Leila Bastos Leal

Reversed phase HPLC determination of tamoxifen in dog plasma and its pharmaco-kinetics after a single oral dose administration

The analytical method developed to evaluate tamoxifen in dog plasma samples was precise, accurate, robust and linear in the range of 5–200 ng/mL. The limits of detection and quantification were 0.981 ng/mL and 2.97 ng/mL, respectively. Besides, the intra-day precision and accuracy variations were 8.78 and 10.16%, respectively. Tamoxifen concentrations were analyzed by combined reversed phase liquid chromatography and UV detection (λ=280 nm). The study was conducted using an open randomized 2-period crossover balanced design with a 1-week washout period between the doses. This simple, rapid and selective method is suitable for pharmacokinetic, bioavailability and bioequivalence studies.

Relative bioavailability of two formulations of venlafaxine extended-release 75-mg capsules in healthy brazilian male volunteers: A single-dose, randomized-sequence, open-label, two-period crossover study in the fasting and fed states

BACKGROUND The oral antidepressant venlafaxine hydrochloride is a selective serotonin-norepinephrine reuptake inhibitor. OBJECTIVE The aim of this study was to evaluate the bioequivalence of a new generic formulation of venlafaxine extended-release 75-mg capsules (test) and the available branded formulation (reference) to comply with regulatory criteria for marketing of the test product in Brazil. METHODS This single-dose, randomized-sequence, open-label, 2-period crossover study was conducted in healthy male volunteers and consisted of separate fast- ing and fed phases. A single oral dose of the test or reference formulation was followed by a 7-day washout period, after which subjects received the alternative formulation. There was a 3-month interval between the fasting and fed portions of the study. There was no standardization of race because of the difficulty of achieving standardization in the Brazilian population. Blood samples were collected before dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 24, 36, and 48 hours after dosing. Venlafaxine concentrations were determined using an HPLC-MS/MS method. The formulations were considered bioequivalent if the 90% CIs of the geometric mean ratios (test:reference) for C(max) and AUC(0-t) were within the regulatory range of 80% to 125%. Adverse events were monitored through-out the study based on vital signs, laboratory tests, interviews, and spontaneous patient reports. RESULTS Forty-eight subjects were enrolled in both phases of the study; all 48 subjects completed the fasting phase, and 1 subject withdrew during the fed phase. The mean (SD) age of participants in the fasting and fed phases was 24.96 (5.5) and 24.90 (4.7) years, respectively; their mean weight was 69.65 (9.6) and 71.00 (10.6) kg and their mean height was 172.0 (6.9) and 173.0 (6.6) cm. Under fasting conditions, the arithmetic mean venlafaxine C(max) was 35.705 (23.946) ng/mL for the test formulation and 34.470 (20.639) ng/mL for the reference formulation, with a geometric mean ratio of 1.04. The arithmetic mean AUC(0-t) for the respective formulations was 562.015 (481.875) and 508.509 (439.456) ng · h/mL, with a geometric mean ratio of 1.11. The arithmetic mean T(max) was 6.188 (1.560) and 5.885 (1.648) hours. Under fed conditions, the arithmetic mean venlafaxine C(max) was 42.892 (24.348) ng/mL for the test formulation and 46.275 (23.011) ng/mL for the reference formulation, with a geometric mean ratio of 0.93. The arithmetic mean AUC(0-t) for the respective formulations was 737.218 (603.998) and 682.124 (524.713) ng · h/mL, with a geometric mean ratio of 1.08. The arithmetic mean T(max) was 6.787 (1.769) and 5.957 (1.661) hours. There were no significant increases in venlafaxine C(max), AUC(0-t), or T(max) for either formulation in the fed phase compared with the fasting phase. In both the fasting and fed portions of the study, the 90% CIs for the ratio (test:reference) of log-transformed C(max) (fasting: 93.24-105.93; fed: 84.67-97.85) and AUC(0-t) (fasting: 102.90-116.71; fed: 98.19-114.41) were within the acceptance range for bioequivalence. The most common adverse events (≥ 5% of subjects) in the fasting phase were nausea (46%), diarrhea (29%), headache (29%), vomiting (15%), and colic (6%); the most common adverse events in the fed phase were nausea (15%), headache (13%), and dizziness (9%). CONCLUSION In this single-dose study in healthy fasting and fed volunteers, the test formulation of venlafaxine extended-release 75-mg capsules met Brazilian regulatory criteria for bioequivalence to the reference formulation.

Gustatory and olfactory dysfunction in laryngectomized patients

UNLABELLED After total laryngectomy surgery, nasal airflow is moved permanently to the tracheostomy opening, compromising the contact of odorant molecules with the nasal cavity, which may reflect changes in the olfactory and gustatory perception in these individuals. OBJECTIVE To evaluate the functions of smell and taste in total laryngectomized patients. STUDY DESIGN a study of series. METHOD The sample included a group of 25 patients submitted to total laryngectomy and another group of 25 patients who did not underwent the procedure. The taste function was evaluated by gustatory strips of filter paper. To assess the olfactory function we employed the Brief Smell Identification Test. RESULTS Among the laryngectomized patients there was more hypogeusia (80%, p < 0.05), as well as hyposmia (88%, p < 0.001), alone and concomitant (72%, p < 0.001). Concerning flavor discrimination, the bitter taste did not differ between the groups - which was different from the other flavors. In the olfactory aspect, laryngectomized patients performed worse in detecting warning and food-related odors. We found that a history of smoking and alcohol consumption were significantly more frequent among laryngectomized patients. CONCLUSION We found a decrease of gustatory and olfactory functions in total laryngectomized patients in this study.

Determination of the critical hydrophile-lipophile balance of licuri oil from Syagrus coronata: application for topical emulsions and evaluation of its hydrating function

The aims of this study were to determine the critical hydrophile-lipophile balance (HLB) of licuri oil, and to perform a clinical assay to evaluate its hydrating effects. For the determination of the HLB, serial emulsions were prepared with the oil. Regarding the clinical study, 13 human subjects were recruited to evaluate the hydrating power of the emulsified preparation containing licuri oil, and comparing it with the same preparation containing sweet almond oil (SAO). The critical HLB of licuri oil was represented by the zones within the concentrations of 10% for the oil and 15% for the pair of tensoactive agents, with a value of 11.8. Both preparations showed similar hydrating power. We propose that licuri oil can be considered a new lipophilic adjuvant with hydrating characteristics, which can be used in cosmetic preparations, replacing consecrated oils, such as SAO.

Assay and physicochemical characterization of the antiparasitic albendazole

O objetivo do trabalho foi caracterizar tres lotes de albendazol com tecnicas analiticas farmacopeicas e complementares a fim de estabelecer especificacoes mais detalhadas para o desenvolvimento de formas farmaceuticas. Os lotes ABZ01, ABZ02 e ABZ03 apresentaram fusao em 208 oC, 208 oC e 209 oC. Foi possivel evidenciar, por difracao de raios X, que os tres lotes apresentaram comportamento cristalino e ausencia de polimorfismo. Atraves da microscopia eletronica de varredura verificou-se que todas as amostras apresentaram cristais com diferentes tamanhos e forte tendencia de agregacao. As amostras foram insoluveis em agua (5,07; 4,27 e 4,52 µg mL-1) e muito pouco soluveis em HCl 0,1M (55,10; 56,90 e 61,70 µg mL-1) e, ainda, apresentaram pureza dentro da faixa especificada pela F.Bras.V (98% a 102%). O metodo farmacopeico de doseamento nao foi reprodutivel, e algumas mudancas foram necessarias. O metodo foi validado e demonstrou ser seletivo, especifico, linear, robusto, preciso e exato. A partir dessa caracterizacao, pode-se concluir que apenas tecnicas farmacopeicas nao sao capazes de detectar diferencas sutis entre os ingredientes farmaceuticos ativos, necessitando, portanto, de uso de outras tecnicas complementares para garantir um rigido controle de qualidade na industria farmaceutica.

Consumption of medicines in high-risk pregnancy: evaluation of determinants related to the use of prescription drugs and self-medication

The use of drugs during pregnancy still represents a challenge for medicine, since the majority of drugs cross the placental barrier with a potential to cause several congenital problems to the fetus, and most of them have not been clinically tested in pregnant patients. At the same time, the medicalization phenomenon, self-medication, and lack of patient information about the misuse of medicines are additional problems. Thus, the aim of this study was to evaluate the pattern of medicine consumption in high-risk pregnancies and the determinants related to this consumption pattern. In order to do so, a cross-sectional descriptive study was performed with puerperal women who had a history of high-risk pregnancy. Statistically significant associations were found between self-medication and fewer prenatal visits, and cigarette use during pregnancy and a higher number of children. According to these data, the vulnerability of this population to the risks of drug use is evident, demonstrating a gap that requires urgent interventions in health-care education.

The development and validation of a method for quantifying olanzapine in human plasma by liquid chromatography tandem mass spectrometry and its application in a pharmacokinetic study.

1. A rapid method using liquid chromatography tandem mass spectrometry for the quantification of olanzapine (OLZ) in human plasma was developed and validated. Venlafaxine was used as the internal standard (IS), and the samples were extracted from 400-μL human plasma with methyl tert-butyl ether for liquid-liquid extraction. 2. Chromatography was performed using an ACE C18, 125 × 4.6-mm i.d., 5-μm column. The mobile phase consisted of water with 0.1% formic acid for solvent A and acetonitrile with 0.1% formic acid for solvent B (50 : 50 v/v) in isocratic mode. The flow rate was 1.2 mL/min. The retention times for OLZ and the IS were 0.78 and 1.04 min, respectively. Tandem mass spectrometry operating in positive electrospray ionization mode with multiple reaction monitoring was used to detect OLZ and the IS (m/z: 313.1 > 256.1 and 278.1 > 260.2, respectively). 3. No significant matrix effects were observed on OLZ and the IS retention times, and the mean recovery of OLZ was 90.08%. The assay was linear in the concentration range of 1-20 ng/mL (R(2) = 0.9976). The intra- and inter-day precision were < 11.60% and the accuracy was < 1.66%. 4. This validated method was successfully applied to a pharmacokinetic study in which 10-mg OLZ tablets were administered to healthy volunteers and their plasma OLZ levels were monitored over time. The tests showed that the OLZ test and reference drug (Zyprexa(®)) were bioequivalent, as 90% of the confidence intervals were within the 80-125% interval proposed by regulatory agencies.A rapid method using liquid chromatography tandem mass spectrometry for the quantification of olanzapine (OLZ) in human plasma was developed and validated. Venlafaxine was used as the internal standard (IS), and the samples were extracted from 400‐μL human plasma with methyl tert‐butyl ether for liquid–liquid extraction. Chromatography was performed using an ACE C18, 125 × 4.6‐mm i.d., 5‐μm column. The mobile phase consisted of water with 0.1% formic acid for solvent A and acetonitrile with 0.1% formic acid for solvent B (50 : 50 v/v) in isocratic mode. The flow rate was 1.2 mL/min. The retention times for OLZ and the IS were 0.78 and 1.04 min, respectively. Tandem mass spectrometry operating in positive electrospray ionization mode with multiple reaction monitoring was used to detect OLZ and the IS (m/z: 313.1 > 256.1 and 278.1 > 260.2, respectively). No significant matrix effects were observed on OLZ and the IS retention times, and the mean recovery of OLZ was 90.08%. The assay was linear in the concentration range of 1–20 ng/mL (R2 = 0.9976). The intra‐ and inter‐day precision were < 11.60% and the accuracy was < 1.66%. This validated method was successfully applied to a pharmacokinetic study in which 10‐mg OLZ tablets were administered to healthy volunteers and their plasma OLZ levels were monitored over time. The tests showed that the OLZ test and reference drug (Zyprexa®) were bioequivalent, as 90% of the confidence intervals were within the 80–125% interval proposed by regulatory agencies.

Microemulsion Formulations for the Transdermal Delivery of Lapachol

This project was carried out to investigate the feasibility of using microemulsions for transdermal delivery of lapachol. From the screening of surfactants and oils, a range of microemulsions were developed using oleic acid, a mixture of Cremophor EL and Tween 20 and water. The solubility of lapachol was determined in these ingredients and in the formulated microemulsions. The microemulsions were characterised using cross-polarising light microscopy, their electrical conductivity, pH, zeta potential and rheology were analysed, and they were also investigated using small-angle X-ray scattering and differential scanning calorimetry. Ex vivo studies were performed using porcine ear skin and Franz diffusion cells to investigate the permeation and retention of lapachol. Systems containing different concentrations of Cremophor EL (8.4–41.6%), Tween 20 (5.4–41.6%) and oleic acid (12–31.9%) are able to form microemulsions. Lapachol was delivered more effectively through the skin from all of the microemulsions tested than by the control (oleic acid). These studies indicated that microemulsions incorporating lapachol were formed successfully and that these enhanced drug delivery and retention in the skin. Microemulsion systems may, therefore, provide promising vehicles for percutaneous delivery of lapachol.

Levobupivacaine Thermogel for Long-acting Analgesia

The adequate management of analgesia, by pharmacological methods or not, is a great challenge. Local anesthetics are used for pain relief, mainly by parenteral, intramuscular, catheter, and other routes of administration. The use of in situ forming systems becomes an alternative for the control of pain. The present research investigates development of thermogels containing poloxamer and levobupivacaine. All formulations were prepared by the cold method; the compatibilities of the excipients were evaluated by DSC, rheology and viscosities, transition temperature, syringeability, release kinetics, and permeation. The compatibility of the tested excipients with the drug was initially observed; all formulations had a viscosity increase at 37°C. Different delivery rates were observed in both the release and permeation studies. The developed systems maintained the in vitro release of the drug for a long period, likely decreasing side effects in vivo and avoiding the need for supplementary analgesia by other routes.

Third-Generation Transdermal Delivery Systems Containing Zidovudine: Effect of the Combination of Different Chemical Enhancers and a Microemulsion System

ABSTRACTThis study aimed to examine the influence of the combination of chemical enhancers and a microemulsion on the transdermal permeation of zidovudine (AZT). Ethanol, 1,8-cineole, and geraniol were incorporated in a microemulsion. The droplet size, zeta potential, rheology, and SAXS analysis were performed. The permeation enhancer effect was evaluated using pig ear skin. Snake skin (Boa constrictor) treated with the formulations was also used as a stratum corneum model and studied by attenuated total reflectance-infrared spectroscopy. As a result, it was observed that the incorporation of the chemical enhancers promoted a decrease of the droplet size and some rheological modifications. The 1,8-cineole associated with the microemulsion significantly increased the permeated amount of AZT. Conversely, ethanol significantly increased the quantity of the drug retained in the skin. The probable mechanism for the cineole and ethanol effects was respectively: fluidization and increasing of the diffusion coefficient, and increasing of the partition coefficient. Surprising, geraniol + microemulsion drastically decreased both the permeated and the retained amount of AZT into the skin. Thus, the adequate association of microemulsion and chemical enhancers showed to be a crucial step to enable the topical or transdermal use of drugs.