Seroma control in axillary lymphadenectomy with Glubran 2® without drain. Multicenter, prospective, randomized, clinical trial. GALA-ND study (Glubran, Axillary Lymphadenectomy, Ambulatory, No Drain).

BACKGROUND: Seroma after breast cancer surgery is a frequent entity; therefore, different products have been described in literature with the aim to reduce it. The most studied ones have been the sealants products, being tested with aspirative drains. Symptomatic seroma represents the 19% after axillary lymphadenectomy without drains. The aim of this study is to analyze the effect of a sealant in the seroma control after axillary lymphadenectomy without drains and identify the risk factors related to symptomatic seroma. METHODS: This is a prospective, multicenter, international, and randomized clinical trial. Patients undergoing conservative surgery and axillary lymphadenectomy for breast cancer will be randomized to control group (lymphadenectomy without sealant) or interventional group (lymphadenectomy with sealant Glubran 2®). In any of the study groups, drains are placed. Patients who received neoadjuvant treatment are included. Measurements of the study outcomes will take place at baseline; at 7, 14, and 30 days post-surgery; and at 6-12 months. The primary outcome is symptomatic seroma. Secondary outcomes are seroma volume, morbidity, quality of life, and lymphedema. DISCUSSION: Several studies compare the use of sealant products in axillary lymphadenectomy but generally with drains. We would like to demonstrate that patients who underwent axillary lymphadenectomy could benefit from an axillary sealant without drains and reduce axillary discomfort while maintaining a good quality of life. Assessing the relationship between axillary volume, symptoms, and related risk factors can be of great help in the control of seroma in patients who received breast cancer surgery. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05280353. Registration date 02 August 2022.

Development of Dipeptide N-acetyl-L-cysteine Loaded Nanostructured Carriers Based on Inorganic Layered Hydroxides.

N-acetyl-L-cysteine (NAC), a derivative of the L-cysteine amino acid, presents antioxidant and mucolytic properties of pharmaceutical interest. This work reports the preparation of organic-inorganic nanophases aiming for the development of drug delivery systems based on NAC intercalation into layered double hydroxides (LDH) of zinc-aluminum (Zn2Al-NAC) and magnesium-aluminum (Mg2Al-NAC) compositions. A detailed characterization of the synthesized hybrid materials was performed, including X-ray diffraction (XRD) and pair distribution function (PDF) analysis, infrared and Raman spectroscopies, solid-state 13carbon and 27aluminum nuclear magnetic resonance (NMR), simultaneous thermogravimetric and differential scanning calorimetry coupled to mass spectrometry (TG/DSC-MS), scanning electron microscopy (SEM), and elemental chemical analysis to assess both chemical composition and structure of the samples. The experimental conditions allowed to isolate Zn2Al-NAC nanomaterial with good crystallinity and a loading capacity of 27.3 (m/m)%. On the other hand, NAC intercalation was not successful into Mg2Al-LDH, being oxidized instead. In vitro drug delivery kinetic studies were performed using cylindrical tablets of Zn2Al-NAC in a simulated physiological solution (extracellular matrix) to investigate the release profile. After 96 h, the tablet was analyzed by micro-Raman spectroscopy. NAC was replaced by anions such as hydrogen phosphate by a slow diffusion-controlled ion exchange process. Zn2Al-NAC fulfil basic requirements to be employed as a drug delivery system with a defined microscopic structure, appreciable loading capacity, and allowing a controlled release of NAC.

Impact of ferulic acid and resveratrol on the effectiveness and safety of sunscreen

Abstract The combination of avobenzone (AVO) and octyl ρ-methoxycinnamate (OMC) is widely used to ensure broad-spectrum photo-protection because they absorb UVA and UVB, respectively. However, they are thermally and photo unstable because they degrade and undergo photo- tautomerization and trans-cis isomerization, thus reducing their photo-protection efficacy during UV exposure. This study aimed to evaluate the potential use of the antioxidants ferulic acid and resveratrol as stabilizing substances in AVO and OMC mixtures in solution or emulsion. The effects of both antioxidants on the thermal/photo-stability and suppression of the filter singlet state, besides skin permeation, were evaluated. Both antioxidants contributed to preserving OMC and AVO during the thermal stability test, which relates to the maintenance of photo-protection even after storing the formulations at high temperatures. Nevertheless, although resveratrol retained part of the OMC trans isomer and suppressed the AVO singlet state when exposed to UV, no contribution to photo-protection stability was observed, contrary to expectations. Regarding the permeation assay, the addition of both antioxidants was accompanied by a reduction of AVO permeation, while resveratrol increased OMC permeation. Thus, the chemical and physicochemical properties of these antioxidants impacted their efficacy and safety profiles; therefore, further studies are required to establish the real cost-benefit ratio for their use in sunscreens.

LESS-PHARMA Study: Identifying and Deprescribing Potentially Inappropriate Medication in the Elderly Population with Excessive Polypharmacy in Primary Care.

Potentially inappropriate medication (PIM) increases adverse drug reactions and mortality, especially in excessively polymedicated patients. General practitioners are often in charge of this process. Some tools have been created to support them in this matter. This study aimed to measure the amount of potentially inappropriate medication among excessively polymedicated patients using several supporting tools and assess the feasibility of these tools in primary care. Several explicit deprescribing criteria were used to identify potentially inappropriate medications. The level of agreement between all the criteria and the acceptance by the general practitioner (GP) was also measured. We analysed whether the drugs proposed for deprescribing were eventually withdrawn after twelve months. The total number of drugs prescribed was 2038. Six hundred and forty-nine drugs (31.8%) were considered potentially inappropriate by at least one of the tools. GPs agreed with the tools in 56.7% of the cases. In a 12-month period, 109 drugs, representing 29.6% of the drugs that GPs agreed to deprescribe, were withdrawn. Elderly excessively polymedicated patients accumulated a great number of PIMs. The use of deprescribing supporting tools, such as explicit criteria, is feasible in primary care, and these tools are well accepted by the GPs. However, eventual withdrawal was carried out in less than half of the cases.

PAMAM Dendrimers: A Review of Methodologies Employed in Biopharmaceutical Classification.

The oral route is the preferred way of drug administration for most drugs, whose treatment success is directly related to the compound intestinal absorption. This absorption process, in its turn, is influenced by several factors impacting the drug bioavailability, which is extremely dependent on the maximum solubility and permeability. However, optimizing these last two factors, without chemical structural modification, is challenging. Although poly(amidoamine) dendrimers (PAMAM) are an innovative and promising strategy as drug delivery compounds, there are few studies that determine the permeability and solubility of PAMAM-drugs derivatives. Considering this scenario, this paper aimed to carry out a literature review of the last five years concerning biopharmaceutical characterizations of dendrimer delivery systems. In vitro methodologies, such as the Parallel artificial membrane permeability assay (PAMPA) (non-cellular based model) and Caco-2 cells (cellular based model), used for the permeability evaluation in the early stages of drug discovery proved to be the most promising methodologies. As a result, we discussed, for instance, that through the usage of PAMPA it was possible to evaluate the higher capacity for transdermal delivery of DNA of TAT-conjugated PAMAM, when in comparison with unmodified PAMAM dendrimer with a P<0.05. We also presented the importance of choosing the best methods of biopharmaceutical characterization, which will be essential to guarantee the efficacy and safety of the drug candidate.

Young woman diagnosed with paraganglioma in primary care.

A 15-year-old young woman was referred to the emergency room for admission by her general practitioner after receiving the results of urinary metanephrines and catecholamines requested to study the tachycardia, sweating and headaches that she had been presenting progressively last year. Imaging tests showed a large right supraumbilical para-aortic paraganglioma that was successfully removed with surgery after previous medical preparation with adrenergic blockers. Genetic testing showed a heterozygous mutation of the gene succinate dehydrogenase-B. The classic triad of symptoms in these disorders consists of headaches, sweating and tachycardia, usually accompanied by hypertension. We wanted to present this case, a challenging diagnosis of paraganglioma in primary care.

Changes in Fatty Acid Dietary Profile Affect the Brain-Gut Axis Functions of Healthy Young Adult Rats in a Sex-Dependent Manner.

Dietary modifications, including those affecting dietary fat and its fatty acid (FA) composition, may be involved in the development of brain-gut axis disorders, with different manifestations in males and females. Our aim was to evaluate the impact of three purified diets with different FA composition on the brain-gut axis in rats of both sexes. Male and female Wistar rats fed a cereal-based standard diet from weaning were used. At young adult age (2-3 months old), animals were divided into three groups and treated each with a different refined diet for 6 weeks: a control group fed on AIN-93G diet containing 7% soy oil (SOY), and two groups fed on AIN-93G modified diets with 3.5% soy oil replaced by 3.5% coconut oil (COCO) or 3.5% evening primrose oil (EP). Different brain-gut axis parameters were evaluated during 4-6 weeks of dietary intervention. Compared with SOY diet (14% saturated FAs, and 58% polyunsaturated FAs), COCO diet (52.2% saturated FAs and 30% polyunsaturated FAs) produced no changes in brain functions and minor gastrointestinal modifications, whereas EP diet (11.1% saturated FAs and 70.56% polyunsaturated FAs) tended to decrease self-care behavior and colonic propulsion in males, and significantly increased exploratory behavior, accelerated gastrointestinal transit, and decreased cecum and fecal pellet density in females. Changes in FA composition, particularly an increase in ω-6 polyunsaturated FAs, seem to facilitate the development of brain-gut axis alterations in a sex-dependent manner, with a relatively higher risk in females.

Development and validation of RP-HPLC method for simultaneous determination of lamivudine, stavudine, and zidovudine in perfusate samples: Application to the Single-Pass Intestinal Perfusion (SPIP) studies

A reversed-phase high performance liquid chromatography (RP-HPLC) method with ultraviolet detection was developed and validated for the simultaneous quantification of antiretroviral drugs lamivudine (3TC), stavudine (d4T), and zidovudine (AZT) in perfusate samples obtained from the Single-Pass Intestinal Perfusion studies. The chromatographic analysis was performed using a Gemini C18 column and didanosine as internal standard (IS). The following parameters were considered for the validation procedure: system suitability, accuracy, precision, linearity and selectivity. The limits of detection were 0.32 µg/mL for 3TC, 0.11 µg/mL for d4T and 0.45 µg/mL for AZT and the limits of quantification were 1.06 µg/mL for 3TC, 0.38 µg/mL for d4T and 1.51 µg/mL for AZT. Repeatability and intermediate precision ranged from 1.05 to 1.31 and 1.50 to 1.87, respectively, and are expressed as percent of relative standard deviation (RSD). Based on these results, the developed and validated RP-HPLC method can be used for simultaneous determination of 3TC, d4T, and AZT in perfusate samples. Furthermore, this method is simple and adequate for measurements of the antiretroviral drugs in the same sample, since those compounds are mostly co-administered. Besides, this work can be used as an initial base for the development of similar methods in the same conditions presented in our study.

In silico and in vitro prediction of gastrointestinal absorption from potential drug eremantholide C.

OBJECTIVES: Analysis of the biopharmaceutical properties of eremantholide C, sesquiterpene lactone with proven pharmacological activity and low toxicity, is required to evaluate its potential to become a drug. METHODS: Preliminary analysis of the physicochemical characteristics of eremantholide C was performed in silico. Equilibrium solubility was evaluated using the shake-flask method, at 37.0 °C, 100 rpm during 72 h in biorelevant media. The permeability was analysed using parallel artificial membrane permeability assay, at 37.0 °C, 50 rpm for 5 h. The donor compartment was composed of an eremantholide C solution in intestinal fluid simulated without enzymes, while the acceptor compartment consisted of phosphate buffer. KEY FINDINGS: Physicochemical characteristics predicted in silico indicated that eremantholide C has a low solubility and high permeability. In-vitro data of eremantholide C showed low solubility, with values for the dose/solubility ratio (ml): 9448.82, 10 389.61 e 15 000.00 for buffers acetate (pH 4.5), intestinal fluid simulated without enzymes (pH 6.8) and phosphate (pH 7.4), respectively. Also, it showed high permeability, with effective permeability of 30.4 × 10-6 cm/s, a higher result compared with propranolol hydrochloride (9.23 × 10-6 cm/s). CONCLUSIONS: The high permeability combined with its solubility, pharmacological activity and low toxicity demonstrate the importance of eremantholide C as a potential drug candidate.

In Situ Intestinal Perfusion in Rodents: Future Perspectives for Application on Absorption Studies and Classification of Drugs.

BACKGROUND: In 1995, the Biopharmaceutics Classification System (BCS) was proposed by Amidon and colleagues as a tool that considers two important parameters regarding drugs: solubility and permeability. Since then, several methods for solubility and permeability studies have been developed for drug delivery and absorption prediction. In recent years, permeability has gained a great highlight and the interaction between a molecule and a biological membrane is not enough to predict the in vivo behavior of a compound. METHOD: Thus, different methods for permeability assessment are currently used for mechanistic studies including involvement of carriers and several transport pathways. Furthermore, the investigation regarding metabolism has been a focus in recent researches. Based on this idea, Wu and Benet proposed a new tool called Biopharmaceutics Drug Disposition Classification System (BDDCS), where drugs are classified into four classes considering their solubility and metabolism. RESULTS: Among several methods for permeability studies, the in situ intestinal perfusion is considered the closest to in vivo conditions due advantages as intact blood supply and innervation. CONCLUSION: This review presents the in situ intestinal perfusion model and its application for permeability/ transport studies of drugs and intestinal metabolism. Also, this paper discusses about how the in situ perfusion studies can be used for classification of drugs and the future perspectives for in vivo absorption prediction.

Solubility evaluation of didanosine: a comparison between the equilibrium method and intrinsic dissolution for biopharmaceutics classification purposes

ABSTRACT BCS (Biopharmaceutics Classification System) and BDDCS (Biopharmaceutics Drug Disposition Classification System) were proposed as tools for classifying drugs into four categories. Both systems consider the solubility as an important characteristic for the classification of compounds in drug development and in vivo disposition prediction. Although some results of drug solubility can be found in the literature, the aforementioned characteristic is not entirely clear when considering didanosine (ddI). Based on that, the solubility of ddI was evaluated using equilibrium and intrinsic dissolution methods. For the equilibrium method, excess amount of ddI was added to each media until obtaining a supersaturated solution and the mixture was submitted to agitation at 37 °C. For the intrinsic dissolution method, the drug was compressed into the Wood's apparatus matrix and subjected to dissolution in each media with agitation at 37 °C. The results obtained from the equilibrium method indicated that it was necessary 139.37 mL of pH 1.2 media, 87.72 mL of pH 4.5 media, 12.54 mL of pH 6.8 media, 5.03 mL of pH 7.5 media and 7.65 mL of purified water for drug solubilization. Furthermore, a very fast intrinsic dissolution rate (IDR) was obtained for each media: 0.1 mg/min/cm² (pH 1.2), 0.2 mg/min/cm² (pH 4.5), 0.2 mg/min/cm² (pH 6.8), 0.1 mg/min/cm² (pH 7.5) and 0.1 mg/min/cm² (purified water). Based on these results, ddI can be considered as a highly soluble drug for both equilibrium and intrinsic dissolution methods.

Single-Pass Intestinal Perfusion (SPIP) and prediction of fraction absorbed and permeability in humans: A study with antiretroviral drugs.

In recent years, the prediction of oral drug absorption in humans has been a challenge for researchers and many techniques for permeability studies have been developed for several purposes, including biowaiver processes. The Single-Pass Intestinal Perfusion (SPIP) method performed in rats can provide permeability results closest to in vivo condition. The purpose of the present study was to evaluate the intestinal permeability of the antiretroviral drugs lamivudine, stavudine and zidovudine using the SPIP method in rats and to predict their permeability (Peff,humans) and fraction absorbed (Fa) in humans. Metoprolol and fluorescein were used as marker compounds of high and low permeability, respectively. The effective permeability (Peff) results showed that stavudine and zidovudine have high permeability characteristics while lamivudine presented the lowest result. From Peff values obtained in rats, the Peff,humans and Fa were calculated. The use of SPIP in rats and calculations for absorption prediction in humans may indicate the transport mechanisms and/or pre-systemic metabolism involved on permeation processes of drugs, since this model is the closest to in vivo conditions.

Dissolution efficiency and bioequivalence study using urine data from healthy volunteers: a comparison between two tablet formulations of cephalexin / Eficiência de dissolução e estudo de bioequivalência utilizando dados de urina de voluntários saudáveis: uma comparação entre duas formulações de comprimidos de cefalexina

The aim of the present study was to assess the bioequivalence of two cephalexin tablet formulations available in the Brazilian market (product A as reference formulation and product B as test formulation). Dissolution efficiency (DE%) was calculated for both formulations to evaluate their in vitrobiopharmaceutical features. The oral bioequivalence study was performed in twenty-four healthy volunteers in a crossover design. Single oral dose (tablet containing 500 mg of cephalexin) of each product was administered with two weeks of washout period. Urinary concentrations of cephalexin were measured by high-performance liquid chromatography (HPLC) method and pharmacokinetics parameters were estimated by urinary excretion data. The bioequivalence was determined by the following parameters: the cumulative amount of cephalexin excreted in the urine, the total amount of cephalexin excreted in the urine and the maximum urinary excretion rate of cephalexin. DE values of immediate-release cephalexin tablets (500 mg) were 68.69±4.18% for product A and 71.03±6.63% for product B. Regarding the dissolution test of the two brands (A and B) analysed, both were in compliance with the official pharmacopeial specifications, since the dissolution of both formulations was superior to 80% of the amount declared in the label after 45 minutes of test (A=92.09%±1.84; B=92.84%±1.08). The results obtained indicated that the products A and B are pharmaceutical equivalents. Confidence intervals for the pharmacokinetic parameters were in compliance with the international standards, indicating that products A and B can be considered bioequivalents and, therefore, interchangeable...

O objetivo do presente estudo foi avaliar a bioequivalência de duas formulações de cefalexina disponíveis no mercado brasileiro (produto A como formulação referência e produto B como formulação teste). A eficiência de dissolução (DE%) foi calculada para ambas as formulações para avaliar suas características biofarmacêuticas. O estudo de bioequivalência oral foi realizado em vinte e quatro voluntários sadios utilizando um desenho cruzado. Uma dose oral única (comprimido contendo 500 mg de cefalexina) de cada produto foi administrada com um período de washout de duas semanas. Concentrações urinárias de cefalexina foram mensuradas por método de cromatografia líquida de alta eficiência (CLAE) e os parâmetros farmacocinéticos foram estimados por dados de excreção urinária. A bioequivalência foi determinada pelos seguintes parâmetros: quantidade acumulada da cefalexina excretada na urina, quantidade total da cefalexina excretada na urina e a taxa de excreção máxima da cefalexina. Os valores de DE dos comprimidos de liberação imediata de cefalexina (500 mg) foram 68,69±4,18% para o produto A e de 71,03±6,63% para o produto B. Com relação ao teste de dissolução das duas marcas analisadas (A e B), ambas apresentaram-se de acordo com as especificações farmacopéicas, uma vez que a dissolução de ambas formulações foi superior a 80% da quantidade declarada após 45 minutos de teste (A=92,09%±1,84; B=92,84% ±1,08). Os resultados obtidos indicaram que os produtos A e B são equivalentes farmacêuticos. Os intervalos de confiança para os parâmetros farmacocinéticos estavam de acordo com os padrões internacionais, demonstrando que os produtos A e B podem ser considerados bioequivalentes e, portanto, intercambiáveis...

Evaluating Potential P-gp Substrates: Main Aspects to Choose the Adequate Permeability Model for Assessing Gastrointestinal Drug Absorption.

The success of an oral drug route administration depends on many factors that interfere in its bioavailability, therapeutic efficacy and clinical safety. In human cells, ATP-dependent efflux transporter proteins, such as P-glycoprotein (P-gp), BCRP and MRP2, reduce the absorption of drugs. A tiered approach chosen to evaluate drugs as substrates or inhibitors of efflux pumps, particularly P-gp, should be carefully selected, since each study method has advantages and intrinsic limitations to their processes. Depending on the adopted study conditions, the results may not correspond to the real characteristics of the drug regarding to its modulation by specific efflux proteins. This mini-review aims at summarizing the role of P-gp in the drugs oral absorption and correlating some of the most used permeability methods to determine the drug condition as P-gp substrate. Studies about P-gp have shown that it is a dynamic protein, facilitating secretion of endogenous compounds, as aldosterone, and protecting cells against xenobiotics. Different efflux assays are employed to evaluate drugs as P-gp substrates. In an initial planning, MDCK-MDR1 tend to be the chosen method for efflux studies due its ability of express P-gp, followed by studies conducted in Caco-2 models. However, it is necessary to evaluate the advantages and disadvantages of each method to generate sound results and to set the correlation in vitro x in situ x in vivo.

Cognitive-motor intervention in Alzheimer's disease: long-term results from the Maria Wolff trial.

BACKGROUND: Little is known about the long-term acceptance and effects of cognitive and motor stimulation interventions (CMSI) in Alzheimer's disease (AD). OBJECTIVE: To evaluate a replicable CMSI program for mild cognitive impairment (MCI) and mild-to-moderate AD persons. METHODS: Eighty-four non-institutionalized subjects with AD were randomized to receive either CMSI, administered by a single care provider, or standard support. Cognition, activities of daily living (ADL), mood, and study partner's subjective burden were assessed by blinded raters. Data on institutionalization, psychiatric medications, and demise were collected by the study physicians. Random effects model and survival analyses were conducted, after 2 and 3 years of study. RESULTS: Three-year assessments could be performed by the physician in 85% and by the blinded rater in 66% of subjects. Significant benefits were observed in basic ADL at the 2- and 3-year assessments, whereas instrumental ADL showed benefits only up to the second year of intervention (p < 0.05). CONCLUSION: Long-term cognitive-motor stimulation is well accepted and produces functional benefits in subjects with AD, with no extra subjective burden in the partner.

Average bioequivalence of single 500 mg doses of two oral formulations of levofloxacin: a randomized, open-label, two-period crossover study in healthy adult Brazilian volunteers

Average bioequivalence of two 500 mg levofloxacin formulations available in Brazil, Tavanic(c) (Sanofi-Aventis Farmacêutica Ltda, Brazil, reference product) and Levaquin(c) (Janssen-Cilag Farmacêutica Ltda, Brazil, test product) was evaluated by means of a randomized, open-label, 2-way crossover study performed in 26 healthy Brazilian volunteers under fasting conditions. A single dose of 500 mg levofloxacin tablets was orally administered, and blood samples were collected over a period of 48 hours. Levofloxacin plasmatic concentrations were determined using a validated HPLC method. Pharmacokinetic parameters Cmax, Tmax, Kel, T1/2el, AUC0-t and AUC0-inf were calculated using noncompartmental analysis. Bioequivalence was determined by calculating 90% confidence intervals (90% CI) for the ratio of Cmax, AUC0-t and AUC0-inf values for test and reference products, using logarithmic transformed data. Tolerability was assessed by monitoring vital signs and laboratory analysis results, by subject interviews and by spontaneous report of adverse events. 90% CIs for Cmax, AUC0-t and AUC0-inf were 92.1% - 108.2%, 90.7% - 98.0%, and 94.8% - 100.0%, respectively. Observed adverse events were nausea and headache. It was concluded that Tavanic(c) and Levaquin(c) are bioequivalent, since 90% CIs are within the 80% - 125% interval proposed by regulatory agencies.

A bioequivalência média de duas formulações de levofloxacino disponíveis no Brasil, Tavanic(c) (Sanofi-Aventis Farmacêutica Ltda, Brasil, produto referência) e Levaquin(c) (Janssen-Cilag Farmacêutica Ltda, Brasil, produto teste) foi determinada por meio da realização de ensaio aleatório, aberto, cruzado, com dois períodos e duas sequências, em 26 voluntários sadios em condições de jejum. Amostras de sangue dos voluntários foram obtidas ao longo de um período de 48 horas após administração de dose única de 500 mg de levofloxacino. As concentrações plasmáticas do fármaco foram determinadas por método cromatográfico validado. Os parâmetros farmacocinéticos Cmax, Tmax, Kel, T1/2el, AUC0-t e AUC0-inf foram calculados por análise não compartimental. A bioequivalência foi determinada pelo cálculo de intervalos de confiança 90% (IC 90%) para as razões entre os valores de Cmax, AUC0-t e AUC0-inf obtidos para os produtos teste e referência, usando dados transformados logaritmicamente. A tolerabilidade foi avaliada pelo acompanhamento dos sinais vitais e resultados de exames laboratoriais, por consultas e por relato espontâneo dos voluntários. ICs 90% para Cmax, AUC0-t e AUC0-inf foram 92.1% - 108.2%, 90.7% - 98.0%, e 94.8% - 100.0%, respectivamente. Os eventos adversos observados foram náusea e cefaleia. Concluiu-se que os produtos Tavanic(c) e Levaquin(c) são bioequivalentes, uma vez que os ICs 90% estão dentro da faixa de 80%-125% proposta pelas agências reguladoras.

Efficacy and safety of aclidinium bromide/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomised study.

BACKGROUND: Aclidinium/formoterol is a twice-daily (BID) fixed-dose combination (FDC) in development for chronic obstructive pulmonary disease (COPD). The efficacy and safety of aclidinium/formoterol versus monotherapy and placebo in patients with COPD was assessed. METHODS: In this 24-week double-blind, parallel-group, active- and placebo-controlled, multicentre Phase III study, patients (≥40 years, post-bronchodilator forced expiratory volume in 1 second [FEV1]/forced vital capacity <70% and FEV1 ≥30% but <80% predicted normal) were randomised 2:2:2:2:1 to aclidinium/formoterol 400/12 µg (n = 385) or 400/6 µg (n = 381), aclidinium 400 µg (n = 385), formoterol 12 µg (n = 384) or placebo (n = 194) BID via Genuair®/Pressair®a. RESULTS: At Week 24, aclidinium/formoterol 400/12 µg and 400/6 µg lead to significant improvements from baseline in 1-hour post-dose FEV1 versus aclidinium (125 mL [95% CI: 90, 160; p < 0 · 001] and 69 mL [95% CI: 34, 105; p < 0.001], respectively) and trough FEV1 versus formoterol (85 mL [95% CI: 51, 119; p < 0.001] and 53 mL [95% CI: 19, 87; p < 0.01], respectively; co-primary endpoints). Additionally, aclidinium/formoterol 400/12 µg and 400/6 µg provided significant improvements in Transition Dyspnoea Index (TDI) focal score versus placebo (1.29 units [95% CI: 0.73, 1.86; p < 0.001] and 1.16 units [95% CI: 0.59, 1.73; p < 0.001], respectively; secondary endpoint). All treatments were well tolerated, with safety profiles of the FDCs similar to those of placebo and monotherapy. CONCLUSIONS: Both aclidinium/formoterol BID doses significantly improved bronchodilation versus monotherapy, and dyspnoea versus placebo, with no increase in safety risk. Aclidinium/formoterol may be an effective treatment for patients with COPD. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01462942.