RESUMO

Lopinavir/ritonavir is a potent coformulation of protease inhibitors used against HIV infection. Lopinavir is the main responsible for viral load suppression, whereas ritonavir is a pharmacokinetic enhancer. Both of them have recently gained relevance as candidate drugs against severe coronavirus disease (COVID-19). However, significant beneficial effects were not observed in randomized clinical trials. This review summarizes the main physical-chemical, pharmacodynamic, and pharmacokinetic properties of ritonavir and lopinavir, along with the analytical methodologies applied for biological matrices, pharmaceutical formulations, and stability studies. The work also aimed to provide a comprehensive impurity profile for the combined formulation. Several analytical methods in four different pharmacopeias and 37 articles in literature were evaluated and summarized. Chromatographic methods for these drugs frequently use C8 or C18 stationary phases with acetonitrile and phosphate buffer (with ultraviolet detection) or acetate buffer (with tandem mass spectrometry detection) as the mobile phase. Official compendia methods show disadvantages as extended total run time and complex mobile phases. HPLC tandem-mass spectrometry provided high sensitivity in methodologies applied for human plasma and serum samples, supporting the therapeutic drug monitoring in HIV patients. Ritonavir and lopinavir major degradation products arise in alkaline and acidic environments, respectively. Other non-chromatographic methods were also summarized. Establishing the impurity profile for the combined formulation is challenging due to a large number of impurities reported. Easier and faster analytical methods for impurity assessment are still needed.

Assuntos

RESUMO

Ezetimibe (EZM) is a selective inhibitor of the sterol transporter Niemann-Pick C1-Like 1 in the small intestine used as an adjunctive therapy to lower cholesterol levels in cases of hyperlipidemia. The goal of this work was to summarize the main physical-chemical, pharmacological and pharmacokinetic characteristics of EZM, as well as to describe the main analytical methodologies for the quantification of the drug. Methods described in the United States Pharmacopeia for EZM raw material and tablets were also presented. The drug has a large number of process-related impurities and degradation products and needs strict quality control of its impurities. Specific chiral methods for the evaluation of its chiral impurities are also a need for EZM. The main advantages and disadvantages of the compiled analytical methods were presented, as well as the limits of detection and quantitation. The fastest and most efficient methods were highlighted. Most methods for analyzing EZM used C8 or C18 stationary phases in gradient mode with binary mobile phases containing acetonitrile and an acidic buffer solution with ultraviolet detection. For analysis of EZM in biological matrices, liquid chromatography-tandem mass spectrometry is generally employed using electron spray ionization in negative ionization mode using multiple reaction monitoring. Different methods in the literature evaluate a large number of impurities for EZM, however new stability-indicating high-performance liquid chromatography methods for the drug are still needed.

Assuntos

RESUMO

Patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may present a significant hypoxemia. The exactly mechanism of such hypoxemia in patients with coronavirus disease 2019 (COVID-19) is not well described. It has been suggested that microthrombosis contributes to this mechanism, increasing pulmonary dead space. However, dead spaces would not be sensible to oxygen supplementation, and also, enlargement of pulmonary vessels it has been evidenced. Shunt mechanism by vasodilatation, instead, could explain decubitus dependence in oxygenation by blood redistribution as observed in these patients, and moreover, would be more sensible to oxygen supplementation than dead spaces. We hypothesized that SARS-CoV-2 causes an intrapulmonary vascular dilatation (IPVD), determining a shunt mechanism by vasodilatation. We performed contrast-enhanced transthoracic echocardiography to search IPVD shunt in patients with confirmed COVID-19, hospitalized in an intensive care unit. Ten patients were recruited; one patient was excluded due to low quality of echocardiographic image, and nine patients were included. IPVD was found in seven (78%) patients, with different grades, including patient with normal compliance and the one without invasive ventilation. We demonstrated that shunt by IPVD is present among patients with COVID-19, and this mechanism is probably implicated in significant hypoxemia observed.

Assuntos

RESUMO

BACKGROUND: Rotigotine is a dopaminergic agonist developed for the treatment of Parkinson's disease and restless leg syndrome. The pure levorotatory enantiomer is marketed in several countries as a transdermal patch. Reports of oxidation and instability in a previous formulation indicate the need to evaluate impurities in both the raw material and pharmaceutical dosage forms of rotigotine to ensure product quality. OBJECTIVE: This review examines the main analytical methods for analyzing rotigotine in raw material and its transdermal patches with the aim of assisting the development of new pharmaceutical formulations and stability studies. METHODS: Analytical methods based on high-performance liquid chromatography for rotigotine from pharmacopoeias and literature were evaluated. A comparison was made between the methods found in the literature and official rotigotine monographs described by the United States, European, and British Pharmacopoeias, including a discussion of their acceptance limits for impurities related to the drug. The different impurities from the synthesis processes and degradation studies of rotigotine were also evaluated, as well as the main articles that describe methods for assessing their chiral purity. RESULTS: Qualified and unofficial official impurities found in forced degradation studies were verified. The methods presented show adequate specificity and selectivity in determining the drug in the presence of its impurities. CONCLUSIONS: The approached methods are promising, but more detailed studies on the stability of rotigotine are still lacking, mainly in the pharmacokinetic and toxicological characterization of its impurities.

Assuntos

RESUMO

Injectable solutions containing epinephrine (EPI) and norepinephrine (NE) are not stable, and their degradation is favored mainly by the oxidation of catechol moiety. As studies of these drugs under forced degradation conditions are scarce, herein, we report the identification of their degradation products (DP) in anesthetic formulations by the development of stability-indicating HPLC method. Finally, the risk assessment of the major degradation products was evaluated using in silico toxicity approach. HPLC method was developed to obtain a higher selectivity allowing adequate elution for both drugs and their DPs. The optimized conditions were developed using a C18 HPLC column, sodium 1-octanesulfonate, and methanol (80:20, v/v) as mobile phase, with a flow rate of 1.5 mL/min, UV detection at 199 nm. The analysis of standard solutions with these modifications resulted in greater retention time for EPI and NE, which allow the separation of these drugs from their respective DPs. Then, five DPs were identified and analyzed by in silico studies. Most of the DPs showed important alerts as hepatotoxicity and mutagenicity. To the best of our acknowledgment, this is the first report of a stability-indicating HPLC method that can be used with formulations containing catecholamines.

Assuntos

RESUMO

RATIONALE: The chromatographic analysis of topiramate and its degradation products is challenging due to the absence of chromophoric moieties in their structures, the wide polarity range of the compounds and their ionization differences. This work proposes two new mass spectrometry approaches for evaluating these analytes. METHODS: Based on the calculated experimental limit of detection (LOD), a highly sensitive high-performance liquid chromatography (HPLC) paired-ion electrospray ionization mass spectrometry (PIESI-MS) method was developed for the determination of topiramate inorganic degradation products. The influence of different solvent systems on the LODs for topiramate and its main degradation products was determined in both positive/negative ionization modes. In addition, a HPLC method to analyze both organic and inorganic degradation products was proposed by mass spectrometry with positive/negative ion switching electrospray ionization. RESULTS: A sensitive HPLC/PIESI-MS method was achieved for the efficient separation of topiramate inorganic degradation products. Both sulfate and sulfamate were detected in the positive selected ion monitoring (SIM) mode with an increased sensitivity compared with the negative SIM mode. The HPLC/ESI-MS analysis with positive/negative ion switching allowed the simultaneous separation and detection of the major degradation products of topiramate in a 10-min run using a single column and a single detector. CONCLUSIONS: Two new alternative MS approaches for analyzing the main degradation products of topiramate were developed. The proposed methods are considered advantageous over the existing methods and can be applied to quality control studies of topiramate.

Assuntos

RESUMO

The analysis of topiramate in the presence of its main degradation products is challenging due to the absence of chromophore moieties and their wide range of polarity. Mixed-mode chromatography has been used in such cases because it combines two or more modes of separation. Charged aerosol detector is also an alternative since its detection is independent of optical properties and analyte ionization. This study is aimed to develop and validate two new stability-indicating methods by high-performance liquid chromatography for the main degradation products of topiramate using mixed-mode chromatography and a charged aerosol detector. Method 1 employed an Acclaim Trinity P1® column (3.0 mm × 150 mm, 2.7 µm) with a mobile phase comprising of 80% ammonium acetate buffer (20 mM, pH 4.0) and 20% methanol at a flow rate of 0.5 mL/min at 35°C. Method 2 utilized a C18 Acclaim 120® column (4.6 mm × 250 mm; 5 µm) with ACN/water (50:50) at a flow rate of 0.6 mL/min at 50°C. Validation of the two methods demonstrated excellent performance with respect to linearity, precision, accuracy, and selectivity. The limits of detection for topiramate, fructose, sulfate, sulfamate, and compound A were 2.97, 12.08, 4.02, 13.91, and 3.94 µg/mL, respectively.

Assuntos

RESUMO

BACKGROUND: Ventilation with low tidal volume (VT) is well recognized as a protective approach to patients with acute respiratory distress syndrome (ARDS), but the optimal level of positive end-expiratory pressure (PEEP) remains uncertain. This study aims to evaluate two protective ventilatory strategies sequentially applied in patients with early ARDS. METHODS: In this prospective cohort study, fifteen patients were ventilated during 24 h with positive end-expiratory pressure (PEEP) adjusted according to the ARDSnet low-PEEP table (ARDSnet-24 h). During the next 24 h, nine patients with PaO2/FIO2 ratio below 350 mmHg were ventilated with PEEP titrated according to the Open Lung Concept protocol (ARDSnet + OLC). In the other six patients, regardless of their PaO2/FIO2 ratio, the ARDSnet remained for a further 24 h (ARDSnet-48 h). Ventilatory variables, arterial blood-gas and cytokine were obtained at baseline, 24 and 48 h. Additionally, whole-lung-computed tomography was acquired at 24 and 48 h. RESULTS: A sustained improvement in PaO2/FIO2 ratio (P = 0.008) with a decrease in collapsed regions (P = 0.008) was observed in the ARDSnet + OLC group compared with the ARDSnet-24 h group. A reduction in IL-6 in plasma (P < 0.02) was observed throughout the protocol in the ARDSnet + OLC group. Compared with the ARDSnet-48 h group, the ARDSnet + OLC presented smaller amounts of collapsed areas (P = 0.018) without significant differences in hyperinflated regions and in driving and plateau pressures. CONCLUSIONS: In this set of patients with early ARDS, mechanical ventilation with an individually tailored PEEP sustained improved pulmonary function with better aeration, without significant increase in hyperinflated areas". TRIAL REGISTRATION: Brazilian Clinical Trials Registry (ReBec). RBR-5zm9pr. 04th November 2015.

Assuntos

RESUMO

Topiramate is an anticonvulsant drug and it has been used worldwide for a wide range of applications. It is mainly indicated for the treatment of partial and generalized seizures, including Lennox Gastant Syndrome and generalized tonic-clonic seizures, and prophylactic treatment of migraine. Different analytical approaches by high-performance liquid chromatography have been described to analyze topiramate because of its lack of chromophore groups, including derivatization with UV-absorbing moieties, derivatization with fluorescent moieties, refractive index detection, conductivity detection, chemiluminescent nitrogen detection, evaporative light scattering detection and MS detection. In addition, some methods for determination of topiramate by capillary electrophoresis have been published as well as by gas chromatography. Thus, it is beneficial to evaluate and compare these papers before selecting the most suitable method/detector to analyze this drug. This systematic review provides a description of the main analytical methods available for the analysis of topiramate in biological matrices. Each of these methods is briefly discussed considering the detector used with HPLC. HPLC coupled with MS is the main technique used for topiramate analysis in biological matrices, mainly in the electrospray ionization-negative mode.

Assuntos

RESUMO

The aim of the present work was to use GastroPlus™ software for the prediction of pharmacokinetic profiles and in vitro-in vivo correlation (IVIVC) as tools to optimize the development of new generic medications. GastroPlus™ was used to simulate the gastrointestinal compartment and was based on the advanced compartmental absorption and transit model. Powder dissolution and efavirenz tablet dissolution studies were carried out to generate data from which correlation was established. The simulated plasma profile, based on the physicochemical properties of efavirenz, was almost identical to that observed in vivo for biobatches A and B. A level A IVIVC was established for the dissolution method obtained for the generic candidate using the Wagner-Nelson (r (2) = 0.85) and for Loo-Riegelman models (r(2) = 0.92). The percentage of fraction absorbed indicated that 0.5% sodium lauryl sulfate may be considered a biorelevant dissolution medium for efavirenz tablets. The simulation of gastrointestinal bioavailability and IVIVC obtained from immediate-release tablet formulations suggests that GastroPlus™ is a valuable in silico method for IVIVC and for studies directed at developing formulations of class II drugs.

Assuntos

Assuntos

Assuntos

RESUMO

The purpose of this study was to propose an analytical procedure that provides the effects of particle size and surface area on dissolution of efavirenz. Five different batches obtained by different micronization processes and with different particle size distribution and surface area were studied. The preformulation studies and dissolution curves were used to confirm the particle size distribution effect on drug solubility. No polymorphic variety or amorphization was observed in the tested batches and the particle size distribution was determined as directly responsible for the improvement of drug dissolution. The influence of the preparation process on the tablets derived from efavirenz was observed in the final dissolution result in which agglomeration, usually seen in non-lipophilic micronized material, was avoided through the use of an appropriate wet granulation method. For these reasons, micronization may represent one viable alternative for the formulation of brick dust drugs.