Relative bioavailability of commercial ampicillin formulations in man

The relative bioavailability of three commercial ampicillin products was examined in 12 human subjects using a crossover experimental design. Based upon the areas under the ampicillin plasma concentration-time curves after the oral administration of 250 mg. ampicillin and using an analysis of variance technique no statistically significant differences were found between the products examined. These findings are in contrast to those of a recent report and appear to be explained by formulation differences. These relatively minor differences in formulation reflect the importance of formulation variables in providing efficient drug therapy. The intrasubject variation associated with several of these products is quite marked and is consistent with the incomplete and erratic absorption of this antibiotic in man.     

Supplementation of calves with stabilized orthosilicic acid

The bioavailability of silicon in stabilized orthosilicic acid was investigated in a double blind, placebo controlled supplementation study of calves maintained on a normal diet. The total dietary Si intake was increased by 4.9% in the form of stabilized orthosilicic acid. After 23 wk of Si supplementation, the serum Si concentration increased (p=0.0001,n=29) by 70% compared to control animals in spite of the low Si dose administered and the Si adequate diet. The individually administered Si dose was significantly associated with the serum Si concentration (r=0.44,p=0.016,n=29). The collagen concentration in dermis was significantly higher (p=0.019,n=4) in the Si group and a positive correlation (r=0.72,p=0.018,n=9) was found between the Si concentration in serum and the collagen concentration in cartilage. The calcium (Ca) and phosphorus (P) concentrations in serum were marginally higher for animals supplemented with Si compared to control animals. In serum, a significant linear relationship was found between the Si and the Ca concentration (r=0.31,p=0.019,n=59), whereas the magnesium concentration correlated marginally with the Si concentration (r=0.25,p=0.068,n=59). In summary, increasing the total dietary Si intake by 4.9% in the form of stabilized orthosilicic acid resulted in a 70% higher Si concentration in serum indicating a high bioavailability of Si in this supplement. The positive correlation between the serum Si concentration and the collagen concentration in cartilage and the serum Ca concentration, respectively, suggest the involvement of Si both in the formation of extracellular matrix components and in Ca metabolism.     

Impact of experimental trauma and niflumic acid administration on antimicrobials' concentration in serum and mandible of rats

Administration of antibiotics and analgesics in surgery or trauma is of great importance for an effective treatment. Trauma, as stress stimulus, causes alterations in various functions of the organism as well as in drug pharmacokinetics. The aim of this study was to determine the effect of trauma upon the serum and bone levels of the antimicrobial ampicillin and cefapirin, with and without co-administration of a non-steroidal anti-inflammatory analgesic (NSAIDs). Fifty-six male Wistar rats were divided into two groups A (control) and B (experimental). Each group consisted of 4 subgroups (n=7) receiving ampicillin, ampicillin with niflunic acid, cefapirin, and cefapirin with niflunic acid. In group B traumatic injury was performed by incision (7 mm length) in the right cheek. The levels of the antibiotics were estimated by the inhibition zone of B. subtilis. An increase in antibiotic levels was observed in group B, being statistically significant only for cefapirin level in the mandible. Upon niflumic acid co-administration a statistically significant rise in serum ampicillin and mandible cefapirin levels was observed in both control and experimental groups (student t-test). It can be concluded that the combination of antibiotics and non-steroid antiinflammatory drugs (NSAIDs) may enhance the antibacterial drug concentration.     

Ampicillin treatment of Neisseria gonorrhoeae in vivo. An experimental study in rabbits

The effect of ampicillin on gonococci was investigated in chambers subcutaneously implanted in rabbits. An intramuscular injection of ampicillin resulted in a rapid increase of the ampicillin concentration in serum, whereas the diffusion of ampicillin into the fluid of a non-infected chamber was comparatively slow. The ampicillin concentration was, however, maintained in the chamber fluid during a prolonged period of time as compared to ampicillin in serum. The concentration profile of ampicillin in the infected chamber was similar to that of the non-infected chamber, though at a lower level. No viable gonococci were detected 120 minutes after the injection of ampicillin. In contrast, the same concentration of ampicillin in a liquid culture resulted in slower reduction in the viability of the gonococcal strain. Even after 300 minutes a small population of gonococci was viable. Thus, a difference in the activity of ampicillin could be observed between the in vitro and the in vivo test situation.     

Amoxycillin: A new Semi-synthetic Penicillin

Amoxycillin (α-amino-p-hydroxybenzylpenicillin) is a new semi-synthetic penicillin with a broad spectrum of antibacterial activity similar to that of ampicillin. Penicillin-sensitive strains of staphylococci, streptococci, and pneumococci were sensitive to concentrations of 0·1 μg or less of amoxycillin/ml. Strains of Haemophilus influenzae were inhibited by a level of 0·5 μg/ml, and most strains of Escherichia coli, Proteus mirabilis, Shigella sonnei, Salmonella species, and Streptococcus faecalis were sensitive to a concentration of 5 μg or less of amoxycillin/ml. Penicillinase-producing strains of Staphylococcus aureus and strains of Pseudomonas aeruginosa, indole-positive Proteus, Klebsiella, and Enterobacter were insensitive to amoxycillin. The new penicillin was bactericidal in activity, as with other penicillins, and its antibacterial activity was not reduced in the presence of serum. After oral administration to volunteer subjects amoxycillin produced serum concentrations twice as high as those obtained with similar doses of ampicillin, and the penicillin was recovered unchanged in high concentrations in the urine. The absorption of amoxycillin was not greatly influenced by food, and administration of probenecid resulted in increased and more prolonged concentrations of amoxycillin in serum.     

Ampicillin Nanoparticles Production via Supercritical CO2 Gas Antisolvent Process

The micronization of ampicillin via supercritical gas antisolvent (GAS) process was studied. The particle size distribution was significantly controlled with effective GAS variables such as initial solute concentration, temperature, pressure, and antisolvent addition rate. The effect of each variable in three levels was investigated. The precipitated particles were analyzed with scanning electron microscopy (SEM) and Zetasizer Nano ZS. The results indicated that decreasing the temperature and initial solute concentration while increasing the antisolvent rate and pressure led to a decrease in ampicillin particle size. The mean particle size of ampicillin was obtained in the range of 220–430 nm by varying the GAS effective variables. The purity of GAS-synthesized ampicillin nanoparticles was analyzed in contrast to unprocessed ampicillin by FTIR and HPLC. The results indicated that the structure of the ampicillin nanoparticles remained unchanged during the GAS process.KEY WORDS: ampicillin, nanoparticles, precipitation, supercritical gas antisolvent     

Development and <Emphasis Type="Italic">In Vitro</Emphasis>/<Emphasis Type="Italic">In Vivo</Emphasis> Evaluation of Etodolac Controlled Porosity Osmotic Pump Tablets

The aim of the current work was the design and evaluation of etodolac controlled porosity osmotic pump (CPOP) tablets exhibiting zero-order release kinetics. Variables influencing the design of (1) core tablets viz., (a) osmogent type (sodium chloride, potassium chloride, mannitol, and fructose) and (b) drug/osmogent ratio (1:0.25, 1:0.50, and 1:0.75), and (2) CPOP tablets viz., (a) coating solution composition, (b) weight gain percentage (1–5%, w/w), and (c) pore former concentration (5%, 10%, and 20%, v/v), were investigated. Statistical analysis and kinetic modeling of drug release data were estimated. Fructose-containing core tablets showed significantly (P < 0.05) more retarded drug release rates. An inverse correlation was observed between drug/fructose ratio and drug release rate. Coating of the optimum core tablets (F4) with a mixture of cellulose acetate solution (3%, w/v), diethyl phthalate, and polyethylene glycol 400 (85:10:5, v/v, respectively) till a 4% w/w weight gain enabled zero-order sustained drug delivery over 24 h. Scanning electron microscopy micrographs of coating membrane confirmed pore formation upon contact with dissolution medium. When compared to the commercial immediate-release Napilac® capsules, the optimum CPOP tablets (F4–34) provided enhanced bioavailability and extended duration of effective etodolac plasma concentration with minimum expected potential for side effects in healthy volunteers.KEY WORDS: cellulose acetate, controlled porosity osmotic pump, etodolac, osmogent, zero order     

Optimization of Process Conditions Using Response Surface Methodology (RSM) for Ethanol Production from Pretreated Sugarcane Bagasse: Kinetics and Modeling

Based on a five level central composite design (CCD) involving the variables substrate concentration (C), pH (P), incubation temperature (T) and fermentation time (H), a response surface methodology (RSM) for the production of ethanol from pretreated sugarcane bagasse by cellulase and yeast Kluyveromyces fragilis was standardized. The design contains a total of 31 experimental trials in which the first 24 organized in a factorial design and from 25 to 31 involving the replications of the central points. Data obtained from RSM on ethanol production were subjected to the analysis of variance (ANOVA) and analyzed using a second order polynomial equation. Maximum ethanol concentration (32.6 g/l) was obtained from 180 g/l pretreated sugarcane bagasse at the optimized process conditions (temperature 35°C, pH 5.5) in 72 h aerobic batch fermentation. Various kinetic models such as logistic model, logistic incorporated leudeking piret model and logistic incorporated modified leudeking piret model have been evaluated and the constants were predicted.     

Design and Evaluation of a Novel Evodiamine-Phospholipid Complex for Improved Oral Bioavailability

A novel evodiamine (EVO)-phospholipid complex (EPLC) was designed to improve the bioavailability of EVO. A central composite design approach was employed for process optimization. EPLC were characterized by differential scanning calorimetry, ultraviolet spectroscopy, Fourier transformed infrared spectroscopy, ¹H-NMR spectroscopy, matrix-assisted laser desorption/ionization time-of-flight spectroscopy, apparent solubility, and dissolution rate. After oral administration of EPLC, the concentrations of EVO at different time points were determined by high-performance liquid chromatography. The optimal formulation for EPLC was obtained where the values of X₁, X₂, and X₃ were 2, 0.5, and 2.5 mg/mL, respectively. The average particle size and zeta potential of EPLC with the optimized formulation were 246.1 nm and −26.94 mV, respectively. The EVO and phospholipids in the EPLC were associated with non-covalent interactions. The solubility of EPLC in water and the dissolution rate of EPLC in phosphate-buffered solution (pH 6.8) were substantially enhanced. The plasma EVO concentration-time curves of EPLC and free EVO were both in accordance with the two-compartment model. The peak concentration and AUC_0−∞ of EPLC were increased, and the relative bioavailability was significantly increased to 218.82 % compared with that of EVO.KEY WORDS: bioavailability, evodiamine, phospholipid complex, process optimization     

Pharmaceutical and Pharmacokinetic Evaluation of a Novel Fast Dissolving Film Formulation of Flupentixol Dihydrochloride

The objective of the present study was to develop fast dissolving oral film of the antipsychotic drug, flupentixol dihydrochloride, to enhance its bioavailability, optimize its therapeutic effect when used to treat depression with anxiety, and increase the convenience and compliance by the mentally ill, developmentally disable, elderly, and pediatric patients. Six formulae were prepared with different concentrations of water-soluble polymers vis. hydroxypropyl methylcellulose (HPMC E5) and carboxymethyl cellulose (CMC) by solvent casting technique. The prepared films were subjected to characterization for folding endurance, weight variations, thickness, disintegration time, drug release pattern, and drug content. Physical compatibility between the drug and excipients was guaranteed in the selected formulation (2% HPMC) by means of differential scanning calorimetry analysis and Fourier-transform infrared spectroscopy. This formulation revealed high stability after testing according to the International Conference on Harmonisation guidelines. In vivo studies based on single phase parallel design were carried out for the optimized formulation in healthy human volunteers. The concentration of flupentixol dihydrochloride in plasma samples was analyzed by a developed validated LC-MS/MS assay method and the pharmacokinetic parameters of the established formulation were compared with the commercially available oral tablets. Faster rate of absorption of flupentixol could be obtained from the oral film formulation and the relative bioavailability was found to be 151.06% compared to the marketed product.KEY WORDS: fast dissolving, flupentixol dihydrochloride, LC-MS/MS analysis, oral film, pharmacokinetics     

Ability of some gastropod egg capsules to protect against low-salinity stress

The ability of the egg capsules of three intertidal gastropod species to protect embryos against low-salinity stress was examined. Encapsulated embryos of Ilyanassa obsoleta (Say), Nucella lamellosa (Gmelin), and N. lima (Gmelin) were far more tolerant of transfer to water of reduced salinity than were embryos which had been prematurely removed from egg capsules and transferred to low-salinity sea water directly. However, the walls of N. lamellosa and N. lima capsules were found to be permeable to salts and at least to small carbohydrate molecules (glucose). Correspondingly, indirect evidence for all three species and direct evidence for N. lamellosa indicates that the osmotic concentration of intracapsular fluid declines to near ambient after transfer of egg capsules to dilute medium. Experiments conducted using embryos of N. lamellosa suggest that the egg capsules may protect embryos by reducing the rate at which the osmotic concentration of intracapsular fluid decreases rather than by reducing the magnitude of the decrease.     

Ionic conditions affecting the release and absorption of an alkaline protease associated with the occlusion bodies of insect baculoviruses

Nearly all of the alkaline protease found in the occlusion bodies of baculoviruses (polyhedra for nuclear polyhedrosis and capsules for granulosis viruses) (Baculovirus, subgroup A and B, family Baculoviridae) can be specifically extracted under high ionic concentration. The extraction is directly proportional to the concentrations of NaCl up to 0.25 m. It is not dependent on pH, species of ions, temperature, and incubation time. The protease is reabsorbed under low ionic concentration by protease-extracted and by heat-treated capsules and polyhedra. The protease from Streptomyces griseus is not absorbed. This indicates that the occlusion body proteins have distinct affinity for certain alkaline proteases.     

An Excellent Delivery System for Improving the Oral Bioavailability of Natural Vitamin E in Rats

This study set out to develop a novel and stable nanoemulsion formulation of natural vitamin E with increased oral bioavailability. The natural vitamin E nanoemulsion was prepared by a modified emulsification technique. The physicochemical characteristics of natural vitamin E nanoemulsion were characterized and its pharmacokinetics study was performed as well. The experimental results showed droplet diameters ranging from 20 to 400 nm (average, 87.7 nm) with a negative electrostatic potential (−23.5 ± 1.5 mv). The pharmacokinetics study of this nanoemulsion and corresponding soft capsule was carried out using noncompartment model method. Compared with the marketed soft capsule, the C_max of the natural vitamin E nanoemulsion was higher, while the T_max was shorter. Thus, plasma concentration–time profiles in rats dosed with nanoemulsion showed a 1.6-fold enhancement in the area under the curve of natural vitamin E compared with the marketed soft capsule. The antioxidative effects of the natural vitamin E nanoemulsion and the marketed soft capsule were also evaluated by the levels of superoxide dismutase (SOD) activity and malondialdehyde (MDA) concentration in serum and liver tissue. According to the SOD activity and the MDA concentration determined, the nanoemulsion was superior to the marketed soft as an antioxidative agent. The overall results demonstrated that the nanoemulsion drug delivery system could be a promising strategy for the delivery of natural vitamin E, which showed great potential for clinical application.Key word: Antioxidation, Nanoemulsion, Natural vitamin E, Oral bioavailability     

Assessing the in situ bioavailability of trace elements to snails using accumulation kinetics

The bioavailability of trace elements in soils is conditioned by both physico-chemical and biological parameters. In this study, the accumulation kinetics of cadmium (Cd), lead (Pb), arsenic (As) and antimony (Sb) were determined for 3 industrially impacted sites to assess the bioavailability of these contaminants to the garden snail (Cantareus aspersus). Mono and multivariate regressions allowed the identification of cation exchange capacity (CEC), silts and organic carbon content as the soil parameters modulating the in situ bioavailability of Cd and Pb. For all elements, the total concentrations in the soils were not good predictor (not significant correlation) of the bioavailability to snails. The Cd, As and Sb assimilation fluxes were correlated with the calcium chloride (CaCl₂) extract concentrations, but this correlation was not observed with Pb. The total soil concentration coupled with soil properties best explained the variation in Pb assimilation, whereas their influences on Cd bioavailability were lower, signifying that other parameters such as contamination sources may modulate Cd bioavailability. Here, the As and Sb in situ accumulation kinetics are described for the first time and highlighted a slight bioavailability to snails at the studied sites. The absence of a correlation between the As or Sb assimilation fluxes and total metals in the soil coupled with the absence of influence of soil properties on their bioavailability may result from the speciation of these metalloids, which are known to modulate their mobility in soils. This study highlights the need to consider both physico-chemical and biological aspects of metal and metalloid bioavailability to assess the risk of metal transfer from soil to organisms.     

Formulation Optimization and <Emphasis Type="Italic">Ex Vivo</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Evaluation of Celecoxib Microemulsion-Based Gel for Transdermal Delivery

Celecoxib (CXB) is a poorly aqueous solubility sulfonamide non-steroidal anti-inflammatory drug (NSAID). Hence, the formulation of CXB was selected for solubilization and bioavailability. To find out suitable formulation for microemulsion, the solubility of CXB in triacetin (oil phase), Tween 80 (surfactant), and Transcutol-P (co-surfactant) was screened respectively and optimized by using orthogonal experimental design. The Km value and concentration of oil, S_mix, and water were confirmed by pseudo-ternary phase diagram studies and central composite design. One percent carbopol 934 was added to form CXB microemulsion-based gel. The final formulation was evaluated for its appearance, pH, viscosity, stability, drug content determination, globule size, and zeta potential. Its ex vivo drug permeation and the in vivo pharmacokinetic was investigated. Further research was performed to ensure the safety and validity by skin irritation study and in vivo anti-inflammatory activity study. Ex vivo permeation study in mice was designed to compare permeation and transdermal ability between microemulsion formulation and conventional gel. The results revealed that optimized microemulsion-based gel gained higher permeation based on smaller globule size and high drug loading of microemulsion. Transdermal ability was also greatly improved. Bioavailability was compared to market Celebrex® by the in vivo pharmacokinetic study in rabbits. The results indicated that CXB microemulsion-based gel had better bioavailability than Celebrex®.     

Gelation conditions and transport properties of hollow calcium alginate capsules

The diameter, membrane thickness, and compression intensity of hollow Ca-alginate capsules were measured at different gelation conditions, such as the reactant concentration, dropping velocity, and gelation time. The optimum operation conditions for preparing capsules were determined at 100 g/L CaCl(2), 10 g/L sodium alginate (Na-alginate), a dropping velocity of 150 droplets/min, and a gelation time of 10 min. Diffusion of some saccharide and amino acid from bulk solution into capsules was investigated, and the diffusion coefficients were calculated by the developed mathematical model. All the tested substances can diffuse easily into the capsules. The combined diffusion coefficients of the capsule D(m) are 92-99% as large as their diffusion coefficients in pure water, while the diffusion coefficients in the capsule membrane D(1) are 60-95% as large as those. By employing polyethylene glycol (PEG) and bovine serum albumin (fraction V) (BSA(V)), the molecular weight cut-off of the capsule was determined. For linear macromolecules, hollow Ca-alginate capsules have a molecular weight cut-off of 4000. No diffusion of BSA(V) into the capsules was observed.     

Effects of a granulosis virus on aphids

When capsules, capsule protein, and free virions of a Pieris rapae granulosis virus were fed to or injected into the aphids Myzus persicae and Rhopalosiphum padi, considerable mortality resulted without apparent infection. Free virus was most effective, boiled capsules the least. Macerates and honeydew of aphids fed on capsules were infectious when bioassayed, but recovery of infectious virus depended upon the concentration of capsules fed to aphids. Electron microscopy of the midguts of aphids revealed that most, if not all, capsules remained intact. It is concluded that granulosis capsules and/or capsule components exert a nonspecific toxic effect on aphids when applied internally. Externally applied capsules, capsules on the leaf surface, or an internally applied plant virus (tobacco mosaic virus) which was used for comparison did not cause lethality.     

Bioavailability of iron in oral ferrous sulfate preparations in healthy volunteers.

The bioavailability of iron in five ferrous sulfate preparations was studied in 10 healthy male volunteers. The preparations were an oral solution, two types of film-coated tablets and two types of enteric-coated tablets. Blood samples were drawn hourly from 8 am to 6 pm on the day before each study day to assess baseline serum iron concentrations and on the study day. Spectrophotometry was used to measure the serum iron concentrations. The area under the curve (AUC), the maximum concentration and the time to achieve the maximum concentration were compared by analysis of variance. The enteric-coated preparations resulted in AUCs less than 30% of the AUC for the oral solution. The two film-coated products produced AUCs essentially equivalent to that of the oral solution. We conclude that the bioavailability of iron in the enteric-coated preparations was low, relative to that of the film-coated products and the oral solution, and that these products should not be considered interchangeable.     

Aspects of Bioavailability of Mercury for Methylation in Pure Cultures of Desulfobulbus propionicus (1pr3)

We have previously hypothesized that sulfide inhibits Hg methylation by decreasing its bioavailability to sulfate-reducing bacteria (SRB), the important methylators of Hg in natural sediments. With a view to designing a bioassay to test this hypothesis, we investigated a number of aspects of Hg methylation by the SRB Desulfobulbus propionicus, including (i) the relationship between cell density and methylmercury (MeHg) production, (ii) the time course of Hg methylation relative to growth stage, (iii) changes in the bioavailability of an added inorganic Hg (Hg_I) spike over time, and (iv) the dependence of methylation on the concentration of dissolved Hg_I present in the culture. We then tested the effect of sulfide on MeHg production by this microorganism. These experiments demonstrated that under conditions of equal bioavailability, per-cell MeHg production was constant through log-phase culture growth. However, the methylation rate of a new Hg spike dramatically decreased after the first 5 h. This result was seen whether methylation rate was expressed as a fraction of the total added Hg or the filtered Hg_I concentration, which suggests that Hg bioavailability decreased through both changes in Hg complexation and formation of solid phases. At low sulfide concentration, MeHg production was linearly related to the concentration of filtered Hg_I. The methylation of filtered Hg_I decreased about fourfold as sulfide concentration was increased from 10⁻⁶ to 10⁻³ M. This decline is consistent with a decrease in the bioavailability of Hg_I, possibly due to a decline in the dissolved neutral complex, HgS⁰.     

Effect of Cuprofilin on experimental atherosclerosis

The effect of Cuprofilin, a newly synthesized C.(II)-chlorophyll complex, was assessed in rats with experimental atherosclerosis. The study was focused on changes in serum cholesterol, lipids, and triglycerides concentration as well as on serum and abdominal aorta Cu and Zn values. It has been ascertained that after 90 d in animals fed a rich lipid diet there was a statistically significant increase in serum cholesterol, triglycerides, and lipid concentration (p < 0.01). A significant augmentation of serum Cu values (p < 0.01) accompanied by a marked lowering of the same element in abdominal aorta (p < 0.01) was also found, as compared to the results registered in the control group. However, Cuprofilin, administered for 90 d in the group of animals with experimental atherosclerosis, significantly decreased the serum cholesterol, triglycerides, and serum lipid values (p < 0.01), increased copper content in aortic tissue (p < 0.01) and lowered serum copper concentration (p < 0.01) as compared to the untreated group. Moreover, in the aorta of administered animals the lipid infiltration has been demonstrated to be significantly diminished vs the untreated group.