the perilymph-endolymph barrier. The second is an electrogenic component which is determined by active ion transport across the perilymph-endolymph barrier. In birds, the EP is between +8 and +20 mV. Little is known about the underlying mechanisms responsible for the measured EP in birds. The present paper studies whether ionic compositions of endo- and perilymph might explain the EP in birds. Concentrations of Na+, K+, Ca2+ and Cl- in pigeon scala vestibuli, scala tympani and scala media were determined with ion-selective microelectrodes. Na+, K+, Ca2+ and Cl- were 150.0, 4.2, 1.4 and 117.0 mM in perilymph (scala tympani and scala vestibuli). In scala media, the concentrations of K+, Ca2+ and Cl- were 140.6, 0.23 and 142.1 mM.

Animals↗

Calcium and cardiac arrest.

Various preparations of calcium are recommended for use in treatment of cardiac arrest and advantages are claimed for one preparation over another because of increased availability of the calcium to the heart. Ionised calcium levels in human blood have been assayed following the addition of calcium increments by use of the calcium electrode. The results showed no difference between calcium chloride and calcium gluconate.

Calcium↗

Binding sites for L-[3H]glutamate on hippocampal synaptic membranes: three populations differentially affected by chloride and calcium ions.

The effects of Cl- and Ca2+ were studied on the specific binding of L-[3H]glutamate to multiple sites on rat hippocampal synaptic membranes. Quisqualate (5 microM) or DL-2-amino-4-phosphonobutyrate (2-APB) (300 microM) was used to discriminate two previously identified classes of binding sites. Saturation isotherms and displacement curves constructed under different ionic conditions suggested that the effects of Cl- and Ca2+ could best be explained by postulating the existence of three major binding site populations in this preparation rather than two. The binding of L-glutamate to Glu A sites exhibits an absolute dependence on Cl-, and Ca2+ markedly increases the maximum density of these sites. Glu A sites bind quisqualate and 2-APB with relatively high affinity. Cl- (47 mM) more than doubles the maximum density of Glu B sites, but Ca2+ appears to have no effect. Glu B sites can be discriminated from the other classes by their relatively low affinity for quisqualate and 2-APB. There is reason to think that the Glu B population is heterogeneous. The novel Glu C population can be virtually selectively labeled by exposing 2-APB-sensitive binding sites to radioligand in Tris-HOAc buffer with Ca2+. Binding of L-[3H]glutamate to these sites is enhanced by both Cl- and Ca2+, but requires neither ion. Ca2+ appears to increase both the affinity of Glu C sites for L-glutamate and their maximum binding site density. In the presence of Ca2+ and Cl-, Glu C sites bind the radioligand with micromolar affinity (KD approximately 2 microM) and high capacity (Bmax approximately 160 pmol/mg protein).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Chloride-dependent calcium transients induced by angiotensin II in vascular smooth muscle cells.

Cl- is essential for the vasoconstrictive response to angiotensin II (ANG II). In vascular smooth muscle cells (VSMC), we determined whether ANG II-induced transient increase in intracellular Ca2+ concentration ([Ca2+]i) is Cl- dependent. After incubating the cells at different extracellular Cl- concentration ([Cl-]e) for 40 min, the ANG II-induced Ca2+ transients at 120 meq/l Cl- were more than twice those at either 80 or 20 meq/l Cl-. Replacing Cl- with bicarbonate or gluconate yielded similar results. In addition, after removal of extracellular Ca2+, ANG II-induced as well as platelet-derived growth factor-induced Ca2+ release exhibited Cl- dependency. The difference of Ca2+ release with high vs. low [Cl-]e was not affected by acutely altering [Cl-]e 1 min before administration of ANG II when [Cl-]i was yet to be equilibrated with [Cl-]e. Pretreatment of a Cl- channel inhibitor, 5-nitro-2-(3-phenylpropylamino)benzoic acid, increased ANG II-induced Ca2+ release and entry at 20 meq/l Cl- but did not alter those at 120 meq/l Cl-. However, after equilibration, a reduced [Cl-]e did not affect thapsigargin-induced Ca2+ release, suggesting that Cl- may not affect the size of intracellular Ca2+ stores. Nevertheless, at high [Cl-], the peak increase of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] induced by ANG II was approximately sixfold that at low [Cl-]. Thus the Cl- -dependent effects of ANG II on Ca2+ transients may be mediated, at least in part, by a Cl- -dependent Ins(1,4,5)P3 accumulation in VSMC.

Angiotensin II↗

Effects of calcium solubility on adsorption by rats with induced achlorhydria.

Gastric X-irradiated, achlorhydric rats and sham-operated controls were fed diets containing very soluble calcium chloride or calcium gluconate or slightly soluble calcium carbonate or tricalcium phosphate for 3 weeks. Calcium was absorbed more efficiently by achlorhydric rats from the very soluble salts from the slihtly soluble salts. The control rats absorbed calcium from the very soluble and slightly soluble calcium salts with similar efficiency. Achlorhydric rats fed slightly soluble calcium salts developed weaker bones with a lower mineral content than did those fed very soluble calcium. Apparently, the very soluble dietary calcium offset the impaired calcium absorption of achlorhydric rats. Calcium solubility had no significant effect on the bones of control animals.

Achlorhydria↗

Calcinosis cutis following the administration of intravenous calcium therapy.

Calcinosis cutis, the cutaneous deposition of calcium salts in the dermis, can occur through a variety of pathogenetic mechanisms, and can be associated with both normal and elevated calcium levels. Iatrogenic causes of calcinosis cutis include extravasation of intravenously administered calcium chloride or calcium gluconate, and traumatic deposition of calcium in the skin, subsequent to electromyography or electroencephalography. We report two cases of calcinosis cutis following intravenous infusion of a calcium-containing salt.

Adult↗

Microscopy analysis of dental titanium casting investment materials.

Scanning electron microscopy (SEM) analysis and qualitative energy dispersive x-ray microanalysis (EDS) of investment materials for dental titanium casting were performed. Two commercial investment materials, Ohara and Castmatic, and an experimental zirconia material were analyzed. The microstructural constituents and the unfired and fired structures were included. Larger refractory particles and matrix embedding smaller particles were observed with each material. Detection of aluminum, silicon, magnesium, zirconium and oxygen provided a basis to reason the presence of alumina (Al2O3), silica (SiO2), magnesia (MgO), and zirconia (ZrO2). Hence, Ohara contained quartz and an alumino-silicate, Castmatic contained magnesia and quartz and experimental zirconia contained zirconia and an alumino-silicate, taken to be kyanite, as components providing refractoriness and expansion. Even though unequivocal detection of phosphorous in the spectra for Ohara was not obtained (P K alpha = 2.013 keV; Zr L alpha = 2.042 keV), an emission peak at 2.0 keV was taken to be due to P and related, along with MgO, to bonding by magnesium phosphate. For Castmatic, unfired strength was thought to be due to calcium chloride and calcium silicate and fired strength to forsterite, (2MgO.SiO2). Detection of calcium and chlorine also suggested bonding of experimental zirconia via calcium chloride. Extensive microcracking occurred around refractory particles and through matrix in experimental zirconia which is likely to have resulted from the firing of kyanite to 1400 degrees C, to the monoclinic to tetragonal transformation of any unstabilized ZrO2, or to the thermal expansion mismatch between kyanite and matrix.

Dental Casting Investment↗

Beef customer satisfaction: factors affecting consumer evaluations of calcium chloride-injected top sirloin steaks when given instructions for preparation.

The objectives of this study were to evaluate whether instructions can help consumers properly prepare top sirloin steaks and to evaluate the use of calcium chloride injection to decrease the sensitivity of top sirloin steaks to degree of doneness, thereby improving customer satisfaction ratings. An in-home study evaluated top sirloin steaks (gluteus medius) as influenced by calcium chloride injection (injected vs. noninjected), consumer segment (beef loyalists = heavy consumers of beef, budget rotators = cost-driven and split meat consumption between beef and chicken, and variety rotators = higher incomes and education and split meat consumption among beef, poultry, and other foods), degree of doneness, cooking method, and instructions (given vs. not given). Consumers evaluated overall like, tenderness, juiciness, flavor like, and flavor amount using 10-point scales. Beef loyalists consistently rated steaks higher for overall like, juiciness, and flavor when instructions were provided (P < 0.05) and rated top sirloin steaks higher for overall like and tenderness when given instructions for grilling (P < 0.05). Budget rotators and variety rotators rated steaks differently among cooking methods (P < 0.05). Correlation and stepwise regression analyses indicated that flavor like was the most highly correlated with overall like, followed by tenderness, flavor amount, and juiciness. Calcium chloride injection had no effect on consumers' likes or dislikes or on tenderness (P < 0.05). For top sirloin steaks, it was likely that preparation played a major role in consumer satisfaction, and beef loyalists benefited the most from providing cooking instructions.

Animals↗