Physiologically-based pharmacokinetic modelling of long-acting injectable cabotegravir and rilpivirine in pregnancy.

AIMS: Long-acting cabotegravir and rilpivirine have been approved to manage HIV in adults, but data regarding safe use in pregnancy are limited. Physiologically-based pharmacokinetic (PBPK) modelling was used to simulate the approved dosing regimens in pregnancy and explore if Ctrough was maintained above cabotegravir and rilpivirine target concentrations (664 and 50 ng/mL, respectively). METHODS: An adult PBPK model was validated using clinical data of cabotegravir and rilpivirine in nonpregnant adults. This was modified by incorporating pregnancy-induced metabolic and physiological changes. The pregnancy PBPK model was validated with data on oral rilpivirine and raltegravir (UGT1A1 probe substrate) in pregnancy. Twelve weeks' disposition of monthly and bimonthly dosing of long-acting cabotegravir and rilpivirine was simulated at different trimesters and foetal exposure was also estimated. RESULTS: Predicted Ctrough at week 12 for monthly long-acting cabotegravir was above 664 ng/mL throughout pregnancy, but below the target in 0.5% of the pregnant population in the third trimester with bimonthly long-acting cabotegravir. Predicted Ctrough at week 12 for monthly and bimonthly long-acting rilpivirine was below 50 ng/mL in at least 40% and over 90% of the pregnant population, respectively, throughout pregnancy. Predicted medians (range) of cord-to-maternal blood ratios were 1.71 (range, 1.55-1.79) for cabotegravir and 0.88 (0.78-0.93) for rilpivirine between weeks 38 and 40. CONCLUSIONS: Model predictions suggest that monthly long-acting cabotegravir could maintain antiviral efficacy throughout pregnancy, but that bimonthly administration may require careful clinical evaluation. Both monthly and bimonthly long-acting rilpivirine may not adequately maintain antiviral efficacy in pregnancy.

Pharmacokinetics and safety of twice-daily ritonavir-boosted atazanavir with rifampicin.

BACKGROUND: Critical drug-drug interactions (DDI) and hepatotoxicity complicate concurrent use of rifampicin and protease inhibitors. We investigated whether dose escalation of atazanavir/ritonavir could safely overcome the DDI with rifampicin. METHODS: DERIVE (NCT04121195, EDCTP) was a dose-escalation trial in people with HIV on atazanavir/ritonavir-based ART in Uganda. Four intensive pharmacokinetic (PK) visits were performed: PK1 300/100 mg OD (baseline); PK2 300/100 mg OD with rifampicin 600 mg; PK3 300/100 mg BID with rifampicin 600 mg OD; PK4 300/100 mg BID with rifampicin 1200 mg OD. Dolutegravir 50 mg BID throughout the study period ensured participants remained protected from subtherapeutic atazanavir concentrations. The data was interpreted with noncompartmental analysis. The target minimum concentration was atazanavir's protein-adjusted IC90 (PA-IC90), 0.014 mg/L. RESULTS: We enrolled 26 participants (23 female) with median (range) age 44 (28-61) years and weight 67 (50-75) kg. Compared with PK1, atazanavir Ctau, and AUC were significantly reduced at PK2 by 96% and 85%, respectively. The escalation to BID dosing (PK3) reduced this difference in Ctau, and AUC24 to 18% lower and 8% higher, respectively. Comparable exposures were maintained with double doses of rifampicin. Lowest Ctau during PK1, PK3, and PK4 were 12.7-, 4.8-, and 8.6-fold higher than PA-IC90, respectively, while 65% of PK2 Ctau were below the limit of quantification (0.03 mg/L), hence likely below PA-IC90. No participant developed significant elevation of liver enzymes, reported an SAE, or experienced rebound viraemia. CONCLUSIONS: Twice daily atazanavir/ritonavir during rifampicin co-administration was well-tolerated and achieved plasma concentrations above the target.

A physiologically based pharmacokinetic model to predict pegylated liposomal doxorubicin disposition in rats and human.

The use of nanoparticles (NPs) can support an enhancement of drug distribution, resulting in increased drug penetration into key tissues. Experimental in vitro data can be integrated into computational approaches to simulate NP absorption, distribution, metabolism and elimination (ADME) processes and provide quantitative pharmacokinetic predictions. The aim of this study is to develop a novel mechanistic and physiologically based pharmacokinetic (m-PBPK) model to predict the biodistribution of NPs focusing on Doxil. The main processes underpinning NPs ADME were represented considering molecular and cellular mechanisms such as stability in biological fluids, passive permeability and uptake activity by macrophages. A whole-body m-PBPK rat and human models were designed in Simbiology v. 9.6.0 (MATLAB R2019a). The m-PBPK models were successfully qualified across doxorubicin and Doxil® in both rat and human since all PK parameters AUC0-inf, Cmax, t1/2, Vd and Cl were within twofold, with an AUC0-inf absolute average-fold error (AAFE) value of 1.23 and 1.16 and 1.76 and 1.05 for Doxorubicin and Doxil® in rat and human, respectively. The time to maximum concentration in tissues for doxorubicin in both rat and human models was before 30 min of administration, while for Doxil®, the tmax was after 24 h of administration. The organs that accumulate most NP are the spleen, liver and lungs, in both models. The m-PBPK represents a predictive platform for the integration of in vitro and formulation parameters in a physiological context to quantitatively predict the NP biodistribution. Schematic diagram of the whole-body m-PBPK models developed for Doxil® in rat and human physiology.

PBPK Modelling of Dexamethasone in Patients With COVID-19 and Liver Disease.

The aim of the study was to apply Physiologically-Based Pharmacokinetic (PBPK) modelling to predict the effect of liver disease (LD) on the pharmacokinetics (PK) of dexamethasone (DEX) in the treatment of COVID-19. A whole-body PBPK model was created to simulate 100 adult individuals aged 18-60 years. Physiological changes (e.g., plasma protein concentration, liver size, CP450 expression, hepatic blood flow) and portal vein shunt were incorporated into the LD model. The changes were implemented by using the Child-Pugh (CP) classification system. DEX was qualified using clinical data in healthy adults for both oral (PO) and intravenous (IV) administrations and similarly propranolol (PRO) and midazolam (MDZ) were qualified with PO and IV clinical data in healthy and LD adults. The qualified model was subsequently used to simulate a 6 mg PO and 20 mg IV dose of DEX in patients with varying degrees of LD, with and without shunting. The PBPK model was successfully qualified across DEX, MDZ and PRO. In contrast to healthy adults, the simulated systemic clearance of DEX decreased (35%-60%) and the plasma concentrations increased (170%-400%) in patients with LD. Moreover, at higher doses of DEX, the AUC ratio between healthy/LD individuals remained comparable to lower doses. The exposure of DEX in different stages of LD was predicted through PBPK modelling, providing a rational framework to predict PK in complex clinical scenarios related to COVID-19. Model simulations suggest dose adjustments of DEX in LD patients are not necessary considering the low dose administered in the COVID-19 protocol.

Evaluation of drug-drug interaction between rilpivirine and rifapentine using PBPK modelling.

Tuberculosis remains the leading cause of death among people living with HIV. Rifapentine is increasingly used to treat active disease or prevent reactivation, in both cases given either as weekly or daily therapy. However, rifapentine is an inducer of CYP3A4, potentially interacting with antiretrovirals like rilpivirine. This in silico study investigates the drug-drug interaction (DDI) magnitude between daily oral rilpivirine 25 mg with either daily 600 mg or weekly 900 mg rifapentine. A physiologically based pharmacokinetic (PBPK) model was built in Simbiology (Matlab R2018a) to simulate the drug-drug interaction. The simulated PK parameters from the PBPK model were verified against reported clinical data for rilpivirine and rifapentine separately, daily rifapentine with midazolam, and weekly rifapentine with doravirine. The simulations of concomitant administration of rifapentine with rilpivirine at steady-state lead to a maximum decrease on AUC0-24 and Ctrough by 83% and 92% on day 5 for the daily rifapentine regimen and 68% and 92% for the weekly regimen on day 3. In the weekly regimen, prior to the following dose, AUC0-24 and Ctrough were still reduced by 47% and 53%. In both simulations, the induction effect ceased 2 weeks after the interruption of rifapentine's treatment. A daily double dose of rilpivirine after initiating rifapentine 900 mg weekly was simulated but failed to compensate the drug-drug interaction. The drug-drug interaction model suggested a significant decrease on rilpivirine exposure which is unlikely to be corrected by dose increment, thus coadministration should be avoided.

Predicting Drug-Drug Interactions between Rifampicin and Ritonavir-Boosted Atazanavir Using PBPK Modelling.

OBJECTIVES: The aim of this study was to simulate the drug-drug interaction (DDI) between ritonavir-boosted atazanavir (ATV/r) and rifampicin (RIF) using physiologically based pharmacokinetic (PBPK) modelling, and to predict suitable dose adjustments for ATV/r for the treatment of people living with HIV (PLWH) co-infected with tuberculosis. METHODS: A whole-body DDI PBPK model was designed using Simbiology 9.6.0 (MATLAB R2019a) and verified against reported clinical data for all drugs administered alone and concomitantly. The model contained the induction mechanisms of RIF and ritonavir (RTV), the inhibition effect of RTV for the enzymes involved in the DDI, and the induction and inhibition mechanisms of RIF and RTV on the uptake and efflux hepatic transporters. The model was considered verified if the observed versus predicted pharmacokinetic values were within twofold. Alternative ATV/r dosing regimens were simulated to achieve the trough concentration (Ctrough) clinical cut-off of 150 ng/mL. RESULTS: The PBPK model was successfully verified according to the criteria. Simulation of different dose adjustments predicted that a change in regimen to twice-daily ATV/r (300/100 or 300/200 mg) may alleviate the induction effect of RIF on ATV Ctrough, with > 95% of individuals predicted to achieve Ctrough above the clinical cut-off. CONCLUSIONS: The developed PBPK model characterized the induction-mediated DDI between RIF and ATV/r, accurately predicting the reduction of ATV plasma concentrations in line with observed clinical data. A change in the ATV/r dosing regimen from once-daily to twice-daily was predicted to mitigate the effect of the DDI on the Ctrough of ATV, maintaining plasma concentration levels above the therapeutic threshold for most patients.

Selective Photodynamic Effects on Breast Cancer Cells Provided by p123 Pluronic®- Based Nanoparticles Modulating Hypericin Delivery.

BACKGROUND: Breast cancer is the most relevant type of cancer and the second cause of cancer- related deaths among women in general. Currently, there is no effective treatment for breast cancer although advances in its initial diagnosis and treatment are available. Therefore, the value of novel anti-tumor therapeutic modalities remains an immediate unmet need in clinical practice. Following our previous work regarding the properties of the Pluronics with different photosensitizers (PS) for photodynamic therapy (PDT), in this study we aimed to evaluate the efficacy of supersaturated hypericin (HYP) encapsulated on Pluronic® P123 (HYP/P123) against breast cancer cells (MCF-7) and non-tumorigenic breast cells (MCF-10A). METHODS: Cell internalization and subcellular distribution of HYP/P123 was confirmed by fluorescence microscopy. The phototoxicity and citototoxicity of HYP/P123 was assessed by trypan blue exclusion assay in the presence and absence of light. Long-term cytotoxicity was performed by clonogenic assay. Cell migration was determined by the wound-healing assay. Apoptosis and necrosis assays were performed by annexin VFITC/ propidium Iodide (PI) by fluorescence microscopy. RESULTS: Our results showed that HYP/P123 micelles had high stability and high rates of binding to cells, which resulted in the selective internalization in MCF-7, indicating their potential to permeate the membrane of these cells. Moreover, HYP/P123 micelles accumulated in mitochondria and endoplasmic reticulum organelles, resulting in the photodynamic cell death by necrosis. Additionally, HYP/P123 micelles showed effective and selective time- and dose dependent phototoxic effects on MCF-7 cells but little damage to MCF-10A cells. HYP/P123 micelles inhibited the generation of cellular colonies, indicating a possible capability to prevent the recurrence of breast cancer. We also demonstrated that HYP/P123 micelles inhibit the migration of tumor cells, possibly by decreasing their ability to form metastases. CONCLUSION: Taken together, the results presented here indicate a potentially useful role of HYP/P123 micelles as a platform for HYP delivery to more specifically and effectively treat human breast cancers through photodynamic therapy, suggesting they are worthy for in vivo preclinical evaluations.

Physiologically-Based Pharmacokinetic Model on the Oral Drug Absorption in Roux-en-Y Gastric Bypass Bariatric Patients: Amoxicillin Tablet and Suspension.

The potential of a physiologically-based pharmacokinetic (PBPK) model to predict oral amoxicillin bioavailability, by considering the physiological changes after "Roux-en-Y gastric bypass" (RYGB) surgery in bariatric patients, was evaluated. A middle-out approach for parameter estimations was undertaken using in vitro, in situ, and in vivo data. The observed versus predicted plasma concentrations and the model sensitivity of the simulated parameters of AUC0-inf and Cmax of amoxicillin (AMX) were used to confirm the reliability of the estimation. The model considers that a drug-transporter (Transp) in the initial segments of the normal intestine plays a significant role in the AMX absorption. A lower fraction absorbed (Fabs) was observed in RYGB patients (54.43% for suspension and 45.21% for tablets) compared to healthy subjects (77.48% capsule). Furthermore, the tablet formulation presented a lower dissolved fraction (Fd) and Fabs compared to the suspension formulation of AMX in RYGB patients (91.70% and 45.21% versus 99.92% and 54.43%, respectively). The AUC0-inf and Cmax were sensitive to changes in Rtintestine, PeffAMX, and Transp for both healthy and RYGB models. Additionally, AUC0-inf and Cmax were also sensitive to changes in the tlag parameter for tablet formulation in RYGB patients. The PBPK model showed a reduction in AMX bioavailability as a consequence of reduced intestinal length after RYGB surgery. Additionally, the difference in the predicted Fd and Fabs between suspension and tablet suggests that liquid formulations are preferable in postbariatric patients.

"Biotin-targeted mixed liposomes: A smart strategy for selective release of a photosensitizer agent in cancer cells".

The high incidence of cancer, necessity of treatment, and prognosis times are urgent issues that need to be addressed. In this work, we present DPPC liposomes coated with F127 triblock copolymers as a promising alternative in drug delivery systems for cancer therapy. The proposed mixed liposomes exhibit adequate size, high stability, and passive targeting that result from the EPR effect. An interesting strategy to obtain both passive and active targeting is the vectorization with a covalent bond between F127 and Biotin (a vitamin). Cancer cells can overexpress Biotin receptors, such as Avidin. Here, we evaluate the cytotoxic effects of the erythrosine-decyl ester (ERYDEC). This is a photosensitizer that can be utilized in photodynamic therapy (PDT) and incorporated in DPPC liposomes coated with F127 (F127/DPPC) and the biotinylated-F127 (F127-B/DPPC). The results showed that DPPC liposomes were efficiently mixed with common F127 or F127B, exhibiting adequate physical properties with simple and low-cost preparation. An HABA/Avidin assay showed the amount of Biotin available at the liposome surface. In addition, ERYDEC interaction with lipid vesicles showed high encapsulating efficiency and slow release kinetics. The ERYDEC monomeric species are represented by high light absorption and high singlet oxygen generation (1O2), which confirm the presence of the drug in its monomeric state, as required for PDT. The ERYDEC/liposome system showed high stability and absence of significant cytotoxic effects (absence of light) in fibroblasts of the Mus musculus cell line. In addition, phototoxicity studies showed that ERYDEC/liposomes were able to inhibit cancer cells. However, in the biotinylated system, the effect was much greater than the common F127 coating. This dramatically decreased the inhibitory concentration of CC50 and CC90. In addition, cellular uptake studies based on fluorescence properties of ERYDEC showed that a two-hour incubation period was enough for the uptake by the cell. Therefore, the new vectorized-coated liposome is a potential system for use in cancer treatments, considering that it is a theranostic platform.

Reduced bioavailability of oral amoxicillin tablets compared to suspensions in Roux-en-Y gastric bypass bariatric subjects.

AIMS: To evaluate the relative bioavailability of oral amoxicillin (AMX) tablets in comparison to AMX suspension in Roux-en-Y gastric bypass bariatric subjects. METHODS: A randomized, double-blind, cross-over study was performed on the bioavailability of oral AMX tablets and suspension in Roux-en-Y gastric bypass subjects operated at least 3 months previously . Doses of 875 mg of the AMX tablet or 800 mg of the AMX suspension were given to all the subjects, allowing a washout of 7 days between the periods. Blood samples were collected at 0, 0.25, 0.5, 1, 1.5, 2, 4, 6 and 8 hours after drug administration and the AMX levels were quantified by liquid chromatography coupled with triple quadrupole tandem mass spectrometry. The pharmacokinetic parameters were calculated by noncompartmental analysis, normalized to an 875 mg dose and the bioavailability of the AMX from the tablets was compared to that from the suspension formulation. RESULTS: Twenty subjects aged 42.65 ± 7.21 years and with a body mass index of 29.88 ± 4.36 kg/m2 were enrolled in the study. The maximum AMX plasma concentration of the tablets and the suspension (normalized to 875 mg) were 7.42 ± 2.99 mg/L and 8.73 ± 3.26 mg/L (90% confidence interval of 70.71-99.11), and the total area under the curve from time zero to infinity were 23.10 ± 7.41 mg.h/L and 27.59 ± 8.32 mg.h/L (90% confidence interval of 71.25-97.32), respectively. CONCLUSION: The tablets presented a lower bioavailability than the suspension formulation and the total absorbed amount of AMX in these subjects was lower in comparison to the standard AMX absorption rates in nonbariatric subjects, regardless of the formulation.

Decontamination and disinfection of wastewater by photocatalysis under UV/visible light using nano-catalysts based on Ca-doped ZnO.

Nano-catalysts based on ZnO-Ca x% (with x = 0, 0.1, 0.3, 0.5, 0.7, and 1.0 mol % Ca2+) were synthesized with a bio-friendly adaptation of the sol-gel method using gelatin as template. These materials were characterized by Fourier Transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), Micro-Raman, transmission electron microscopy (TEM), scanning electron microscopy (SEM), N2 physisorption, photoacoustic absorption spectroscopy (PAS), and photoluminescence spectroscopy (PL). The Raman results indicated that the signal, attributed to an E1(LO) mode at 580 cm-1, was characteristic of oxygen vacancies that decreased with the increased Ca2+ content in doped oxides. This agreed with the PL results, which showed that the green emission centered at 510 nm and attributable to structural defects in ZnO decreased for Ca-doped ZnO. Our oxides are constituted by nanoparticles with rod-like and spherical morphologies. All the nano-catalysts exhibited the band gap characteristics of semiconductor materials around 3.0 eV. ZnO-Ca 1.0% exhibited the best photocatalytic performance for degradation of Methyl Orange (MO) model dye, degrading about 82% after 240 min of UV-Vis irradiation at pH 7.0. The reaction mechanism was influenced by hydroxyl (OH) and superoxide (O2-) radicals and mainly by active holes (h+). This doped oxide also demonstrated efficiency in wastewater disinfection against heterotrophic bacteria and total coliforms, exhibiting a potential use as an antimicrobial agent for the treatment of hospital wastewater. Furthermore, our nanoparticles did not show significant cytotoxic effects on L929 fibroblast cells.

Thermal Magnetic Field Activated Propolis Release From Liquid Crystalline System Based on Magnetic Nanoparticles.

Intra-periodontal pocket drug delivery systems, such as liquid crystalline systems, are widely utilized improving the drug release control and the therapy. Propolis is used in the treatment of periodontal diseases, reducing the inflammatory and infectious conditions. Iron oxide magnetic nanoparticles (MNPs) can improve the treatment when an alternating external magnetic field (AEMF) is applied, increasing the local temperature. The aim of this study was to develop a liquid crystalline system containing MNPs for intra-periodontal pocket propolis release. MNPs were prepared using iron salts and the morphological, size, thermal, x-ray diffraction, magnetometry, and Mössbauer spectroscopy analyses were performed. Cytotoxicity studies using Artemia salina and fibroblasts were also accomplished. The systems were prepared using polyoxyethylene (10) oleyl ether, isopropyl myristate, purified water, and characterized by polarized optical microscopy, rheometry, and in vitro drug release profile using a periodontal pocket simulator apparatus. The antifungal activity of the systems was investigated against Candida spp. using an AEMF. MNPs displayed nanometric size, were monodisperse, and they displayed very low cytotoxicity. Microscopically homogeneous formulations were obtained displaying important physicochemical and biological properties. The system displayed prolonged release of propolis and important in vitro fungicide activity, which was increased when the AEMF was applied, indicating a potentially alternative therapy for the treatment of the periodontal disease.

Response surface method optimization of a novel Hypericin formulation in P123 micelles for colorectal cancer and antimicrobial photodynamic therapy.

The photodynamic properties of Hypericin (Hyp) may be used as an alternative treatment for malignancies of the lower gastrointestinal tract and for the prevention of surgical-site infection; however, its use in photodynamic therapy has been limited because of its poor hydrosolubility. Therefore, in order to improve its water solubility and its photodynamic effect, Hyp was encapsulated in Pluronic P123 (P123) and the photodynamic effects against intestinal and epidermal bacteria and against two lineages of intestinal colon carcinoma cells were investigated. Two response surface methods (RSM) were used to achieve the best in vitro photodynamic activity against Enterococcus faecalis, Escherichia coli and Staphylococcus aureus: in the first (full 23 RSM), Hyp concentration (HC*), incubation time (IT*) and LED-light time (LT*) were considered as the independent variables and E. faecalis inhibition as the dependent variable. In the second (full 32 RSM), Hyp concentration (HC*) and P123 concentration (CC*) were considered as independent variables and E. faecalis, E. coli and S. aureus inhibition as dependent variables. The optimized experimental conditions achieved were: Hyp concentration=37.5µmol/L; P123 concentration=21.5 µmol/L and 6.3J/cm2, which resulted in 2.86±0.12 and 2.30±0.31CFU log-reductions of E. faecalis and S. aureus. No effect was seen against E. coli. The cytotoxic effects of Hyp/P123 were also investigated for Caco-2 and HT-29 intestinal colon carcinoma cells at Hyp/P123 concentrations of 1, 0.5, 0.25 and 0.1µmol/L for Caco-2 cells and 4, 3, 2 and 1µmol/L for HT-29 cells. The cytotoxic concentrations for 50% (CC50) and 90% (CC90) of Hyp/P123 were 0.443 and 0.870µmol/L for Caco-2 cells and 1.4 and 2.84µmol/L for HT-29 cells. The P123 nanocarrier played a significant role in the permeation of Hyp through the cell membrane leading to significant cell death, and showed itself to be a promising photosensitizer for PDT that could be suitable for the treatment of colonic diseases since it is effective against positive Gram bacteria and intestinal colon carcinoma cells.

Rapid and efficient method for the quantification of lychnopholide in rat plasma by liquid chromatography-tandem mass spectrometry for pharmacokinetic application.

Lychnopholide is a sesquiterpene lactone usually obtained from Lychnophora and Eremanthus species and has pharmacological activities that include anti-inflammatory and anti-tumor. Lychnopholide isolated from Eremanthus matogrossenssis was analyzed in this study. The aims of this study were to develop and validate an analytical methodology by LC-MS/MS and to quantify lychnopholide in rat plasma. Chromatographic separation was achieved on a C18 column using isocratic elution with the mobile phase consisting of methanol and water (containing 0.1% formic acid) at a flow rate of 0.4 mL/min. The detection was performed in multiple-reaction monitoring mode using electrospray ionization in positive mode. The method validation was performed in accordance with regulatory guidelines and the results met the acceptance criteria. The linear range of detection was 10-200 ng/mL (r > 0.9961). The intra- and inter-day assay variability were <6.2 and <11.7%, respectively. The extraction recovery was approximately 63% using liquid-liquid extraction with chloroform. Lychnopholide was detected in plasma up to 60 min after intravenous administration in rats. This rapid and sensitive method for the analysis of the sesquiterpene lactone lychnopholide in rat plasma can be applied to pharmacokinetic studies of this compound. Copyright © 2016 John Wiley & Sons, Ltd.

Recovery of drug residues in equipment and utensils used by compounding pharmacies after standard cleaning procedure / Recuperação de resíduos de drogas em equipamentos e utensílios utilizados por farmácias de manipulação após o procedimento de limpeza padrão

Compounding pharmacies have been cited by some athletes as being responsible for compounding capsules contaminated with drugs banned by the International Olympic Committee (IOC). Therefore, the present study was carried out to quantify the amount of residue remaining in the equipment and utensils used for compounding capsules after standard cleaning procedures. For this purpose, captopril (CAP) and acetylsalicylic acid (ASA) were used since these are hard to clean, in addition to hydrochlorothiazide (HTZ) as a banned drug by the IOC. The amounts of residues found in the equipment were: 181.0 ± 91.8, 1208 ± 483.8 and 431.7 ± 71.3 ppm for ASA, CAP and HTZ, respectively. The continuous compounding of these drugs, followed each time by the standard cleaning procedure, showed a linear accumulation of residues for ASA (r²=0.96) and CAP (r²= 0.88). The residues quantified were greater than the FDA limit for impurities for CAP (>0.1%) but not for HTZ. However, the HTZ residue may be detected in the urine of athletes on IOC tests. Therefore, it was concluded that compounding pharmacies should therefore improve their cleaning procedures and test these in order to attain limits below 10 ppm, thereby avoiding the contamination of other products...

As farmácias de manipulação têm sido citadas por alguns atletas como sendo responsáveis pela manipulação de cápsulas contaminadas com fármacos proibidos pelo Comitê Olímpico Internacional (COI). Portanto, o presente estudo foi realizado para quantificar o montante de resíduo remanescente nos equipamentos e utensílios usados para manipular cápsulas após o procedimento padrão de limpeza. Para este propósito, o captopril (CAP) e o ácido acetilsalicílico (ASA) foram usados por serem fármacos de difícil remoção e a hidroclorotiazida (HTZ), por ser um fármaco proibido pelo COI. As quantidades de resíduos encontradas nos equipamentos após a limpeza foram 181,0 ± 91,8, 1208 ± 483,8 e 431,7 ± 71,3 ppm para ASA, CAP e HTZ, respectivamente. A manipulação contínua dos fármacos seguida pelo procedimento de limpeza mostrou acúmulo de resíduo linear para ASA (r²=0,96) e CAP (r²=0,88). A quantidade de resíduo de CAP foi maior que o limite de impureza sugerido pelo FDA (>0,1%), mas não para HTZ, mas mesmo assim, o resíduo de HTZ pode ser detectado na urina dos atletas submetidos aos testes do COI. Em conclusão, as farmácias de manipulação deveriam, portanto, melhorar o procedimentos de limpeza e testá-los para que alcancem limites abaixo de 10 ppm para evitar contaminação nos outros produtos...