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Three patients who developed urticaria shortly after air-contrast barium enema studies of the colon are described. Only a single similar instance was found in the literature. One of the patients had a positive prick skin test to methylparaben, which was the preservative in the barium mixture used and, therefore, is presumed to be the responsible allergen.
OBJECTIVE: When percutaneous bone biopsy is done by radiologists, local anesthetics such as lidocaine are routinely used. Although percutaneous bone biopsy of neoplasms is well accepted, it has been suggested that this procedure not be used to diagnose osteomyelitis because of a reported bactericidal effect of lidocaine and related drugs on certain organisms. The purposes of this study were to determine if lidocaine is bactericidal in vitro and to determine if it has an effect on the culture of bacteria in specimens obtained by percutaneous bone biopsy in vivo. SUBJECTS AND METHODS: The minimal inhibitory concentration and minimal bactericidal concentration of 1% lidocaine hydrochloride (10 mg/ml preserved with methylparaben) were determined in vitro for seven bacteria known to be frequent causes of osteomyelitis by using conventional clinical microbiologic methods. Percutaneous core bone biopsy for suspected osteomyelitis was done in 28 patients: 21 with and seven without the use of lidocaine. Sites sampled included vertebrae (14); calcanei, pubis, and ischia (two each); and intervertebral disks (eight). Six of the 21 patients who had percutaneous biopsy with lidocaine also had an open surgical biopsy without lidocaine. The results of cultures of the specimens were compared. Histologic evaluation and radiographic follow-up were used to identify false-negative results. RESULTS: The minimal inhibitory and the minimal bactericidal concentrations, respectively, of lidocaine (in milligrams per milliliter) were as follows: Klebsiella pneumoniae, 5.0 and > 5.0; group B streptococci, 2.5 and 5.0; Staphylococcus aureus, > 5.0; and > 5.0; methicillin-resistant S. aureus, > 5.0 and > 5.0; Escherichia coli, 2.5 and > 5.0; Pseudomonas aeruginosa, 5.0 and 5.0; Salmonella species, 5.0 and > 5.0. We found no difference in bacterial growth and the number of false-negative results between patients who had biopsies with and those who had biopsies without lidocaine. Fifty percent of patients who had growth on cultures of specimens from percutaneous biopsies done with lidocaine had no growth on cultures of specimens from surgical biopsies done without lidocaine. This likely occurred because the surgical specimens were not obtained under cross-sectional imaging guidance. CONCLUSION: Up to a 50% mixture of lidocaine has no significant effect in vitro on the bacterial growth of the seven organisms that cause osteomyelitis most frequently, and no inhibitory effect on bacterial growth was seen in biopsies done with lidocaine in vivo. The inhibitory effect of lidocaine therefore occurs at a greater concentration than is used clinically. We conclude that lidocaine used for biopsy does not interfere with the diagnosis of osteomyelitis.
We have previously found that NK cell activity is present in rat lung lavage and inhibited by lidocaine. The purpose of this report is to characterize further the inhibition by lidocaine on NK activity. Peripheral blood lymphocytes from normal human volunteers were assayed in a four-hour 51chromium release assay in the presence of varying concentrations of lidocaine during or prior to the lytic assay. During the assay, increasing concentrations of lidocaine inhibited NK activity. This effect was not related to pH and at high concentrations was unrelated to methylparaben found in topical lidocaine. Preincubation of effector cells for one hour with different concentrations of lidocaine produced similar results which were temperature dependent and related to incubation time. Preincubation of effector cells in lidocaine (0.5g%) for one to ten minute intervals at 37 degrees C resulted in 60 to 92% inhibition, respectively. The lidocaine did not alter effector cell viability nor did it affect the phenotypes of the effector cells as determined by flow cytometry. Lidocaine's inhibition of NK activity remained the same for cells which were further purified by plastic adherence, nylon wool filtration and percoll density centrifugation. The effect was not reversed by a 16 hour incubation in tissue culture medium. In a single cell assay, we determined that the inhibition was at the level of cell lysis.
The purpose of this study was to investigate the use of beta-D(+) glucose-glucose oxidase (EC 1.1.3.4)-catalase (EC 1.11.1.6) (BDG-GO-CAT) as a new antioxidant system in solutions. A novel method for estimation of activity of the system was developed using a dissolved oxygen (DO) meter and an oxygen probe. The method can be used to determine the enzymatic activity of the system at GO concentrations of 0.005 to 0.030 unit/ml, with an r2 of 0.995 for the linearity of the standard curve, and can be adapted for analysis in any solution. At room temperature of 23.0 degrees +/- 2.0 degrees C, the maximum activity of the BDG-GO-CAT system was found to occur at pH 5.40. The half-life values for the stability of GO-CAT in 0.10 M phosphate buffer solutions of pH 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, and 10.0 were 9.78, 49.43, 53.46, 36.51, 12.68, 1.84, and 0.80 weeks, respectively. Dextrose was used in place of beta-D(+) glucose for cost-saving purposes, and a standard curve for the activity of GO-CAT was obtained using 20 mg/ml dextrose. The BDG-GO-CAT was effective as a DO-scavenger in closed containers, when the containers were opened and exposed to atmosphere for 2 days between tests, and upon reclosing them. Pharmaceutical excipients such as ethanol, glycerin, propylene glycol, methylparaben, propylparaben, artificial strawberry flavor, and sodium benzoate did not show any adverse effect on the activity of BDG-GO-CAT. Sorbitol, high-fructose corn syrup, sucrose, and polyethylene glycol 3350 increased the rate of DO removal. Sodium carboxymethyl-cellulose (CMC) at 2.0% w/v decreased the rate of DO removal. These studies indicate that the BDG(dextrose)-GO-CAT system warrants serious consideration for use an antioxidant system in aqueous formulations.
The stability and the behavior of patent blue (Alphazurine 2G) dye in a vehicle such as lidocaine hydrochloride injection were studied with regard to medication orders which may be prepared by hospital pharmacists. The patent blue family of dyes are sulfonated diaminotriphenylmethane, vital, acid dyes which have been used as diagnostic aids in both lymphography and burn debridement. A literature review, including some toxicological information, is presented. The occurrence of the sodium salt form and the equilibrium solubility of the patent blue sample studied are reported. Some implications of patent blue injections include: Clinical literature reports of toxicities, the unapproved status of patent blue by the Food and Drug Administration, results of stability studies, and the formation of viscid, water-insoluble precipitates of patent blue in combination with lidocaine hydrochloride. The extemporaneous preparation and subsequent use of parenteral prescriptions of patent blue dye in vehicles containing lidocaine hydrochloride and methylparaben are not recommended.
A study of the diffusion of parabens from topical formulations is presented here. In particular, four different topical formulations, namely, a water-in-oil emulsion, an oil-in-water emulsion, and two hydrophilic gels (Pemulen gel and Carbopol gel) were produced, containing a mixture of three common parabens, namely, methylparaben (MP), ethylparaben (EP), and propylparaben (PP). An analytical method based on liquid extraction, followed by reversed-phase HPLC for the quantitative determination of MP, EP, and PP, was developed. The method allowed good separation of paraben mixtures and high percentages of recovery (> than 97%). The diffusion kinetics of parabens from the produced formulations was determined by an in vitro system based on a Franz cell assembled with a synthetic membrane, followed by a reversed-phase HPLC analytical method. The comparative study demonstrated that, in the case of emulsions, diffusion coefficients are a function of the substituent of preservatives: the higher the solubility, the higher the diffusion of parabens. On the contrary, in the case of the hydrophilic gels, the higher the parabens solubility, the lower the diffusion coefficients. The method described here could represent a means of controlling the extent of diffusion of parabens from topical formulations in order to minimize percutaneous absorption and to control the availability of microbes.
The subconjunctival injection of commercial gentamicin, given either as a single dose or as repeated injections, caused a hyperemic conjunctival response. Simultaneously there was a toxic myopathy induced in the extraocular muscles. The overall response, followed with light microscopy, occurred as a focal infiltrate of polymorphonuclear leukocytes with progression over a few days to a mononuclear cell infiltrate that accompanied fiber degeneration. Injections of each ingredient of commercial gentamicin individually showed that only gentamicin caused the muscle response; methylparaben, EDTA, and sodium bisulfite were without effect. The pH of the solution was eliminated as a contributing factor as was osmolarity of the injection. Increasing recognition is being given to post-operative complications caused by the prophylactic subconjunctival injection of gentamicin following cataract, and other intraocular surgery. The present data offer a mechanistic explanation for many of these toxic findings.
Permeability of Silastic tissue expander shells to lidocaine was studied to investigate the feasibility of intraluminal lidocaine injection for pain relief during soft-tissue expansion. Both intact expanders and an apparatus using isolated Silastic membrane segments were used to partition solutions of various lidocaine concentrations, and the rate of diffusion was quantitatively measured using a fluorescence polarization immunoassay. Lidocaine flux was found to follow Fick's law of passive diffusion with respect to time, surface area, and concentration gradient for the first 9 hours, with a permeability coefficient of 10.3 +/- 2.6 micrograms (h.cm2.percent)-1 (mean +/- SD) and diffusion coefficient of 7.5 x 10(-7) cm2/min for an average membrane thickness of 473 +/- 23 microns. After 9 hours, the lidocaine flux decreased exponentially, although the concentration gradient across the membrane remained essentially the same order of magnitude. Plasma proteins in the outer bathing solution and methylparaben used as a preservative in the standard lidocaine formulation had no influence on the change in transport flux with time. At the end of the linear portion of the diffusion curve, less than 2 percent of the total intraluminal lidocaine had crossed the membrane. Potential toxicity in the event of implant rupture limits the maximum total lidocaine dose to approximately 500 mg within an expander at any one time. Within these limits, the capacity for lidocaine delivery of 500 mg lidocaine by a 640-cc tissue expander would be only 6 mg during the first 9 hours after administration.(ABSTRACT TRUNCATED AT 250 WORDS)
The influence of auxiliary substances and pH on the chemical transformations of insulin in pharmaceutical formulation, including various hydrolytic and intermolecular cross-linking reactions, was studied. Bacteriostatic agents had a profound stabilizing effect--phenol > m-cresol > methylparaben--on deamidation as well as on insulin intermolecular cross-linking reactions. Of the isotonicity substances, NaCl generally had a stabilizing effect whereas glycerol and glucose led to increased chemical deterioration. Phenol and sodium chloride exerted their stabilizing effect through independent mechanisms. Zinc ions, in concentrations that promote association of insulin into hexamers, increase the stability, whereas higher zinc content had no further influence. Protamine gave rise to additional formation of covalent protamine-insulin products which increased with increasing protamine concentration. The impact of excipients on the chemical processes seems to be dictated mainly via an influence on the three-dimensional insulin structure. The effect of the physical state of the insulin on the chemical stability was also complex, suggesting an intricate dependence of intermolecular proximity of involved functional groups. At pH values below five and above eight, insulin degrades relatively fast. At acid pH, deamidation at residue A21 and covalent insulin dimerization dominates, whereas disulfide reactions leading to covalent polymerization and formation of A- and B-chains prevailed in alkaline medium. Structure-reactivity relationship is proposed to be a main determinant for the chemical transformation of insulin.
A simple, rapid, and precise method is developed for the quantitative simultaneous determination of metformin and pioglitazone in a combined pharmaceutical-dosage form. Separation is achieved with a Zorbax XDB C(18), 15-cm analytical column using buffer-acetonitrile (66:34, v/v) of pH 7.1, adjusted with orthophosphoric acid as the mobile phase. The buffer used in the mobile phase contains 10mM disodium hydrogen phosphate and 5mM sodium dodecyl sulphate in double-distilled water. The instrumental settings are flow rate of 1 mL/min, column temperature at 40 degrees C, and detector wavelength of 226 nm. The internal standard method is used for the quantitation of the ingredients of this combination. Methylparaben is used as an internal standard. The method is validated and shown to be linear for metformin and pioglitazone. The correlation coefficients for metformin and pioglitazone are 0.9991 and 0.9999, respectively. The relative standard deviations for six replicate measurements in two sets of each drug in the tablets are always less than 2%.
Certain safe over-the-counter (OTC) sexual lubricants such as Astroglide, KY Liquid, Replens, Vagisil, ViAmor, and Wet Stuff inhibit both cell-free HIV and the production of HIV by infected leukocytes in vitro even in the presence of seminal fluid. To identify which components of the lubricants were active against HIV, we tested five components (glycerin, methylparaben, propylparaben, polyquaternium-32, and propylene glycol). The paraben preservatives and propylene glycol in the lubricants did not inhibit HIV, while the common natural homeostatic metabolite, glycerin, and the thickener polyquaternium-32 did strongly inactivate infectious HIV and HIV-infected leukocytes. Activity against HIV and HIV-infected cells by glycerin was stable through 24 hours at 37 degrees C. Glycerin and polyquaternium-32 were active at minimum concentrations of approximately 2% and 0.01%, respectively--well within the highest FDA safety guidelines. Both active components disrupted infected leukocytes within 5 minutes which resulted in inhibition of infectious HIV production by infected leukocytes of greater than 25 to 100-fold. These components do not disrupt vaginal epithelial cells in vivo. These components also rapidly inactivate cell-free HIV by 10- to 30-fold. Thus, we may conclude that the active components of the OTC lubricants are glycerin and polyquaternium-32. Using these components, OTC sexual lubricants could be reformulated to optimize their anti-HIV activity. Furthermore, clinical trials of these lubricants and components seem to be indicated because of their FDA safety level, wide availability, and low cost.
Three methods were applied for the analysis of 2 multicomponent mixtures containing dextromethorphan hydrobromide, phenylephrine hydrochloride, chlorpheniramine maleate, methylparaben, and propylparaben, together with either sodium benzoate (Mix 1) or ephedrine hydrochloride and benzoic acid (Mix 2). In the first method, liquid chromatography was used for their simultaneous determination using an ODS column with a mobile phase consisting of acetonitrile-phosphate buffer, pH 2.7 (40 + 60, v/v), containing 5mM heptanesulfonic acid sodium salt and ultraviolet (UV) detection at 214 nm. Also, 2 chemometric methods, principal component regression, and partial least squares were used. For both chemometric calibrations, a concentration set of the mixture consisting of each compound in each mixture was prepared in distilled water. The absorbance data in the UV spectra were measured for the 76 or 71 wavelength points in the spectral region 210-240 or 210-224 nm considering the intervals of deltagamma = 0.4 or 0.2 nm for Mix 1 and Mix 2, respectively. The 2 chemometric methods did not require any separation step. These methods were successfully applied for the analysis of the 2 multicomponent combinations in synthetic mixtures and in commercial syrups, and the results were compared with each other.
Acetohexamide (AH) is nominated as the prohibited ingredients in cosmetics in Japanese Pharmaceutical Affairs Act. So the analytical method for AH was investigated by HPLC. The lotion or milky lotion of 0.5g was put into a 10-ml volumetric flask. After adding 1.0ml of AH solution at 50 microg/ml into the volumetric flask, the mixture was made up to 10ml with methanol as the testing solution. Creams were procedured as follows; 0.5 g of cream was put into a 10-ml volumetric flask. After adding 1.0ml of tetrahydrofuran into the volumetric flask, the mixture was stirred for several minutes and the ingredients of the creams were dissolved. After adding 1.0ml of AH solution at 50 microg/ml into the volumetric flask, the mixture was made up to 10ml with methanol. One milliliter of the mixture including AH at 5 microg/ml was exactly put into a test tube with a cap and then 1 ml of water and 1 ml of hexane were added. After shaking vigorously, stand for several minutes. After centrifuging, the hexane layer was eliminated and the residual mixture was used as the test solution. The testing solution of 20 microl was analyzed by HPLC using the ODS column (CAPCELL PAK C18 column, 4.6 x 250mm), the mixture of acetonitrile and 50 mmol/l phosphate buffer(pH 5.3)(3:1) and the detection wavelength of 247 nm. The working curve from 0.5 to 6.0 microg/ml showed a linear line between the concentrations of AH and the peak areas. There was no interference of peak of AH with the ingredients such as methylparaben, ethylparaben in the lotions, milky lotion and creams.
Cyproheptadine hydrochloride (CH) is nominated as the prohibited ingredients in cosmetics in Japanese Pharmaceutical Affairs Act. So the analytical method for CH was investigated by HPLC. The lotion or milky lotion of 0.5 g was put into a 10-ml volumetric flask. After adding 1.0ml of CH solution at 50 microg/ml into the volumetric flask, the mixture was made up to 10ml with methanol as the test solution. Creams were procedured as follows; 0.5 g of cream was put into a 10-ml volumetric flask. After adding 1.0 ml of tetrahydrofuran into the volumetric flask, the mixture was stirred for several minutes and the ingredients of the creams were dissolved. After adding 1.0 ml of CH solution at 50 microg/ml into the volumetric flask, the mixture was made up to 10ml with methanol. This mixture was transferred to a centrifuging tube with a cap and then the tube was centrifuged for 5 minutes at 3000 rpm. The supernatant was used as the test solution. The test solution of 20 microl was analyzed by HPLC using the ODS column (CAPCELL PAK C18 column, 4.6 x 250 mm), the mixture of 1% acetic acid with 10 mmol/l sodium octanesulfonate and acetonitrile (11:9) and the detection wavelength of 286 nm. The working curve from 0.5 to 6.0 microg/ml showed a linear line between the concentrations of CH and the peak areas. There was no interference of peak of CH with the ingredients such as methylparaben, ethylparaben in the lotions, milky lotion and creams.
Phospholipids--stabilized submicron emulsions require the addition of preservatives to destroy or inhibit the growth of microorganisms when these preparations are non-sterile products or when packed in multi-dose containers. This study examined the distribution of four paraben esters--methylparaben, ethylparaben, propylparaben, and butylparaben--that were added into submicron emulsions by de novo emulsification. The distribution of preservative compounds among different phases was determined after separation of submicron emulsions by ultracentrifugation. The compounds with higher lipophilicity were concentrated in the oil phase and phospholipids-rich phase, leading to an increase in oil droplet size. However, the effect of the paraben distribution on zeta potential and pH of emulsion fluctuated depending on the type of phospholipid used. The lower lipophilic compounds were mostly found in the aqueous phase and mesophase. These results signify the possibility that the chemical structures and lipophilicity of preservative compounds affected their distribution in phospholipid-stabilized submicron emulsions. We conclude that the higher concentration of preservatives or their combination may be required for efficient preservation of submicron emulsion products.
An isocratic reversed phase high-performance liquid chromatographic (HPLC) method with ultraviolet detection at 230 nm has been developed for the determination of buclizine hydrochloride in human serum and dosage formulation. Methylparaben was successfully used as an internal standard. Good chromatographic separation between buclizine and internal standard peaks was achieved by using a stainless steel analytical column Nucleosil, C18 (10 microm, 25 cm x 0.46 cm). The system was operated at room temperature using a mobile phase consisting of acetonitrile-water (1:1) (pH 2.6) with phosphoric acid 85% at a flow rate of 2 ml/min. The calibration curve for buclizine hydrochloride in human serum was linear over the tested concentration range of 10, 3, 1.5, 0.5, 0.15, 0.05, and 0.025 microg/ml with a correlation coefficient of 0.9999. The intra- and inter-run precision and accuracy results were 98.07 to 100.34. The proposed method was validated for selectivity, linearity, accuracy, and precision. The method was found to be suitable for the quality control of buclizine hydrochloride in bulk drug as well as in human serum.
A procedure used to assay four antihistamines--brompheniramine maleate, chlorpheniramine maleate, pheniramine maleate and pyrilamine maleate in combination--is discussed. The method requires a high-pressure liquid chromatograph and an intermediate polarity column. The method is accurate and appears to be stability-indicating. The four antihistamines can be separated and assayed accurately. There is no interference from the two commonly used decongestants, phenylephrine hydrochloride and phenylpropanolamine hydrochloride, from the expectorant potassium guaiacolsulfonate, from the preservative propyl paraben or from two other antihistamines, diphenhydramine hydrochloride and bromdiphenhydramine hydrochloride. Guaifenesin, methylparaben and sodium benzoate interfere only with pheniramine maleate. Methapyrilene hydrochloride interferes only with pyrilamine maleate.
Pharmaceutical drug products often contain antimicrobial agents as a preservative in their formulation. These excipients are required to destroy or impede the growth of microorganisms that inadvertently enter the product during manufacturing. Unfortunately, these preservatives may also interfere with microbiological assays used to determine product sterility or bioburden levels. The extent of interference by these preservatives can be quite significant, but varies depending on the method used. The most frequently used method for testing parenteral drug products is the membrane filtration technique. Membrane filters are composed of a wide variety of materials such as cellulose, polycarbonate, acrylic polypropylene, Teflon, and nylon. This study evaluated the adsorption characteristics that nylon filters, obtained from five different manufacturers, had on the filtration of solutions of four different antimicrobial compounds (phenol, methylparaben, propylparaben, and benzalkonium chloride). The adsorption properties were determined using both HPLC and microbiological assay techniques. The data revealed that there was a wide range in the amounts of antimicrobial agent (2.3 to 94.1%) bound to the membrane filters when direct product filtration was used without a subsequent rinse step. However, when a rinse step is included, only propylparaben showed any significant "true" adsorption (less than 1 to 33.3%), but showed only marginal bacterial inhibition. Interestingly, the microbiological assays indicated that with a saline rinse step, only benzalkonium chloride was lethal for the two challenge organisms even though the percent adsorbed as measured by HPLC was below 1%. This discrepancy is significant because it demonstrates the analytical limitation when using HPLC to detect minimal concentrations of benzalkonium chloride that may be deleterious to microorganisms.(ABSTRACT TRUNCATED AT 250 WORDS)