Pedro Eduardo Fröehlich

Pharmacokinetic evaluation of doxorubicin plasma levels in normal and overweight patients with breast cancer and simulation of dose adjustment by different indexes of body mass

Although being used for decades in the treatment of several types of cancer, either alone or in association, only a few data about the pharmacokinetics of doxorubicin (DOX) in humans are available. DOX is frequently used in association with other anticancer drugs in the management of breast cancer. Pharmacokinetic data available in the literature show that after i.v. administration DOX follows a two-compartment open model, with a fast distribution phase followed by a very slow elimination phase. The objective of this work is to perform a pilot study in order to verify if the usual dose adjustment based on body surface area (BSA) would be producing the same plasma concentration-time profiles in patients with normal (<25) and above normal (>25) body mass index (BMI). In order to assess the pharmacokinetics of DOX after a short-term i.v. infusion of 60mg/m(2) of BSA, an experimental design using only five plasma samples of each patient was applied. Samples were collected at 0.00, 0.66 (right after the end of infusion), 1.66, 8.66, and 24.66h. DOX pharmacokinetic profiles were evaluated after quantification of DOX using a new HPLC method developed and validated. Pharmacokinetic parameters (AUC(0-24.66) and C(max)) were analyzed by non-compartmental and compartmental approaches. Significant differences (α=0.05) between overweight and normal weight groups were found with respect to AUC and C(max). After adjustment of dose by weight and by BMI, the compartmental model was used to simulate plasma concentrations and new values for C(max) and AUC(0-24.66) were calculated. The new values obtained using both body weight (BW) and BMI were closer to the normal group than those obtained with BSA. According to the simulation, the differences of AUC and C(max) between the overweight group and the group of patients with normal weight were lower when the dose was adjusted by BW and BMI. These results suggest that more studies must be conducted, with more patients, in order to evaluate the best dose adjustment for DOX in women with breast cancer and overweight.

The effect of a single dose versus a daily dose of cholecalciferol on the serum 25-hydroxycholecalciferol and parathyroid hormone levels in the elderly with secondary hyperparathyroidism living in a low-income housing unit

We designed a randomized, double-blind, controlled clinical trial to compare the effect of two regimens for administering cholecalciferol on the serum 25-hydroxycholecalciferol [25(OH)D] levels and in the reversion of secondary hyperparathyroidism in the elderly living in a low-income housing unit in the city of Porto Alegre, southern Brazil. We studied 28 individuals ranging in age from 65 to 102 years with serum parathyroid hormone (PTH) levels greater than 48 pg/ml and normal or reduced serum calcium levels. Subjects were randomized to receive oral cholecalciferol, as a single dose of 300 000 IU (group 1) or 800 IU (group 2) daily for 9 months. Both groups received 1250 mg calcium carbonate per day. Serum 25(OH)D and PTH levels were measured at baseline and after 1, 2, 3, 6, and 9 months. Serum 25(OH)D levels in group 1 were significantly higher than in group 2 during the study (P < 0.001). After 1 (P < 0.001) and 2 (P < 0.04) months of treatment, mean serum 25(OH)D levels were higher in group 1. The number of subjects who reached serum 25(OH)D levels ≥20 ng/dl was higher in group 1, after the first (P < 0.001) and third (P = 0.008) months. In the short term, a single 300 000 IU oral dose of vitamin D3 was more effective than 800 IU per day to increase serum 25(OH)D levels in elderly persons, living in a low-income housing unit, who were taking 500 mg elementary calcium supplement per day.

Determination of cocaine/crack biomarkers in colostrum by LC–MS following protein precipitation

Drug abuse by nursing mothers is an ongoing concern because it may cause many adverse effects to the newborns. The development of analytical methods to analyze drugs of abuse in colostrum (first milk produced after birth) has a huge importance, because it enables the monitoring and the correct follow-up to users and newborns. A liquid chromatography mass spectrometry (LC-MS) method was developed and validated for the determination of cocaine and smoked cocaine (crack) biomarkers in colostrum. Cocaine (COC) and its major metabolite benzoylecgonine (BZE), the pyrolytic products anhydroecgonine methyl ester (AEME) and anhydroecgonine (AEC) were analyzed after a simple protein precipitation procedure using atropine (ATP) as internal standard (IS). Applying a chemometric approach study, all peaks were chromatographically separated at isocratic condition with a Kinetex HILIC column for polar compounds, at 30°C in 12min. One ion was detected for the quantification and three ions for confirmation of each analyte. The method was linear for all analytes in the concentration range of 5-300ng/mL with correlation coefficients (r) between 0.9983 and 0.9996. The lower limit of quantification (LLOQ) was 5ng/mL with acceptable validation parameters. Matrix effect was assessed by post-extraction addition approach and showed good results, demonstrating that protein precipitation cleaning procedure is fast, reliable and demand small quantities of organic solvent. The LC-MS method is fast and cheap compared to other equipments and was also successfully applied to assess real samples of colostrum from nursing mothers who were suspect of cocaine/crack abuse.

Development and validation of discriminating method of dissolution for fosamprenavir tablets based on in vivo data

The aim of this work is to develop and validate a dissolution test for fosamprenavir tablets (Telzir(®)) based on in vivo data. The appropriate conditions were determined after testing sink conditions in dissolution medium, rotation speed and stability of the drug. In vivo release profiles were obtained from the literature. The fraction (and percentage) of dose absorbed (FA) was calculated by deconvolution, using the Wagner-Nelson method. For this formulation, the best dissolution conditions were achieved using a USP apparatus 1 900 ml of medium containing HCl 0.01 M at a rotation speed of 75 rpm. Under these conditions a significant linear relationship between fraction of drug absorbed versus dissolved was obtained (R(2)=0.984) and a level-A IVIVC was established. The in vitro dissolution samples were analyzed using a HPLC method and the validation was performed according to USP protocol. The method showed accuracy, precision, linearity and specificity within the acceptable range. The discriminatory power of the dissolution method was challenged. The kinetics of dissolution was determined using model-dependent methods. The dissolution profiles were best described by the Hixson-Crowell model. The dissolution test was validated and could be applied to evaluate the dissolution profile of fosamprenavir tablets.

Amphetamine-type medicines: a review of pharmacokinetics, pharmacodynamics, and toxicological aspects.

Amphetamine-like drugs are sympathomimetic agents with marked central and peripheral stimulant properties. Despite the street illegal drugs such as amphetamine and ecstasy, some amphetamine-like compounds are also legally marketed under medical prescription in the treatment of attention deficit-hyperactivity disorder (methylphenidate) and obesity/overweight (fenproporex and diethylpropione). However, similar with what happens with their illicit analogues, therapeutic amphetamine-like drugs also share important toxicological risks. Although methylphenidate is considered the first choice in the treatment of attention deficit-hyperactivity disorder, its high popularity among teenagers and children is raising concern in the medical community. Regarding weight-loss purposes, the use of amphetamine-like compounds are very controversial, though. Thus, the present review will address pharmacokinetic, pharmacodynamic, and toxicological aspects of amphetamine-like compounds used with therapeutic aims.

Development and validation of dissolution test for lopinavir, a poorly water-soluble drug, in soft gel capsules, based on in vivo data

The objective of the present study was to develop and validate a dissolution test for lopinavir soft gel capsules (Kaletra), using a simulated absorption profile based on in vivo data. Different conditions such as surfactant concentration, apparatus and rotation speed were evaluated. In vivo release profiles were obtained from the literature. The fraction (and percentage) of dose absorbed (FA) was calculated by using Wagner-Nelson method. The best in vitro dissolution profile was obtained using Apparatus 2 (paddle) at 25 rpm, 1000 ml of medium with 2.3% of sodium lauryl sulfate and pH 6.0. Under these conditions a level-A in vitro-in vivo correlation (IVIVC) was obtained (r = 0.997). The in vitro dissolution samples were analyzed using a HPLC method and the validation was performed according to USP protocol. The method showed accuracy, precision, linearity and specificity within the acceptable range. Both the HPLC method and the in vitro dissolution method were validated and could be used to evaluate the release profile of lopinavir soft gel capsules.

Trends in counterfeits amphetamine-type stimulants after its prohibition in Brazil

Brazil is one of the worlds highest users of anorectic drugs, mainly diethylpropione, fenproporex and sibutramine. The present work focuses on physical and chemical characteristics of 17 counterfeited capsules containing amphetamine-type stimulants (ATS) from three seizures conducted by Brazilian Federal Police. The physical profile was useful in indicating forgery, bring complementary information, but the use of this data singly was not sufficient to distinguish between authentic and counterfeited medicines. The chemical analysis revealed that the seizures capsules labeled as Desobesi-M (fenproporex 25mg), actually contained the active pharmaceutical ingrediente (API) sibutramine. The amount of this API ranged from 1/3 to 2 times the amount of drug found in commercial product, may reach twice the recommended daily dose. Multivariate analysis with application of principal component analysis on data from spectroscopy attenuated total reflectance Fourier transform infrared classified the samples according to their similarities, indicating that two seizures had common origin. This study represents the first step in the elucidation of falsification of ATS in Brazil. Considering the forensic intelligence these information are valuable in order to develop and establish a database that enables correlate samples from different locations and/or suppliers and to map the profile and trends of trafficking.

From Bacteria to Antineoplastic: Epothilones A Successful History

Malignancies are a major cause of morbidity and mortality worldwide. Cancer is a cell disease, characterized by a deviation of the control mechanisms of proliferation and differentiation of cells. Among the treatments available, chemotherapy is often the first choice. Epothilones are a new class of anticancer drugs that act by interacting with cellular microtubules interrupting the proliferation of cancer cells. Many synthetic and semi-synthetic analogues of epothilones have been prepared aiming improvement in effectiveness and tolerability, based on QSAR studies. These analogues have been effective for treatment of tumors resistant to first-line treatments. Six new epothilones are being subjected to clinical trials. Ixabepilone (Ixempra®) was approved by FDA in 2007, patupilone is in phase III clinical trial for ovarian and peritoneum cancer. Sagopilone, desoxiepothilone and KOS-1584 are in phase II clinical trials, for the treatment of recurrent glioblastoma and advanced metastatic breast cancer, metastasic breast cancer and metastatic pulmonary cancer, respectively. Desoxiepothilone reached only phase II trials and BMS-310705 reached phase III/IV trials, but were not approved for clinical use due to adverse effects such as neurotoxicity and severe diarrhea, which were dose-limiting. Furthermore, the low t1/2 (40h) in comparison with other class analogues, does not recommend the clinical use of this derivative. Some other synthetized epothilones presented antineoplastic activity in vitro, but are not yet submitted to clinical studies. Neuropathies and diarrhea are adverse effects presented by some substances of this class of anticancer drugs.

UV-Derivative Spectrophotometric Determination of Ritonavir Capsules and Comparison with LC Method

Abstract An ultraviolet-derivative spectrophotometric method (UV-D) has been proposed as an alternative to a previously described liquid chromatographic (LC) method for the quantitative determination of ritonavir in soft gelatin capsules. The spectrophotometric method is based on recording the second-derivative spectra for ritonavir at 222.3 nm of its solutions in methanol. The linear dynamic range was 10.0–30.0 µg · mL−1 with a correlation coefficient of 0.9995. Mean recoveries were between 99.2% and 100.2% for the tested capsules samples. Mean intra- and interassay relative standard deviations (RSDs) were less than 2.0%. The statistic analysis showed that LC and UV-D methods were equivalent to assay ritonavir capsules.

Lisdexamfetamine: A pharmacokinetic review

Lisdexamfetamine (LDX) is a d-amphetamine (d-AMPH) pro-drug used to treat Attention Deficit and Hyperactivity Disorder (ADHD) and Binge Eating Disorder (BED) symptoms. The in vivo pharmacodynamics of LDX is the same as that of its active product d-AMPH, although there are a few qualitative and quantitative differences due to pharmacokinetics. Due to the specific pharmacokinetics of the long-acting stimulants, this article revises the pharmacokinetic studies on LDX, the newest amphetamine pro-drug. The Medline/Pubmed, Science Direct and Biblioteca Virtual em Saúde (Lilacs and Ibecs) (2007-2016) databases were searched for articles and their list of references. As for basic pharmacokinetics studies, since LDX is a newly developed medication, there are few results concerning biotransformation, distribution and the use of different biological matrices for analysis. This is the first robust review on this topic, gathering data from all clinical pharmacokinetics studies available in the literature. The particular pharmacokinetics of LDX plays a major role in studying this pro-drug, since this knowledge was essential to understand some reports on clinical effects in literature, e.g. the small likelihood of reducing the effect by interactions, the effect of long duration use and the still questionable reduction of the potential for abuse. In general the already well-known pharmacokinetic properties of amphetamine make LDX relatively predictable, simplifying the use of LDX in clinical practice.