Toxicological evaluation of lactose and chitosan delivered by inhalation.

These days, inhalation constitutes a promising administration route for many drugs. However, this route exhibits unique limitations, and formulations aimed at pulmonary delivery should include as few as possible additives in order to maintain lung functionality. The purpose of this work was to investigate the safety of lactose and chitosan to the pulmonary tissue when delivered by inhalation. The study was carried out with 18 Wistar rats divided in three groups receiving distilled water, lactose or chitosan. A solution of each excipient was administered by inhalation at a dose of 20 mg. The lungs were excised and processed to determine several biochemical parameters used as toxicity biomarkers. Protein and carbonyl group content, lipid peroxidation, reduced and oxidized glutathione (GSSG), myeloperoxidase (MPO), cooper/zinc and manganese superoxide dismutase, catalase, glutathione S-transferase and glutathione peroxidase were determined. Results of myeloperoxidase activity and glutathione disulfide lung concentrations showed a relevant decrease for chitosan group compared to control: 4.67 +/- 2.27 versus 15.10 +/- 7.27 (P = 0.011) for MPO and 0.89 +/- 0.68 versus 2.02 +/- 0.22 (P = 0.014) for GSSG. The other parameters did not vary significantly among groups. Lactose and chitosan administered by inhalation failed to show toxic effects to the pulmonary tissue. A protective effect against oxidative stress might even be attributed to chitosan, since some biomarkers had values significantly lower than those observed in the control group when this product was inhaled. Nevertheless, caution must be taken regarding chemical composition and technological processes applied to incorporate these products during drug formulation, in particular for dry powder inhalators.

Paraquat poisonings: mechanisms of lung toxicity, clinical features, and treatment.

Paraquat dichloride (methyl viologen; PQ) is an effective and widely used herbicide that has a proven safety record when appropriately applied to eliminate weeds. However, over the last decades, there have been numerous fatalities, mainly caused by accidental or voluntary ingestion. PQ poisoning is an extremely frustrating condition to manage clinically, due to the elevated morbidity and mortality observed so far and due to the lack of effective treatments to be used in humans. PQ mainly accumulates in the lung (pulmonary concentrations can be 6 to 10 times higher than those in the plasma), where it is retained even when blood levels start to decrease. The pulmonary effects can be explained by the participation of the polyamine transport system abundantly expressed in the membrane of alveolar cells type I, II, and Clara cells. Further downstream at the toxicodynamic level, the main molecular mechanism of PQ toxicity is based on redox cycling and intracellular oxidative stress generation. With this review we aimed to collect and describe the most pertinent and significant findings published in established scientific publications since the discovery of PQ, focusing on the most recent developments related to PQ lung toxicity and their relevance to the treatment of human poisonings. Considerable space is also dedicated to techniques for prognosis prediction, since these could allow development of rigorous clinical protocols that may produce comparable data for the evaluation of proposed therapies.

Sodium salicylate prevents paraquat-induced apoptosis in the rat lung.

The nonselective contact herbicide, paraquat (PQ), is a strong pneumotoxicant, especially due to its accumulation in the lung through a polyamine uptake system and to its capacity to induce redox cycling, leading to oxidative stress-related damage. In the present study, we aimed to investigate the occurrence of apoptotic events in the lungs of male Wistar rats, 24, 48, and 96 h after PQ exposure (25 mg/kg ip) as well as the putative healing effects provided by sodium salicylate [(NaSAL), 200 mg/kg ip] when administered 2 h after PQ. PQ exposure resulted in marked lung apoptosis, in a time-dependent manner, characterized by the "ladder-like" pattern of DNA observed through electrophoresis and by the presence of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL)-positive cells (TPC) as revealed by immunohistochemistry. The two main caspase cascades (the extrinsic receptor-mediated and the intrinsic mitochondria-mediated) and the expressions of p53 and activator protein-1 (AP-1) were also evaluated, to obtain an insight into apoptotic cellular signaling. PQ-exposed rats suffered a time-dependent increase of caspase-3 and caspase-8 and a decrease of caspase-1 activities in lungs compared to the control group. A marked mitochondrial dysfunction evidenced by cytochrome c (Cyt c) release was also observed as a consequence of PQ exposure. In addition, fluorescence electrophoretic mobility shift assay (fEMSA) revealed a transcriptional induction of the p53 and AP-1 transcription factors in a time-dependent manner as a consequence of PQ exposure. NaSAL treatment resulted in the remission of the observed apoptotic signaling and consequently of lung apoptosis. Taken together, the present results showed that PQ activates several events involved in the apoptotic pathways, which might contribute to its lung toxicodynamics. NaSAL, a recently implemented antidote for PQ intoxications, proved to protect lungs from PQ-induced apoptosis.

[Immunological characteristics of limbal epithelial cells: in vitro analysis of TLR4 function]. / Características inmunológicas de las células epiteliales limbales: análisis in vitro de la función del TLR4.

OBJECTIVE: The aim of the present study was to determine the expression of TLR4 on human limbal epithelial cells cultivated in vitro, and to determine its cellular function after stimulation with lipopolysaccharide (LPS). METHODS: Limbal epithelial cells were isolated from sclera-corneal rims and stimulated for 24 hours with different doses of LPS from E. coli and from Pseudomonas. After stimulation, the cells were harvested, stained with antibodies against human TLR4 and analysed by flow cytometry. mRNA was obtained and RT-PCR was performed for the identification of TLR4. Secretion of TNF-alpha by these cells was evaluated by ELISA of the supernatant. RESULTS: Limbal epithelial cells expanded in vitro constitutively expressed the TLR4 molecule. After stimulation of cells with LPS the average fluorescence intensity increased, indicating that the expression of extracellular TLR4 was augmented. The expression of TLR4 mRNA was also increased with LPS stimulation, with maximum expression measured at 10 ng/ml LPS. The level of TNF-alpha in the supernatant was not different between the stimulated and the non-stimulated cells. CONCLUSIONS: Although stimulation of in vitro limbal epithelial cells with LPS up-regulates the extracellular expression of TLR4, the function of TLR4 does not seem to be associated with the secretion of TNF-alpha by these cells. These results are consistent with the proposal that the corneal epithelium is an immunosilent site in the eye.

P-glycoprotein induction: an antidotal pathway for paraquat-induced lung toxicity.

The widespread use of the nonselective contact herbicide paraquat (PQ) has been the cause of thousands of deaths from both accidental and voluntary ingestion. The main target organ for PQ toxicity is the lung. No antidote or effective treatment to decrease PQ accumulation in the lung or to disrupt its toxicity has yet been developed. The present study describes a procedure that leads to a remarkable decrease in PQ accumulation in the lung, together with an increase in its fecal excretion and a subsequent decrease in several biochemical and histopathological biomarkers of toxicity. The administration of dexamethasone (100 mg/kg ip) to Wistar rats, 2 h after PQ intoxication (25 mg/kg ip), decreased the lung PQ accumulation to about 40% of the group exposed to only PQ and led to an improvement in tissue healing in just 24 h as a result of the induction of de novo synthesis of P-glycoprotein (P-gp). The involvement of P-gp in these effects was confirmed by Western blot analysis and by the use of a competitive inhibitor of this transporter, verapamil (10 mg/kg ip), which, given 1 h before dexamethasone, blocked its protective effects, causing instead an increase in lung PQ concentration and an aggravation of toxicity. In conclusion, the induction of P-gp, leading to a decrease in lung levels of PQ and the consequent prevention of toxicity, seems to be a new and promising treatment for PQ poisonings that should be further clinically tested.

Single high dose dexamethasone treatment decreases the pathological score and increases the survival rate of paraquat-intoxicated rats.

Dexamethasone (DEX), a synthetic corticosteroid, has been successfully used in clinical practice during paraquat (PQ) poisonings due to its anti-inflammatory activity, although, as recently observed, its effects related to de novo synthesis of P-glycoprotein (P-gp), may also strongly contribute for its healing effects. The main purpose of this study was to evaluate the effects of a single high dose DEX administration, which induces de novo synthesis of P-gp, in the histological and biochemical parameters in lung, liver, kidney and spleen of acute PQ-intoxicated rats. Four groups of rats were constituted: (i) control group, (ii) DEX group (100 mg/kg i.p.), (iii) PQ group (25mg/kg i.p.) and (iv) PQ+DEX group (DEX injected 2h after PQ). The obtained results showed that DEX ameliorated the biochemical and histological lung and liver alterations induced by PQ in Wistar rats at the end of 24 hours. This was evidenced by a significant reduction in lipid peroxidation (LPO) and carbonyl groups content, as well as by normalization of the myeloperoxidase (MPO) activities. Moreover, DEX prevented the increase of relative lung weight. On the other hand, these improvements were not observed in kidney and spleen of DEX treated rats. Conversely, an increase of LPO and carbonyl groups content and aggravation of histological damages were observed in the latter tissues. In addition, MPO activity increased in the spleen of PQ+DEX group and urinary N-acetyl-beta-D-glucosaminidase activity, a biomarker of renal tubular proximal damage, also augmented in this group. Nevertheless, it is legitimate to hypothesize that the apparent protection of high dosage DEX treatment awards to the lungs of the PQ-intoxicated animals outweighs the increased damage to their spleens and kidneys, because a higher survival rate was observed, indicating that DEX treatment may constitute an important and valuable therapeutic drug to be used against PQ-induced toxicity.

Kinetics of paraquat in the isolated rat lung: Influence of sodium depletion.

Paraquat accumulates in the lung through a characteristic polyamine uptake system. It has been previously shown that paraquat uptake can be significantly prevented if extracellular sodium (Na+) is reduced, although the available data correspond to experiments performed using tissue slices or incubated cells. This type of in vitro study fails to give information on the actual behaviour occurring in vivo since the anatomy and physiology of the studied tissue is disrupted. Accordingly, the aim of the present study was to explore the usefulness of the isolated rat lung model when applied to characterize the kinetic behaviour of paraquat in this tissue after bolus injection under standard experimental conditions as well as to evaluate the influence of iso-osmotic replacement of Na+ by lithium (Li+) in the perfusion medium. The obtained results show that the present isolated rat lung model is useful for the analysis of paraquat toxicokinetics, which is reported herein for the first time. It was also observed that Na+ depletion in the perfusion medium leads to a decreased uptake of paraquat in the isolated rat lung, although it seems that this condition does not contribute to improve the elimination of paraquat once the herbicide reaches the extravascular structures of the tissue, since the paraquat tissue wash-out phase is similar under both experimental conditions assayed.

[Expression of B7 molecules and TLR-9 on corneal epithelial cells infected with adenovirus: clinico-pathological implications in viral keratoconjunctivitis]. / Expresión de moléculas B7 y TLR:9 en células epiteliales corneales infectadas con adenovirus: implicaciones clínico-patológicas en la queratoconjuntivitis viral.

PURPOSE: B7 molecules are a family of proteins that co-stimulate T cells during immune activation. Normally the corneal epithelial cells (CEC) do not express these molecules on their cell surface. Toll-like receptors play an important role in the innate immune response to invading pathogens and recently have been demonstrated to be expressed on mice cornea. The objective of this study was to determine whether adenoviral infection induces B7 molecules and TLR9 on human CEC. METHODS: CEC were isolated from human corneas treated with dispase-II, and grown in the presence of supplemented hormonal epithelial medium until confluence. Then CEC were then infected with adenovirus 5 (Ad5) and cultured for different times. The CEC were then recovered and stained against human CD80, CD86, TLR-9 and cytokeratin. All cells were analyzed by flow cytometry. RESULTS: Ad5 infection of CEC induced the expression of B7 molecules and TLR-9 after 24 hours in culture, rising to maximum levels at 72 hours. B7 expression at 72 hours was as follows: CD80 expression on infected CEC was 62% (standard error [SE] 2.6) versus 3% (SE 1.2) on non-infected CEC (p<0.001); CD86 expression on infected CEC was 95% (SE 2.1) versus 5% (SE 1.2) on non-infected CEC (p<0.001). TLR-9 expression at 72 hours was 80% (SE 1.2) on infected CEC versus 5% (SE 1) on non-infected CEC (p<0.001). CONCLUSIONS: Ad5 infection induced the expression of B7 molecules and TLR-9 on CEC.

[Pharmacokinetic/pharmacodynamic analysis to optimize antibacterial treatments: prediction of efficacy by using Montecarlo simulation techniques]. / Optimización de la terapia antibacteriana mediante análisis farmacocinético/farmacodinámico: predicción de la eficacia con técnicas de simulación de Montecarlo.

The aim of this work is to provide a methodology to predict the potential efficacy of standard dosage schedules established for antimicrobials when used in clinical practice and administered to patients with different demographic characteristics. It is based on the application of pharmacokinetic and pharmacodynamic criteria (PK/PD analysis) to optimize dosification of this type of drug. Pharmacokinetic parameters such as the area under the plasma concentration-time curve (AUC) or maximum plasma concentration (Cmax) can be estimated from population kinetic models for each type of patient. Microbiological information, such as the MIC value, is also required. Using the above mentioned information and applying the Montecarlo simulation technique the probability of achieving the recommended value of a substituted variable related to efficacy may be estimated. The proposed methodology has been applied to levofloxacin when reportedly administered to patients showing different characteristics. The results reveal that this method allows us to know a priori whether or not the standard dosage is appropriate for a particular patient for whom the treatment is indicated. In summary, the proposed methodology provides us with a strategy for dosage individualization of antimicrobial agents that can be applied before initiating the treatment with no need for monitoring drug concentration, leading to an increase of clinical efficacy as well as a decreased risk of resistance development.

Clinical pharmacokinetics of statins.

This article reviews the pharmacokinetic properties of HMG-CoA reductase inhibitors (or statins), as reported in humans. Most data presented here refer to commercially available statins (atorvastatin, fluvastatin, lovastatin and simvastatin), although statins that have recently been withdrawn (cerivastatin) or are currently under development (glenvastatin, pitavastatin and rosuvastatin) will also be considered. All statins with the exception of pitavastatin show very low systemic bioavailability due to an extensive first pass effect at the intestinal and/or hepatic level. Such a characteristic can be advantageous, since the liver is the target organ for statins. Unlike most statins, lovastatin and simvastatin are administered as inactive lactone prodrugs. Statins differ mainly in the degree of metabolism and the number of active and inactive metabolites. All statins but pravastatin show highly active metabolites, the pharmacological activity depending on the kinetic profile of both parent compound and active metabolites. Pravastatin has the lowest protein binding (50% vs. > 90%) and is eliminated by both metabolism and renal excretion. Atorvastatin shows the longest terminal half-life (11-14 h vs. 1-3 h). Pharmacokinetic interactions with statins are very likely to occur, particularly for those statins that are CYP3A4 substrates. However, although of extreme interest in clinical practice, this subject was extensively reviewed in a previous article and therefore is not discussed here.

Preclinical pharmacokinetics of statins.

This review summarizes the pharmacokinetic properties of HMG-CoA reductase inhibitors (or statins) reported in animals. Lovastatin and simvastatin are administered as lactone prodrugs in contrast to other statins, which are generally formulated in the pharmacological active hydroxy acid form. Pharmacokinetics vary with the statin and animal species considered. Oral absorption is rapid and the bioavailability low due to an extensive first-pass metabolism. Pitavastatin is the exception, with high bioavailability in all species except monkeys (80% vs. 18%). Plasma protein binding is high for all statins (> 95%) except pravastatin (60%). Regardless of the dosing schedule (single or multiple), animal species and statin, the highest tissue levels are found in the liver--the target organ. Elimination is rapid with metabolism being the main elimination route for all statins, except for pitavastatin, which is only slightly metabolized, and pravastatin, which aside from metabolism is also eliminated by renal excretion. Statins undergo enterohepatic circulation and are recovered mainly in feces via bile, the extent of which is species-dependent. Metabolism varies with the statin and animal species, particularly the beta-oxidation of the dihydroxy heptanoic side chain that occurs primarily in rodents.

A retrospective analysis of pharmacokinetic-pharmacodynamic parameters as indicators of the clinical efficacy of ceftizoxime.

OBJECTIVE: To analyse the relationship between a series of estimated pharmacokinetic-pharmacodynamic parameters and the reported efficacy of ceftizoxime. DESIGN: Retrospective literature search and analysis using different correlation models. METHODS: The following parameters were calculated for each group of patients included in the study from the simulated plasma concentration curves corresponding to the dosage regimen administered: (i) peak concentration at steady state divided by the minimum inhibitory concentration (CmaxSS/MIC); (ii) the time that the plasma drug concentration exceeded the MIC scaled to 24 hours at steady state [(tSS)24h > MIC]; (iii) the total area under the concentration-time curve over 24 hours at steady state divided by the MIC [(AUC(SS))24h/MIC]; and (iv) the AUC at steady state for the period of time that the concentration is above the MIC over a period of 24 hours divided by the MIC [(AUIC(SS))24h]. A univariate correlation analysis was performed considering efficacy [rate (%) of clinical cure or bacterial eradication] as the dependent variable and the pharmacokinetic-pharmacodynamic parameter as the independent variable, using linear and nonlinear models. RESULTS: (tSS)24h > MIC was the only parameter that was statistically correlated with efficacy, the linear model being the best choice among the 4 relationship approaches tested. A biased frequency distribution of reported efficacy data constricts the correlation analysis to a narrow range of efficacy and hinders interpretation of the results. CONCLUSIONS: The reporting of cases with low efficacy rates as well as those with high efficacy rates, including information on patient idiosyncrasies and the infecting organisms, would be of great help in performing retrospective analyses of the use of antimicrobial agents, leading to the optimisation of therapy with this type of drug in clinical practice.

A retrospective analysis of pharmacokinetic/pharmacodynamic indices as indicators of the clinical efficacy of ciprofloxacin.

A retrospective analysis of the relationship between estimated pharmacokinetic/pharmacodynamic indices and the reported efficacy of ciprofloxacin has been carried out using different correlation models. f1.gif" BORDER="0">, T(ss) > MIC, f2.gif" BORDER="0"> and AUIC(ss) were calculated for each clinical case included in the study, from simulated plasma level curves corresponding to the dosage regimen administered. A univariate correlation analysis was performed considering efficacy (%) as the dependent variable and indices as the independent variables according to linear and non-linear pharmacokinetic-pharmacodynamic models (PK-PD models). The results prove that log-transformation of the independent variable improves the data fitting to linear model. The four estimated indices show a log-linear relationship with outcome, T(ss) > MIC and AUIC(ss) being the parameters best correlated with percentage efficacy. The E(max) model with intrinsic response is an additional correlation strategy for T(ss) > MIC, leading to estimated values of E(max) and E(0) of 100.34 +/- 25.09% and 24.40 +/- 11.7%, respectively. The wide range of bacteria responsible for the infections considered, including Gram-positive pathogens such as staphylococci, might explain the good correlation between T(ss) > MIC and percentage efficacy found for ciprofloxacin in this study.

Determination of tissue spaces of the isolated hindlimb of the rat using netilmicin as an extracellular space indicator.

The kinetic behaviour of drugs in extracellular space is of interest as it influences the drug's access to, and permanence in, those areas of the body upon which drugs exert pharmacological or toxicological actions. A series of experiments was carried out to characterize the vascular, interstitial and cellular spaces of the isolated hindlimb of the rat. Certain specific experimental conditions were met: body weight was under 230 g to avoid fat tissue in the preparations; a perfusion flow rate of 3 mL min(-1); and 3% of bovine albumin in the perfusate supplied at 25 degrees C to the tissues. The isolation of the hindlimb followed the method described by Ruderman with some modifications to restrict the perfusion to the right hindlimb. Tritiated water, netilmicin and methylene blue were injected separately and efferent fluid samples were collected for 15 min after solute injection. Analysis of the efferent curves was performed to calculate the statistical moments (AUC, area under concentration-time curve; MTT, mean transit time; VTT, variance of mean transit times) and solute distribution volumes, which were subsequently used to estimate the tissue spaces of the isolated hindlimb. The results revealed that methyl blue and netilmicin can be respectively used as alternatives to radiolabelled indicators of the vascular and extracellular spaces of tissues included in the rat isolated hindlimb.

Influence of dose on the distribution kinetics of ciprofloxacin and ofloxacin in the isolated hindlimb of the rat.

The aim of this study was to determine whether the dose influences the distribution kinetics of ciprofloxacin and ofloxacin in muscle- bone- and skin-tissues included in the isolated hindlimb of the rat. Experiments were carried out in the isolated perfused hindlimb of the rat, administering a single dose of 45, 450 or 900 microg of each quinolone as a bolus injection. Outflow perfusate samples were collected for 20 min and drug levels were determined by an HPLC technique. The mean transit time (MTT) and the distribution volume of ciprofloxacin significantly increased with the dose injected (MTT=1.47+/-0.69, 8.74+/-0.27 and 9.52+/-2.95 min for 45, 450 and 900 microg, respectively). A similar situation was observed with ofloxacin, although the increase in these parameters was less pronounced (MTT=3.65+/-0.86, 7.92+/-2.03 and 8.32+/-1.70 min for 45, 450 and 900 microg, respectively). The distribution of ciprofloxacin and ofloxacin in the rat hindlimb appears to be a dose-dependent process, at least for the dose range considered in this study. This might explain the high variability in the distribution coefficients reported for these drugs in literature.

A review of the isolated kidney as an experimental model for pharmacokinetic studies.

Traditional distribution studies have been based on methods affording steady-state partition coefficient or sparsely defined tissue profiles. Isolation organ techniques provide a methodology for complete description of drug disposition at any particular tissue; the kidney constitutes a case for importance for those drugs eliminated by renal excretion of those whose toxicological or pharmacological target space is located at this level. The aim of the present review is to analyze the use of the isolated perfused kidney in pharmacokinetic studies and its potential in this field.

Basis of anti-infective therapy: pharmacokinetic-pharmacodynamic criteria and methodology for dual dosage individualisation.

Antimicrobial therapy should be designed on the basis of microbiological, as well as pharmacokinetic, criteria; microbiological parameters provide information about the susceptibility of the pathogen responsible for the infectious process while pharmacokinetic parameters give information about the potential ability of the drug in question to reach and remain at the sites of infection in the body. Microbiological parameters such as the minimum inhibitory concentration, minimum bactericidal concentration, bacterial titre, bactericidal rate and 'post-antibiotic effect' (PAE) must be considered. Among the pharmacokinetic parameters, the maximum serum concentration at steady state (CmaxSS), area under the concentration-time curve (AUC) and length of time that the serum concentrations exceed a particular value are the most useful in this context. Different relationships between these parameters, known as efficacy indices, have been established to predict the potential efficacy of antibacterial therapy. Antimicrobial dosage individualisation should be based on the optimisation of the efficacy index that best correlates with patient response. It seems appropriate to establish the degree of correlation among the different efficacy indices and clinical response observed in patients by means of a correlation analysis. This type of analysis can be either retrospective or prospective and may be based on linear or maximum response models. Simulation of the plasma concentration curves obtained with the particular regimen administered offers a methodology which is easy to apply and provides the pharmacokinetic information necessary to calculate the different efficacy indices. Information about the susceptibility of the pathogen to the antibacterial in question and about the response to the treatment used is also necessary for the correlation analysis. This type of analysis determines which of the indices is best correlated with efficacy and, hence, is the index to be optimised when attempting to individualise antibacterial therapy for different situations.

Distribution of ciprofloxacin in the isolated rat lung in the presence and absence of tissue oedema.

A series of experiments with the isolated perfused rat lung was carried out to study the distribution of ciprofloxacin in this tissue under different experimental conditions; the influence of drug administration rate and the presence of oedema were evaluated by comparison of the statistical moment and distribution coefficient values as well as the unit disposition function (UDF) profiles in the tissue. The polyexponential character of the outflow perfusate curves indicates a distribution behaviour which does not correspond to the 'well stirred model' but rather to the existence of some type of diffusion barriers and/or tissue binding. The presence of oedema in the tissue, induced by insufficient oxygenation of perfusate, significantly increases the distribution coefficient of ciprofloxacin and leads to relevant modifications in the unit disposition function (UDF) of the isolated lung, while administration rate does not significantly affect the kinetic behaviour of the drug in this tissue.

In vitro study of the interaction between quinolones and polyvalent cations.

The aim of the present study was to evaluate the influence of aluminium and iron on the in vitro dissolution kinetics of ciprofloxacin and ofloxacin as well as the usefulness of this type of in vitro data to predict modifications in in vivo absorption processes as a consequence of different factors, such as the widely documented in vivo interaction between quinolones and cations. Fitting of experimental data to different theoretical in vitro dissolution profiles was performed by non-linear regression methods and the statistical moments were calculated from raw experimental data. Analysis of residuals applied to dissolution curves as well as statistical comparison of the estimated parameters were carried out to evaluate the in vitro interaction. The results reveal significative modifications of the dissolution profiles of these quinolones as a consequence of the presence of cations, especially for Fe2+ which decreases 34.7% the maximum amount dissolved for ciprofloxacin and 29.1% for ofloxacin. Al3+ also produces a decrease of the total amount of quinolone dissolved although less relevant than Fe2+. Analysis of residuals proved to be the best statistical method to evaluate differences between whole dissolution profiles, at least under the experimental conditions used.