In vitro transcorneal permeation of ketorolac tromethamine from buffered and unbuffered aqueous ocular drops

In vitro transcorneal permeation of ketorolac tromethamine from 0.5% w/v solutions containing equimolar (0.02 M) concentrations of citrate (pH 6.5), phosphate (pH 6.5 and 7), citrate-phosphate (pH 7) and borate (pH 7) buffers was studied using goat cornea. Cumulative % permeation was maximum with phosphate buffered drops of pH 6.5. The effect of pH and ionic strength on permeation of ketorolac tromethamine from buffered (phosphate) drops was next investigated. Cumulative % permeation of ketorolac tromethamine from buffered drops was pH dependent being maximum at pH 4.5. Adjustment of ionic strength of drops to 0.2 resulted in decreased permeation of drug. Permeation of ketorolac tromethamine from unbuffered drops of varying pH and ionic strength 0.2 was also pH dependent and was maximum at pH 4.5. Buffered drops of pH between 4.5-5.5, ionic strength 0.2, provided better permeation of drug compared to unbuffered drops of same pH and ionic strength. Above pH 6.5 unbuffered drops showed better permeation than buffered drops. Increase in molarity of phosphate buffer (pH 4.5) used in making drops, between 0 to 0.15 M increased permeation. Aqueous drops of ketorolac tromethamine formulated in 0.15 M phosphate buffer of pH 4.5 and ionic strength 0.2 showed maximum cumulative % permeation in vitro. Considering lacrimation induced drug loss in vivo, by buffer of high concentration, ketorolac tromethamine drops formulated in buffer of low molarity, pH 4.5 and ionic strength 0.2 appear suitable.     

In vitro transcorneal permeation of ketorolac from oil based ocular drops and ophthalmic ointment

Transcorneal permeation of ketorolac from oil based ocular drops and ophthalmic ointments was studied in vitro, using goat cornea. Cumulative (%) permeation of ketorolac through cornea, was found to be maximum with 0.2% (w/v) ketorolac drops in sesame oil followed by formulations in corn oil and soyabean oil. Ketorolac 1% (w/v) drops in castor oil increased the quantity permeated but cumulative (%) permeation was less. Permeation profiles of ketorolac were in consistence with the partition characteristic of drug between oil and aqueous phase. Formulations favouring corneal permeation of ketorolac increased corneal hydration. Addition of benzyl alcohol, a preservative, to oil drops reduced permeation of ketorolac and corneal hydration indicating possible protective effect of benzyl alcohol against corneal damage. Permeation studies on ointment formulations containing either ketorolac acid or ketorolac tromethamine salt indicated better permeation for formulation containing ketorolac tromethamine aqueous solution. Thus for better transcorneal permeation, ketorolac 0.2% (w/v) drops, formulated in sesame oil, containing 0.5% v/v benzyl alcohol and ophthalmic ointment containing 0.5% (w/w) ketorolac tromethamine in dissolved state appear suitable.     

Determination of flurbiprofen and ibuprofen in dog serum with automated sample preparation

Methods for the determination of flurbiprofen and ibuprofen in dog serum were developed using high-performance liquid chromatography and automated serum extraction. Sample extraction was automated by use of cartridges packed with a styrene-divinylbenzene macroreticular resin in a microprocessor-controlled centrifugal system. The average recoveries were 98.9% for flurbiprofen and 94.5% for ibuprofen. The limits of detection were approximately 0.04 microgram/ml for flurbiprofen at 254 nm and 0.5 microgram/ml for ibuprofen at 230 nm. The relative standard deviations for the determination of a laboratory standard between days was 2.4% (20 microgram/ml) for flurbiprofen and 1.7% (13 microgram/ml) for ibuprofen. Peak height ratios were linear with concentrations of 0.04--100 microgram/ml for flurbiprofen and 1.0-50 microgram/ml for ibuprofen. These methods are simple, rapid, sensitive, and specific. The use of an automated sample preparation procedure improved the between-day precision by a factor of two when compared to a manual extraction procedure. These methods were applied to bioavailability studies in dogs.     

Clofibric acid increases the undirectional chiral inversion of ibuprofen in rat liver preparations

1. The formation of (S)-ibuprofen from (R)-ibuprofen was monitored in perfused rat livers and in rat hepatocytes and the rate constants calculated. 2. Pre-treatment of animals for three days with clofibric acid markedly increased the (R)-to-(S) inversion of ibuprofen in both preparations. In contrast, clofibric acid did not elicit such a reaction with flurbiprofen, an analogue that does not undergo inversion under control conditions. 3. An increase in the chiral inversion was also seen when clofibric acid was added to the perfusion medium or to hepatocyte suspensions. In the latter system this increase was shown to be concentration dependent. 4. Pre-treatment of rat combined with addition of clofibric acid to the perfusion medium produced a cumulative stimulation of (R)-to-(S) inversion of ibuprofen. 5. Clofibric acid added to hepatocyte suspensions transiently increased intracellular concentrations of coenzyme A whereas (R)-ibuprofen transiently decreased CoA concentrations. The two effects cancelled each other upon co-incubation of the two compounds. 6. It is postulated that the metabolic interaction observed between clofibric acid and (R)-ibuprofen may be due to changes in intracellular concentrations of CoA.     

Study of the effective dose of a topical antifungal agent, omoconazole nitrate, on the basis of percutaneous pharmacokinetics in guinea-pigs and mice

The clinically useful optimum dose of omoconazole nitrate, a topical antifungal agent, has been examined by analysing the percutaneous pharmacokinetics of the drug to assess its pharmacological activity in an in-vivo study. Creams containing omoconazole nitrate were prepared on a pilot basis. The therapeutic effect of the omoconazole nitrate creams was examined in an in-vivo pharmacological dermatophytosis infection model in guinea-pigs. Creams containing 0.25% or higher concentrations of omoconazole nitrate resulted in significant inhibition compared with no treatment and with vehicle-treated controls. In the mycological examination no growth of dermatophytes was observed for creams containing 1% or higher concentrations. In an in-vitro hairless mouse skin-permeability test a non-linear least squares program based on a fast inverse Laplace transform algorithm was used to calculate the partition and diffusion parameters of omoconazole nitrate in the stratum corneum and viable epidermis. The time-course of drug concentrations in the skin of the guinea-pig, estimated on the basis of these parameters, led to predictions that percutaneous drug concentrations on the guinea-pig would require 10 or more days to reach equilibrium in the skin; that drug concentrations in the corneum-viable epidermis border, where dermatophytes are considered to grow, would exceed the minimum effective concentration when 0.1% higher concentration creams were used; and that for binding to keratin drug concentrations would reach the practical minimum effective concentration when creams containing 0.5% or more omoconazole nitrate were used. These results show that partition and diffusion parameters obtained from in-vitro skin permeation studies can be used to predict in-vivo percutaneous pharmacokinetics and to estimate therapeutically effective concentrations.     

Isolyte S, a physiologic multielectrolyte solution, is preferable to normal saline to wash cell saver salvaged blood: conclusions from a prospective, randomized study in a canine model

OBJECTIVES: The purpose of this study is to compare normal saline with Isolyte S as the wash solutions during high-volume cell saver autologous blood transfusion. Normal saline, the standard wash solution in cell saver autologous blood transfusion, is associated with acid-base and electrolyte derangements. Isolyte S is a physiologic, balanced multielectrolyte crystalloid solution that approximates the electrolyte content of plasma. DESIGN: Open-label, prospective, randomized study. SETTING: Research laboratory in a Department of Veterans Affairs medical center. SUBJECTS: Fourteen mongrel dogs, weighing 22 to 23 kg each. INTERVENTIONS: Fourteen mongrel dogs were prospectively randomized to receive normal saline (n = 7) or Isolyte S (n = 7). Animals were anesthetized, received heparin for anticoagulation, and underwent 18 cycles of cell saver autotransfusion. In each cycle, 125 mL of blood was arterially withdrawn, and washed with either normal saline (mEq/L) (sodium 154, chloride 154) or Isolyte S (mEq/L) (sodium 141, potassium 5, magnesium 3, chloride 98, phosphate 1, acetate 28, and gluconate 23). The washed blood was retransfused. MEASUREMENTS AND MAIN RESULTS: Acid-base and electrolyte analyses were performed throughout the study on the systemic blood of each group and compared. By the end of the study, the Isolyte S group had a normal pH and an increased bicarbonate concentration (mEq/L: normal values 24 to 32; normal saline 9.0 +/- 1.9 vs. Isolyte S 13.2 +/- 3.0 [p < .01]) and an increased magnesium concentration (mg/dL: normal values 1.6 to 2.4; normal saline 1.6 +/- 0.2 vs. Isolyte S 2.2 +/- 0.2 [p < .0001]). Additionally, the Isolyte S group had a lower chloride concentration (mEq/L: normal values 95 to 110; normal saline 130 +/- 9 vs. Isolyte S 117 +/- 7 [p < .02]) and a lower potassium concentration (mEq/L: normal values 3.5 to 5.0; normal saline 4.4 +/- 0.5 vs. Isolyte S 3.7 +/- 0.3 [p < .01]). There were no significant differences between normal saline or Isolyte S in the values of PCO2, lactic acid, sodium, total and ionized calcium, inorganic phosphorus, total protein, albumin, hemoglobin, and hematocrit. CONCLUSIONS: Fewer systemic acid-base and electrolyte derangements were observed when blood was washed with Isolyte S. Differences between the normal saline and Isolyte S groups are ascribed primarily to the constituents of the wash solution. We conclude that Isolyte S, a physiologic, balanced, multielectrolyte solution, should be considered as the wash solution in high-volume autologous cell saver blood processing and transfusion.     

Prospects for quantitative trait locus methodology in gerontology

One hundred and eight camels (Camelus dromedarius) from Trypanosoma evansi endemic areas of the Thar Desert of Rajasthan State, India, were evaluated by various diagnostic tests including parasitological tests (wet blood film-WBF, stained thick blood film), chemical test (mercuric chloride), biological test (mouse subinoculation-MSI), and immunodiagnostic tests based on antibody detection (double immunodiffusion test-DID, card agglutination test-CATT), antigen detection (double antibody sandwich enzyme linked immunosorbent assay-Ag-ELISA). Of the tested camels 49 were found infected using the WBF of which nine gave false negative results with the mercuric chloride test. The efficacy of MSI was 87.03 percent, while the mercuric chloride test was 60.18 percent efficient. The diagnostic efficacy of CATT (72.22 percent) was found to be much better than DID (28.70 percent). Ag-ELISA was 86.11 percent efficient in detecting trypanosomal antigens. A good correlation was found between the positive results obtained by wet blood film, CATT and Ag-ELISA. It was inferred that CATT can be used to study the seroprevalence of T. evansi with great ease, however, trypanosome antigen detection may give a more accurate idea of the prevalence of T. evansi in an endemic area.     

Physical map of the Clostridium difficile chromosome

The present study was designed to investigate the effect of mercuric chloride administration on copper, zinc, and iron concentrations in the liver, kidney, lung, heart, spleen, and muscle of rats. The results showed that after dose and time exposure to mercuric chloride, the concentration of mercury in the six tissues was significantly elevated. Data showed that there were no interaction between mercury and tissue iron. There was a considerable elevation of the content of copper in the kidney and liver. The most significant changes in the copper concentration took place in the kidneys. About a twofold increase in the copper content of the kidney was noted after exposure to mercuric chloride (3 mg and 5 mg/kg). Only slight elevations in the copper content occurred in the liver especially in high dose and longer exposure time. In the remaining organs, the copper content was not changed significantly (p > 0.05). The most significant changes in the zinc concentration took place in liver, kidney, lung and heart (5 mg/kg). Marked changes in kidney zinc concentrations were observed at any of the specified doses. Zinc concentrations were significantly increased in kidney of rats sacrificed 9-48 h after s.c. injection of HgCl2 (5 mg/kg); in liver obtained from rats at 18, 24 or 48 h after injection; and in lung after 24 or 48 h of treatment. The heart and spleen zinc concentrations were elevated at 24 and 48 h after injection of HgCl2 (5 mg/kg), respectively. The results of this study implicate that effects on copper and zinc concentrations of the target tissues of mercury may play an important role in the pathogenesis of acute mercuric chloride intoxication.     

Killing effects of 5-fluorouracil on human biliary tract cancer cell lines

Previous studies have established that a partially quaternized derivative of chitosan, N-trimethyl chitosan chloride (TMC), can be used as an absorption enhancer for large hydrophilic compounds across mucosal surfaces. This study evaluates and compares the effects of the degree of quaternization of TMC, in a neutral environment, on the permeability of intestinal epithelial cells in vitro, where normal chitosan salts are ineffective as absorption enhancers. The effects of TMC-H [61.2% quaternized, (0.05-1.5% w/v)], TMC-L [12.3% quaternized, (0.5-1.5% w/v)], and chitosan hydrochloride [0.5-1.5% w/v] on the transepithelial electrical resistance (TEER) and permeability, for the hydrophilic model compound [14C]mannitol, of intestinal epithelial Caco-2 cell monolayers, were investigated at pH values of 6.20 and 7.40. The viability of the monolayers was checked with the trypan blue exclusion technique. At a pH of 6.20, all the polymers caused a pronounced reduction (37-67% at 0.5% w/v concentrations) in the TEER of Caco-2 cells. On the contrary, at a pH of 7.40, only TMC-H was able to decrease the TEER values, even in a concentration as low as 0.05% w/v (35% reduction). Comparable results were obtained with the permeation of [14C]mannitol. Large increases in the transport rate (18-23-fold at 0.5% w/v concentrations) were found at pH 6.20, whereas only TMC-H was able to increase the permeation of [14C]mannitol at pH 7.40 (31-48-fold at 0.05-1.5% w/v concentrations of TMC-H). For all the polymers studied, no deleterious effects to the cells could be demonstrated with the trypan blue exclusion technique. It is concluded that highly quaternized TMC is a potent absorption enhancer and the potential use of this polymer, especially in neutral and basic environments where normal chitosan salts are not effective, is expected to be an important contribution to the development of effective delivery systems for hydrophilic compounds such as peptide drugs.     

Stability of methacholine chloride solutions under different storage conditions over a 9 month period

Methacholine chloride solutions, routinely used for testing bronchial hyperreactivity, have been shown to degrade over time. The data published addressing the optimal conditions for methacholine chloride storage are conflicting and incomplete. This study investigated the effects of a variety of conditions on the stability of methacholine chloride. Methacholine chloride, dissolved in phosphate buffered saline (PBS) or sodium chloride (NaCl) at 50 and 0.39 g x L(-1), was subjected to various light and temperature conditions for 9 months. Methacholine chloride degradation was determined by high performance liquid chromatography, and all solutions underwent bacterial and pH testing. By 9 months, all 50 g x L(-1) solutions of methacholine chloride had degraded by 65+/-0.8%. All 0.39 g x L(-1) solutions in NaCl had degraded by 11.0+/-0.33%. The 0.39 g x L(-1) solutions in PBS which had been frozen, refrigerated or stored at room temperature had degraded by 8.0%, 16.0+/-0.3% and 63.8+/-0.5%, respectively. The pH of methacholine chloride was 7.2 in PBS at 0.39 g x L(-1), 5.8 in PBS at 50 g x L(-1), 3.9 in NaCl at 0.39 and 2.7 in NaCl at 50 g x L(-1). Bacterial contamination was minimal. The results of this study demonstrate that methacholine chloride is more stable at the higher concentration. However, the pH of the more concentrated solutions of methacholine chloride in sodium chloride could cause bronchoconstriction in some subjects. We therefore recommend storing methacholine chloride at 50 g x L(-1) in phosphate-buffered saline.     

Percutaneous absorption of ibuprofen from different formulations. Comparative study with gel, hydrophilic ointment and emulsion cream

In a three-way cross-over study on 6 healthy adult volunteers, the percutaneous absorption of ibuprofen (CAS 15687-27-1) was studied with 3 topical formulations containing 5% w/w ibuprofen in a gel (Iprogel) or in a hydrophilic ointment or in an emulsion cream. By analysis of the plasma drug concentrations appearing after topical application, the relative drug bioavailability was calculated in terms of Cmax (maximum blood concentration of the drug), AUC (area under the curve of drug plasma concentrations at various time points) and Tmax (the time required for appearance of maximum drug concentration in the blood). The gel formulation showed the highest drug concentration in blood, reached in the shortest period, whereas that from the hydrophilic ointment showed the lowest drug concentration, reached at the slowest rate. The absorption from the reference product containing the drug as an o/w emulsion cream was less than with the gel formulation but higher than that found with the hydrophilic ointment.     

T lymphocyte responses to anti-neutrophil cytoplasmic autoantibody (ANCA) antigens are present in patients with ANCA-associated systemic vasculitis and persist during disease remission

The cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel has been identified in the cardiac muscle of a number of mammalian species, including humans. The goal of this study was to begin quantifying the structural requirements necessary for arylaminobenzoate block of the CFTR channel. The cardiac cAMP-dependent Cl- current (ICl) was measured using the whole-cell arrangement of the patch-clamp technique in guinea pig ventricular myocytes during stimulation of protein kinase A with forskolin. At drug concentrations below the IC50 value for channel block, reduction of ICl by the arylaminobenzoates occurred in a strongly voltage-dependent manner with preferential inhibition of the inward currents. At higher drug concentrations, block of both the inward and outward ICl was observed. Increasing the length of the carbon chain between the benzoate and phenyl rings of the arylaminobenzoates resulted in a marked increase in drug block of the channel, with IC50 values of 47, 17, and 4 microM for 2-benzylamino-5-nitro-benzoic acid, 5-nitro-2-(2-phenylethylamino)-benzoic acid, and 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB), respectively. Increasing the carbon chain length further with the compound 5-nitro-2-(4-phenylbutylamino)-benzoic acid, caused no additional increase in the potency of drug block (IC50 = 4 microM). Inhibition of ICl by the arylaminobenzoates was modulated by the pH of the external solution; increasing the pH from 7.4 to 10.0 greatly weakened NPPB block, whereas decreasing the pH to 6.4 enhanced block. In addition, block of ICl was observed during intracellular dialysis of NPPB, and this action was not affected by raising the external pH.     

Multiresidue liquid chromatographic method for determining residues of mono- and dibasic penicillins in bovine muscle tissues

A liquid chromatographic method with UV detection at 325 nm was developed for simultaneous determination of amoxicillin, ampicillin, penicillin G, and cloxacillin residues in bovine muscle tissue as their mercaptide derivatives. The penicillins are extracted from bovine tissues with 0.1 M phosphate buffer (pH 8.5), cleaned up on a t-C18 Sep-Pak cartridge, and eluted with 2 mL acetonitrile. After the acetonitrile in the eluate is evaporated to dryness, the residue is dissolved in 200 microL (40 + 60, v/v) acetonitrile-phosphate buffer (pH 6.5) and derivatized with acetic anhydride and mercuric chloride in the presence of 1,2,4-triazole at 65 degrees C for 30 min. Gradient analysis on a Spherisorb 5 microns ODS(2) (octadecyl silane) analytical column using a binary mobile phase consisting of acetonitrile and 0.10 M phosphate buffer (pH 6.5) in the presence of 0.0157 M sodium thiosulfate at 1 mL/min permits determination of each intact penicillin in bovine muscle tissue at > or = 10 ppb with recoveries > or = 72%. This laboratory method provides detection sensitivities equivalent to those of rapid tests used for screening beta-lactam drug residues in bovine tissue samples for regulatory enforcement.     

Linear and non linear competition plots in the deoxyribose assay for determination of rate constants for reaction of nonsteroidal antiinflammatory drugs with hydroxyl radicals

Performing the deoxyribose (DR) assay for determination of the rate constants for reaction of non steroidal antiinflammatory drugs with hydroxyl radicals led to some unusual competition plots. The molecules from the arylpropionic family of drugs: ibuprofen, flurbiprofen, ketoprofen and naproxen produced the linear relationship. However, acemetacin, diclofenac Na, flufenamic acid, indometacin, indometacin, niflumic acid, tolmetin Na and sulindac presented non linear competition plots manifesting at relatively low drug concentrations. This effect was corrected by increasing DR concentrations from 2.8 mM to 15 mM. The modification did not affect rate constants values for those derivatives which already presented a linear plot at 2.8 mM, but allowed to calculate rate constants for other compounds. It is suggested that the experimental conditions have to be adapted particularly for those derivatives with a relatively high rate constant for reaction with the radical species. The oxicam derivatives (tenoxicam and piroxicam) presented another kind of deviation that revealed a prooxidant effect in this system: non linear plots were also observed at relatively low drug concentrations, but in the opposite direction than for the other molecules. This last effect was independent of DR concentration but could be corrected by increasing ascorbate concentration in the system.     

The effect of concentration and temperature on diffusivity of metal compounds

The effect of concentration and temperature on diffusivity of various metal compounds which are frequently used in hydrometallurgical applications has been investigated. A diaphragm cell technique has been adopted in this study. Diffusivity of cobalt, nickel, copper, and iron compounds was measured in water with and without ammonia. The effect of chloride, nitrate, and sulfate on diffusivity of these metals in the above-mentioned solutions was studied. The effect of cyanide concentration on diffusivity of gold, silver, copper, and iron in solution was also investigated. The range of the concentration of solutions used in this study was 10^-4 to 0.5 M. Temperature was varied between 15 °C and 45 °C. An empirical model for metal chloride, nitrate, and sulfate systems has been developed to predict diffusivity of various metal compounds when concentration, charge, size, and mobility of diffusing species are known. The predicted values of diffusivity of numerous metal compounds by this model are in good agreement with the observed values for the ionic strength less than 0.5 M. Formerly Research Fellow, Department of Metallurgical Engineering, South Dakota School of Mines and Technology     

Stability of bethanechol chloride, pyrazinamide, quinidine sulfate, rifampin, and tetracycline hydrochloride in extemporaneously compounded oral liquids

The stability of five drugs commonly prescribed for use in oral liquids but not commercially available as such was studied. Bethanechol chloride 5 mg/mL, pyrazinamide 10 mg/mL, quinidine sulfate 10 mg/mL, rifampin 25 mg/mL, and tetracycline hydrochloride 25 mg/mL were each prepared in a 1:1 mixture of Ora-Sweet and Ora-Plus (Paddock Laboratories), a 1:1 mixture of Ora-Sweet SF and Ora-Plus, and cherry syrup and placed in 120-mL amber clear polyethylene terephthalate bottles. Three bottles of each liquid were stored at 5 degrees C and three at 25 degrees C, all in the dark. Samples were taken initially and at various times up to 60 days for analysis by high-performance liquid chromatography and assessment of appearance and odor; pH was measured. A mean of at least 90% of the initial drug concentration was retained for 60 days in the liquids containing bethanechol chloride, pyrazinamide, or quinidine sulfate and for 28 days in the rifampin-containing liquids and the mixture of tetracycline hydrochloride and Ora-Sweet-Ora-Plus at both 5 and 25 degrees C. Tetracycline hydrochloride concentrations of 90% or more of the initial concentration were retained in the liquids prepared with Ora-Sweet SF-Ora-Plus for 10 days at 5 degrees C and 7 days at 25 degrees C and in those prepared with cherry syrup for 7 days at 5 degrees C and 2 days at 25 degrees C. No substantial changes in the appearance, odor, or pH of any liquid were observed. At 5 and 25 degrees C, bethanechol chloride 5 mg/mL, pyrazinamide 10 mg/mL, and quinidine sulfate 10 mg/mL were stable in three extemporaneously compounded oral liquids for 60 days and rifampin 25 mg/mL was stable for 28 days. The stability of tetracycline hydrochloride 25 mg/mL varied with the vehicle.     

Purification, characterization, and antifungal activity of chitinase from Fusarium chlamydosporum, a mycoparasite to groundnut rust, Puccinia arachidis

Chitinase (EC 3.2.1.14) was isolated from the culture filtrate of Fusarium chlamydosporum and purified by ion-exchange chromatography and gel filtration. The molecular mass of purified chitinase was 40 kDa as estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Chitinase was optimally active at a pH of 5 and stable from pH 4 to 6 and up to 40 degrees C. Among the metals and inhibitors tested, mercuric chloride completely inhibited the enzyme activity. The activity of chitinase was high on colloidal and pure chitin. The purified chitinase inhibited the germination of uredospores of Puccinia arachidis and also lysed the walls of uredospores and germ tubes. The results from these experiments indicated that chitinase of F. chlamydosporum plays an important role in the biocontrol of groundnut rust.     

Transbuccal delivery of acyclovir: I. In vitro determination of routes of buccal transport

PURPOSE: To determine the major routes of buccal transport of acyclovir and to examine the effects of pH and permeation enhancer on drug permeation. METHODS: Permeation of acyclovir across porcine buccal mucosa was studied by using side-by-side through diffusion cells at 37 degrees C. The permeability of acyclovir was determined at pH range of 3.3 to 8.8. Permeability of different ionic species was calculated by fitting the permeation of data to a mathematical model. Acyclovir was quantified using HPLC. RESULTS: Higher steady state fluxes were observed at pH 3.3 and 8.8. The partition coefficient (1-octanol/buffer) and the solubility of acyclovir showed the same pH dependent profile as that of drug permeation. In the presence of sodium glycocholate (NaGC) (2-100 mM), the permeability of acyclovir across buccal mucosa was increased 2 to 9 times. This enhancement was independent of pH and reached a plateau above the critical micelle concentration of NaGC. The permeabilities of anionic, cationic, and zwitterionic species were 3.83 X 10-5, 4.33 X 10-5, and 6.24 x 10-6 cm/sec, respectively. CONCLUSIONS: The in vitro permeability of acyclovir across porcine buccal mucosa and the octanol-water partitioning of the drug were pH dependent. A model of the paracellular permeation of the anionic, cationic, and zwitterionic forms of acyclovir is consistent with these data. The paracellular route was the primary route of buccal transport of acyclovir, and the enhancement of transbuccal transport of acyclovir by sodium glycocholate (NaGC) appeared to operate via this paracellular route.     

Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats

A 3-day monolithic polyacrylate adhesive dispersion type delivery system containing methadone was fabricated and in vitro permeation through hairless mouse and human cadaver skins was conducted. The effect of skin permeation enhancers was also investigated. Skin permeation rate across human cadaver skin was found to be lower than that of hairless mouse. Skin permeation profiles across both types of skins showed a membrane permeation controlled cumulative amount permeated (Q) versus time (t) relationship. Skin permeation rate was found to be dependent on both adhesive film thickness and loading dose of the drug in the matrix. Effective skin permeation rate across the hairless mouse skin was obtained from a patch with 1.5 mm thickness and 15% w/w loading dose. n-Decylmethyl sulfoxide and Azone were found to produce an effective skin permeation rate of methadone through human cadaver skin at a 5% w/w concentration. These initial studies demonstrated the feasibility of methadone administration through intact skin from a transdermal patch.     

Ibuprofen treatment of endotoxin-induced mastitis in cows

Ibuprofen treatment was compared with saline solution treatment in an endotoxin-induced experimental model of bovine mastitis. Acute mastitis was induced in healthy lactating Holstein cows (n = 12) by intramammary inoculation of 1 mg of Escherichia coli 026:B6 lipopolysaccharide in a single quarter per cow. Cows were assigned at random to ibuprofen (25 mg/kg of body weight, IV, n = 6) or 0.9% sodium chloride solution control (1.25 ml/kg, IV, n = 6) treatment groups. Ibuprofen or saline solution was administered once, 2 hours after endotoxin administration. The clinical course of endotoxin-induced mastitis and hematologic, clinical biochemical, and plasma mineral changes were monitored and compared between ibuprofen-treated and control cows. Clinical monitoring and blood sample collection were performed at 0, 2, 4, 6, 8, 12, 24, 48, 96, and 192 hours after endotoxin challenge. Rectal temperature and heart and respiratory rates were significantly (P < or = 0.05) increased in saline treated cows, compared with cows treated with ibuprofen. Blood eosinophil count and serum phosphorus, sodium, and total carbon dioxide concentrations were significantly (P < or = 0.05) decreased in saline-treated cows, compared with cows treated with ibuprofen. Ibuprofen treatment did not significantly change ruminations per minute, electrical conductivity of milk, quarter size, or quarter inflammation. The remaining hematologic, serum biochemical, plasma mineral, and coagulation values also were not changed significantly in response to ibuprofen treatment. Untoward effects attributed to ibuprofen administration were not observed. These results indicate that ibuprofen may provide empiric relief of clinical signs of coliform-induced mastitis.