Level A IVIVC for immediate release tablets confirms in vivo predictive dissolution testing for ibuprofen.

A bioequivalence study comparing two fixed dose combination tablets containing 200 mg ibuprofen and 30 mg pseudoephedrine hydrochloride showed bioequivalence for pseudoephedrine AUC and Cmax, but the reference product showed higher Cmax than the test product in fasted conditions. The main difference between products was the presence of tribasic calcium phosphate in the reference tablet, resulting in an increased surface pH of the dissolving ibuprofen particles under gastric and intestinal conditions and, consequently, higher solubility of ibuprofen. A mechanistic model based on mass balance and ionization equilibria was used to calculate the pH of the particle surface under different buffer conditions. The discrepancies in surface pH between test and reference tablet were pronounced in 0.1 M and 0.01 M hydrochloric acid and in diluted maleate 7 mM pH 6.5 and phosphate 5 mM pH 6.7 buffers (but negligible in compendial phosphate buffer pH 6.8. Only those dissolution tests using pre-treatment in acidic conditions could be used to build a one-step in vitro-in vivo correlation (IVIVC). This work shows the potential of these discriminatory and in vivo predictive dissolution methods to obtain IVIVCs for BCS class IIa drugs and for extending BCS biowaivers to BCS class IIa drugs.

Impact on intestinal permeability of pediatric hyperosmolar formulations after dilution: Studies with rat perfusion method.

INTRODUCTION: There is no consensus on administering hyperosmolar formulations by mouth to neonates. In 1976, the Committee on Nutrition of the American Academy of Pediatrics published a recommendation of not administer formulations with an osmolarity higher than 400 mOsm/L due to the possible damage to intestine and relationship with necrotizing enterocolitis. Since this recommendation, exists a general trend of reducing osmolality of oral formulations without considering the pharmacokinetics of absorption of the drugs. The objective of this study was to characterize the permeability values of drugs formulated at different osmolalities by using a well-established rat intestinal perfusion model and to measure the osmolality of the most used formulations in our neonatology unit. METHODS: For the osmolality measurement study, most common used oral drugs were selected (compounded formulations and drug products). Osmolality of three dilutions (1:1, 1:4 and 1:8) were measured using a cryoscopic descent osmometer. Atenolol, caffeine, furosemide, hydrocortisone and paracetamol were selected for the permeability study. Three suspensions were elaborated of each drug (150 mOsm/kg, 300 mOsm/kg and 1500 mOsm/kg). Permeability values and absorption rate coefficients were determined in complete small intestine using in situ "closed loop" perfusion method. RESULTS: The formulations that resulted to be hyperosmolar (>400 mOsm/kg) were 86% (70% of these proved to be above 1500 mOsm/kg). The permeability study shown that the osmolality is inversely proportional to the apparent permeability of the drug in the studied drugs. The permeability values obtained with hyperosmolar samples were lower compared to 150 mOsm/kg or 300 mOsm/kg. CONCLUSIONS: Osmolality parameter is of particular relevance in oral drug administration in neonate because the risk of damaging the gastrointestinal tract and because of the risk that modifying osmolality also modifies its permeability, resulting in a potential change in bioavailability.

Giardiasis: Characteristics, Pathogenesis and New Insights About Treatment.

Giardia intestinalis infection causes enterocytes damage and loss of brush border of the epithelial cells of the intestine that leads to shortening of microvilli and altered epithelial barrier function. This pathology results in aqueous diarrhoea, steatorrhea, nausea, abdominal pain, vomiting and weight loss. However, most infections are asymptomatic. The main consequence of Giardia colonization is nutrients malabsorption. Several families of drugs with good efficacy are used for Giardia treatment, but sometime dosing regimens are suboptimal and emerging resistance begins to question their clinical value. Moreover, some of these drugs can cause side effects that result in patient discomfort and low adherence to the treatment. This paper reviews the drugs currently used for the treatment against Giardia: the mechanism of action, the efficacy, the normal dosing, side effects and in vitro and clinical studies. In addition, new therapies against Giardia such as those based on phytochemicals, Lactobacillus and nanotechnology are collected in this paper, trying to find the ideal treatment for this disease with maximum efficacy and minimum adverse effects.

How to: identify non-tuberculous Mycobacterium species using MALDI-TOF mass spectrometry.

BACKGROUND: The implementation of MALDI-TOF MS for microorganism identification has changed the routine of the microbiology laboratories as we knew it. Most microorganisms can now be reliably identified within minutes using this inexpensive, user-friendly methodology. However, its application in the identification of mycobacteria isolates has been hampered by the structure of their cell wall. Improvements in the sample processing method and in the available database have proved key factors for the rapid and reliable identification of non-tuberculous mycobacteria isolates using MALDI-TOF MS. AIMS: The main objective is to provide information about the proceedings for the identification of non-tuberculous isolates using MALDI-TOF MS and to review different sample processing methods, available databases, and the interpretation of the results. SOURCES: Results from relevant studies on the use of the available MALDI-TOF MS instruments, the implementation of innovative sample processing methods, or the implementation of improved databases are discussed. CONTENT: Insight about the methodology required for reliable identification of non-tuberculous mycobacteria and its implementation in the microbiology laboratory routine is provided. IMPLICATIONS: Microbiology laboratories where MALDI-TOF MS is available can benefit from its capacity to identify most clinically interesting non-tuberculous mycobacteria in a rapid, reliable, and inexpensive manner.

Evaluation of clinicians' knowledge and practices regarding medical radiological exposure: findings from a mixed-methods investigation (survey and qualitative study).

OBJECTIVES: To assess the impact of initiatives aiming to increase clinician awareness of radiation exposure; to explore the challenges they face when communicating with patients; to study what they think is the most appropriate way of communicating the long-term potential risks of medical radiological exposure to patients. DESIGN: A quantitative and qualitative evaluation through a survey and focal groups. SETTING: San Juan Hospital and Dr Peset Hospital (Southeast Spain) and clinicians from Spanish scientific societies. PARTICIPANTS: The surveys were answered (a) in person (216: all the radiologists (30), urologists (14) and surgeons (44) working at both participant hospitals; a sample of general practitioners from the catchment area of one hospital (45), and a consecutive sample of radiologists attending a scientific meeting (60)) or (b) electronically through Spanish scientific societies (299: radiologists (45), pneumologists (123), haematologists (75) and surgeons (40)). Clinicians were not randomly selected and thus the results are limited by the diligence of the individuals filling out the survey. PRIMARY AND SECONDARY OUTCOME MEASURES: Clinicians' knowledge and practices regarding medical radiological exposure, and what they considered most appropriate for communicating information to patients. RESULTS: Nearly 80% of the clinicians surveyed had never heard of the European recommendations. Fewer than 20% of the clinicians surveyed identified correctly the radiation equivalence dose of intravenous urography or barium enema. It was reported by 31.7% that they inform patients about the long-term potential risks of ionising radiation. All participants agreed that the most appropriate way to present information is a table with a list of imaging tests and their corresponding radiation equivalence dose in terms of chest X-rays and background radiation exposure. CONCLUSIONS: Medical radiological exposure is frequently underestimated and rarely explained to patients. With a clear understanding of medical radiological exposure and proper communication tools, clinicians will be able to accurately inform patients.

Tubulin acetylation promoting potency and absorption efficacy of deacetylase inhibitors.

BACKGROUND AND PURPOSE: Histone deacetylase 6 (HDAC6) and silent information regulator 2 (SIRT2) control the dynamics of the microtubule network via their deacetylase activities. Tubulin polymerization promoting protein (TPPP/p25) enhances microtubule acetylation by its direct binding to HDAC6. Our objective was to characterize the multiple interactions of the deacetylases and to establish the inhibitory potency and the pharmacokinetic features of the deacetylase inhibitors, trichostatin A (TSA) and AGK2. EXPERIMENTAL APPROACH: The interactions of deacetylases with tubulin and TPPP/p25 were quantified by elisa using human recombinant proteins. The effect of inhibitors on the tubulin acetylation was established in HeLa cells transfected with pTPPP and CG-4 cells expressing TPPP/p25 endogenously by celisa (elisa on cells), Western blot and immunofluorescence microscopy. The pharmacokinetic features of the inhibitors were evaluated by in situ kinetic modelling of their intestinal transport in rats. KEY RESULTS: Deacetylases interact with both tubulin and TPPP/p25, notwithstanding piggy-back binding of HDAC6 or SIRT2 to the TPPP/p25-associated tubulin was established. Much higher inhibitory potency for TSA than for AGK2 was detected in both HeLa and CG-4 cells. Pioneer pharmacokinetic studies revealed passive diffusion and diffusion coupled with secretion for TSA and AGK2 respectively. Both inhibitors exhibited greater permeability than some other well-established drugs. CONCLUSIONS AND IMPLICATIONS: TPPP/p25-directed deacetylase inhibition provides mechanisms for the fine control of the dynamics and stability of the microtubule network. Deacetylase inhibitors with chemical structures similar to TSA and AGK2 appear to be excellent candidates for oral drug absorption.

Prevalence and variables associated with solitary pulmonary nodules in a routine clinic-based population: a cross-sectional study.

OBJECTIVE: To determine the prevalence of solitary pulmonary nodules (SPNs) in chest radiology studies and patient's features associated with malignancy in a non-high-risk clinical population. METHODS: Patients ≥35 years were referred for thoracic imaging in two hospitals (2010-2011). Eight radiologists determined the presence and characteristics of SPN. Selected variables were collected from radiological register and medical records. Observer agreement in the diagnosis of SPN was assessed. RESULTS: 25,529 patients were included: 23,102 (90.5%) underwent chest radiograph and 2,497 (9.5%) a CT. The prevalence of SPN was 2.1% (95% CI 1.9 - 2.3) in radiographs and 17.0% (95% CI 15.5 - 18.5) in CT. In patients undergoing chest radiograph, detection of SPN with an irregular border was more frequent among smokers. In patients who had a CT, larger SPNs appeared to be associated with 60 years of age or over, diagnosis of a respiratory illness, or male gender. In addition, an irregular border was also more common among men. CONCLUSIONS: The prevalence of SPNs detected by both radiograph and CT was lower than that shown in screening studies. Patient characteristics such as age, sex, respiratory disease, or smoking habit were associated with nodule characteristics that are known to be related with malignancy. KEY POINTS: There is a lower SPN prevalence in the clinical population than in screening studies. SPN prevalence is associated with some patient characteristics: sex, age, imaging test. Nodule characteristics related to malignancy were associated with some patient characteristics.

El informe de la radiología simple. Algo más que un imperativo legal / Reporting plain films: more than just a legal requirement

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Ion-pair strategy for enabling amifostine oral absorption: rat in situ and in vivo experiments.

This study shows the effect of ion pair formation on intestinal absorption and oral bioavailability of amifostine. Amifostine is a prodrug used as a highly potent and selective radiotherapy and chemotherapy protectant but due to its low lipophilicity and charge at physiological pH range, its trans epithelial transport and its potential for oral drug delivery is very low. Ion pair formation with negatively charged counter ions was evaluated by in situ rat perfusion studies as a possible strategy to enhance intestinal absorption of amifostine. Succinic acid, phthalic acid and benzoic acid were used as counter ions. Rat intestinal perfusion studies confirmed a statistically significant increase in amifostine permeability in the presence of the counter ions in the order of succinic>phthalic>benzoic. Rat pharmacokinetic studies in vivo were performed to calculate oral absolute bioavailability of amifostine alone and with ion pairs in order to confirm the in situ perfusion results and the applicability of the ion pair approach. Intravenous and intraduodenal administrations were done in rats using a permanent jugular vein cannulation technique and a duodenal cannulation method to avoid drug degradation in stomach. In vivo oral bioavailability studies demonstrated a 20-30-fold increase in amifostine bioavailability with succinic acid depending on counter ion ratio and 10-fold increase with phthalic acid as ion pair. In summary ion pair strategy with succinic acid could enable amifostine oral administration on enteric coated formulations.

Mathematical modeling of oral absorption and bioavailability of a fluoroquinolone after its precipitation in the gastrointestinal tract.

The objective was to characterize the in vivo absorption and bioavailability (BA) of a low solubility, high permeability fluoroquinolone (CNV97101) that precipitates in the gastrointestinal (GI) tract by mathematical modeling approach. In situ rat intestinal perfusion studies were performed to characterize the absorption mechanism. The oral fraction absorbed in vivo was lower than the predicted based on the in situ intestinal permeability. Two additional routes of administration, intraduodenal (ID) and intraperitoneal (IP) were investigated to explore if precipitation in stomach and subsequent partial re-dissolution were the causes of the lower in vivo BA. Ex vivo precipitation studies with the stomach content of fasted rats were also carried out. Fitting procedures were performed with NONMEM VII 1.2. The in situ experiments confirmed simultaneous passive and carrier-mediated absorption processes. The ex vivo experiments confirmed precipitation in stomach lowering in vivo the oral fraction absorbed compared with the IP and ID administrations. Due to the almost complete availability of CNV97101 following IP administration, a first hepatic pass could be excluded. The ex vivo assay results and the pharmacokinetic modeling of in vivo data supported the hypothesis of precipitation in the stomach and partial re-dissolution. Nevertheless, other factors such as residence time in the GI may reduce the fraction absorbed even for low oral doses for which re-dissolution was almost complete in vivo.

Assessment of fexofenadine hydrochloride permeability and dissolution with an anionic surfactant using Caco-2 cells.

The purpose of this study was to estimate the effect of the anionic surfactant sodium dodecyl sulphate (SDS) on the permeability and dissolution of fexofenadine hydrochloride (FEX) and the transepithelial electrical resistance (TEER) with Caco-2 cells. The dissolution profile of FEX was evaluated at different pH values (1.2, 3.2, 4.2, 4.5, 5.2 and 6.8) at 37 +/- 0.5 degrees C and chracterized in presence of SDS. The dissolution of FEX was increased in the presence of SDS. For permeability studies, apical to basolateral and basolateral to apical permeability was assesed with various concentrations of FEX (50, 100, 500, 1000 and 5000 microM) and in the presence of SDS. The FEX transport changed with 10 and 50 microM of SDS and the TEER values, after 120 min, decreased. In conclusion, a low and concentration-dependent permeability was found for FEX across the Caco-2 cells. FEX transport increased and TEER decreased with increasing SDS concentrations. These results supports the use of SDS as anionic surfactant in these concentration; SDS can be used safely as permeation and dissolution enhancer for the oral delivery of FEX.

Influence of polyunsaturated fatty acids on Cortisol transport through MDCK and MDCK-MDR1 cells as blood-brain barrier in vitro model.

Transport across the blood-brain barrier is a relevant factor in the pharmacological action of many drugs and endogenous substances whose action site is located in brain. An overactive P-gp has been suggested to be of relevance for the resistance of the HPA system to be suppressed by glucocorticoids, which is one of the best described biological abnormalities in certain types of depression. PUFA acids have shown clinical efficacy in depressed patients and the hypothesis is that these compounds are able to reduce HPA axis activity as this effect has been shown in animal models of depression. The objective of the present work was (1) to characterize Cortisol transport through MDCK and MDCK-MDR1 cell lines (as in vitro models of the BBB) to confirm its transport mechanism as substrate of P-gp and (2) to evaluate the effect of PUFA acids as enhancers of Cortisol transport in the BBB model and explore the enhancement mechanism. Transport studies of Cortisol were performed in both directions, from apical-to-basolateral and from basolateral-to-apical sides. The in vitro experiments showed that Cortisol transport is concentration dependent and it is affected by several transporters (absorption and secretion processes). The results indicate that PUFA acids increase Cortisol transport in the BBB models but not through the inhibition of P-gp efflux but thanks to membrane fluidification and some effect on tight junction integrity.

Drug penetration across the blood-brain barrier: an overview.

The brain is one of the most protected organs in the body. There are two key barriers that control the access of endogenous substances and xenobiotics (drugs or toxins) to the CNS. These physiological structures are the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier. The BBB represents the main determinant of the effective delivery of drugs to the CNS. Good access through the BBB is essential if the target site is located within the CNS or, in contrast, can be a disadvantage if adverse reactions occur at central level. The development of new drugs targeted to the CNS requires a better knowledge of the factors affecting BBB permeation as well as in vitro and in silico predictive tools to optimize screening, and to reduce the attrition rate at later stages of drug development. This review discusses the particular characteristics of the biology and physiology of the BBB with respect to the permeation and distribution of drugs into the brain. The factors affecting rate, extent and distribution into the brain are discussed and a brief description of the in silico, in vitro, in situ and in vivo methods used to measure BBB transport are presented. Finally, the lastest proposals and strategies to enhance transport across the BBB of new CNS drugs are summarized.

Progress in the development of early diagnosis and a drug with unique pharmacology to improve cancer therapy.

Cancer continues to be one of the major health and socio-economic problems worldwide, despite considerable efforts to improve its early diagnosis and treatment. The identification of new constituents as biomarkers for early diagnosis of neoplastic cells and the discovery of new type of drugs with their mechanistic actions are crucial to improve cancer therapy. New drugs have entered the market, thanks to industrial and legislative efforts ensuring continuity of pharmaceutical development. New targets have been identified, but cancer therapy and the anti-cancer drug market still partly depend on anti-mitotic agents. The objective of this paper is to show the effects of KAR-2, a potent anti-mitotic compound, and TPPP/p25, a new unstructured protein, on the structural and functional characteristics of the microtubule system. Understanding the actions of these two potential effectors on the microtubule system could be the clue for early diagnosis and improvement of cancer therapy.

Biowaiver monographs for immediate release solid oral dosage forms: aciclovir.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing (biowaiver) for the approval of immediate release (IR) solid oral dosage forms containing aciclovir are reviewed. Aciclovir therapeutic use and therapeutic index, pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA) studies were also taken into consideration in order to ascertain whether a biowaiver can be recommended. According to the Biopharmaceutics Classification System (BCS) and considering tablet strengths up to 400 mg, aciclovir would be BCS Class III. However, in some countries also 800 mg tablets are available which fall just within BCS Class IV. Aciclovir seems not to be critical with respect to a risk for bioinequivalence, as no examples of bioinequivalence have been identified. It has a wide therapeutic index and is not used for critical indications. Hence, if: (a) the test product contains only excipients present in aciclovir solid oral IR drug products approved in ICH or associated countries, for instance as presented in this article; and (b) the comparator and the test product both are very rapidly dissolving, a biowaiver for IR aciclovir solid oral drug products is considered justified for all tablet strengths.

Poly(epsilon-caprolactone) microparticles formed by the emulsion-evaporation method: effect of the variables of the different steps of the process on their size.

In the present work the influence of the variables of the microencapsulation procedure on the size of poly (epsilon-caprolactone) microparticles (PECL-MP) obtained by the solvent evaporation method is analysed. This study will allow to choose the work conditions necessary to obtain a suitable PECL-MP size for parenteral administration. Agitation rate in the emulsion formation step, polymer concentration and organic/aqueous phase volume ratio were the variables of the microencapsulation procedure that showed a highest influence on the PECL-MP size. High polymer concentrations and low internal phase volumes had a negative effect on the microencapsulation yield. Neither the conditions of the organic solvent evaporation nor the freeze-dry process (when a cryoprotector as threalose was used) influenced on PECL-MP size. The usefulness of this study was confirmed by getting PECL-MP loaded with naloxone and with a mean diameter within 30-40 microm, suitable for parenteral administration.

Uso inadecuado de adrenalina en las reacciones de anafilaxia: a propósito de dos casos / Inappropriate epinephrine (adrenaline) use during anaphylactic reactions: a report of 2 cases

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[Prescription errors in patients admitted to an internal medicine department from the emergency room]. / Errores de prescripción en pacientes que ingresan en un servicio de medicina interna procedentes de urgencias.

OBJECTIVE: To identify and quantify emergency room prescription errors upon patient admission in an internal medicine unit, assess their severity and causes, and evaluate their potential clinical impact. METHOD: Discrepancies found between emergency room and internal medicine unit prescriptions were analyzed by 4th-year resident pharmacists. Prescription errors were collected and classified according to their severity and potential morbidity, and a medical analysis of service value was performed according to Overhage's method. Furthermore, pharmacist actions regarding therapeutic regimen optimization are described. RESULTS: Of 177 patients, 50 had prescription errors, for a total of 141 errors. Seven percent of prescriptions had an error. Mean errors per patient amounted to 0.8 (SD 1.51). Most commonly involved medications included anti-asthmatic and anti-infectious agents, and fluid therapy agents. On severity assessment 12.8% were considered severe, and 57.4% were considered significant. The main cause was omission of a needed therapy. Potential pharmacotherapeutic morbidity is related to adverse effects and cardiovascular disease. Medical assessment considered 12% very significant, and 52% significant. Pharmacist actions were directed towards effectiveness improvement in 57% of cases, and safety in 43.2% of cases. CONCLUSIONS: Emergency departments, as main entry points for patient admission to hospital, should be considered a priority in prescription quality improvement programs.