Influence of Organic Matter on the Sorption of Cefdinir, Memantine and Praziquantel on Different Soil and Sediment Samples.

Pharmaceuticals are known for their great effects and applications in the treatment and suppression of various diseases in human and veterinary medicine. The development and modernization of science and technologies have led to a constant increase in the production and consumption of various classes of pharmaceuticals, so they pose a threat to the environment, which can be subjected to the sorption process on the solid phase. The efficiency of sorption is determined by various parameters, of which the physicochemical properties of the compound and the sorbent are very important. One of these parameters that determine pharmaceutical mobility in soil or sediment is the soil−water partition coefficient normalized to organic carbon (Koc), whose determination was the purpose of this study. The influence of organic matter, suspended in an aqueous solution of pharmaceutical (more precisely: cefdinir, memantine, and praziquantel), was studied for five different types of soil and sediment samples from Croatia. The linear, Freundlich, and Dubinin−Raduskevich sorption isotherms were used to determine specific constants such as the partition coefficient Kd, which directly describes the strength of sorbate and sorbent binding. The linear model proved to be the best with the highest correlation coefficients, R2 > 0.99. For all three pharmaceuticals, a positive correlation between sorption affinity described by Kd and Koc and the amount of organic matter was demonstrated.

Sorption of cefdinir, memantine, praziquantel and trimethoprim in sediment and soil samples.

The everyday use of various pharmaceuticals to treat humans or animals means that they are increasingly found in the environment. Contamination of the soil can cause the active ingredients to be strongly sorbed to the soil or sediment. In the worst case, they can also be expected to occur in the aquatic environment due to their different polarity. In this study, four drugs from different therapeutic classes (trimetoprim, memantine, cefdinir, praziquantel) were used in dissolved form in two sediment and three soil samples to obtain data that can describe their fate and behavior in the environment. The sorption affinities of the pharmaceuticals were described using linear, Freundlich and Dubinin-Radushkevich sorption isotherms. The highest Kd values were obtained for cefdinir, while memantine and praziquantel tended to be present in water due to their very low sorption coefficients. The studied influence of pH showed a negative trend for memantine and trimetoprim, while an increase in ionic strength resulted in higher Kd values for all drugs. The sorption mechanism for all tested samples was best described by the pseudo-secondary kinetic model (R2 > 0.9999).

Development of an analytical method for the determination of pimavanserin and its impurities applying analytical quality by design principles as a risk-based strategy.

Pimavanserin is an atypical antipsychotic indicated for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis. As it is a relatively new drug on the market, limited number of pharmacokinetic information and analytical methods are available. This paper presents an ultra-high performance chromatography for the simultaneous determination of pimavanserin and its four process impurities. The method was developed applying analytical quality by design (AQbD) principles as a risk-based approach. Critical method attributes (CMAs) were selected as a resolution between the worst separated compounds (impurity B and impurity C), a duration of analysis defined by the retention time of the last eluting peak (impurity D), a capacity factor of the first eluted impurity (impurity A), a tailing factor and a theoretical plate number. Risk assessment in the early stage of method development pointed out critical method parameters (CMPs): column temperature, gradient time and pH-value of the mobile phase (water phase, eluent A). Design of experiments (DoE), using DryLab®4 software, was applied to evaluate the influence of CMPs on CMAs and to determine method operable design region (MODR). Based on the risk assessment and the results of robustness and precision tests, a control strategy with system suitability criteria was proposed. Developed method was validated according to ICH Q2 (R1) guideline with respect to the selectivity, LOD, LOQ, linearity, precision, accuracy, robustness and stability. A forced degradation study was performed to provide an evidence of the stability-indicating property of the method. Degradation products of pimavanserin were identified using ultra high-performance liquid chromatography coupled to high resolution mass spectrometry (UHPLC-qTOF). Additionally, potential degradation products were assessed in silico with the help of Zeneth® software and good agreement with experimentally identified degradation products was achieved. Main degradation products were formed during acid and base hydrolysis (m/z 223.16 [M+H]+ at RRT 0.37) and under oxidative stress conditions (m/z 444.26 [M+H]+ at RRT 0.57). The results revealed that the pimavanserin undergoes degradation through acid and base hydrolysis of urea and N-oxidation of aliphatic tertiary amine.

A simple and sensitive LC-MS/MS method for determination and quantification of potential genotoxic impurities in the ceritinib active pharmaceutical ingredient.

A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was used for quantification of four potential genotoxic impurities (PGIs) in the ceritinib active pharmaceutical ingredient. Chromatographic separation was achieved using a YMC-Triart C18 column, with 0.1% formic acid in water as mobile phase A and acetonitrile as mobile phase B in gradient elution mode at a 0.5 mL min-1 flow rate. Quantification of impurities was carried out using triple quadrupole mass detection with electrospray ionization in multiple reaction monitoring mode. The method was fully validated with good linearity over the concentration range of 0.5-5.0 ppm of the ceritinib test concentration for all four PGIs. The correlation coefficient obtained in each case was >0.998. The recoveries were found satisfactory over the range between 83.7 and 107.3% for all selected impurities. The developed method was able to quantitate all four PGIs at a concentration level of 1 ng mL-1 (0.5 ppm with respect to 2 mg mL-1 ceritinib).

Combined Albenazole-Praziquantel Treatment in Recurrent Brain Echinococcosis: Case Report.

We present a 40-year-old woman with a history of relapsing echinococcosis who had undergone a number of surgical procedures for cyst removal (right pulmectomy, cardiac surgery and 6 subsequent brain surgeries and two gamma knife procedures) and was admitted to University Hospital for Infectious Diseases "Fran Mihaljeviæ", Zagreb, Croatia in 2014 for pre-operative medical treatment of brain hydatidosis in the right parietal region. We aimed to attain a high cyst albendazole sulphoxide (ASO) concentration in order to achieve a more pronounced protoscolex inactivation and a high serum ASO concentration (reflecting the tissue concentrations) to reduce the risk of disease recurrence. The patient was treated with a higher dose of albendazole (15 mg/kg/day for 4 wk) that we had found effective in patients with liver hydatidosis, and combined with praziquantel over the last 14 d at a dose that is typically used to treat neurocysticercosis with an intention to improve ASO bioavailability. Neither serum nor cerebrospinal fluid concentrations on day 10 apparently differed from those on day 24 indicating a lack of an effect of praziquantel on ASO bioavailability. Intra-cystic ASO concentration was below the lower limit of quantification, but above the limit of detection. After the 7th episode of the disease and combined albendazole-praziquantel and surgery treatment, the patient achieved a 3-year remission. With the apparent lack of a meaningful pharmacokinetic praziquantel-albendazole interaction, this is most likely ascribable to the use of a higher albendazole dose than previously.

Nitrofurantoin in sediments and soils: Sorption, isotherms and kinetics.

Nitrofurantoin is nitrofuran antibacterial drug that is most used as a veterinary pharmaceutic compound. This compound, as well as other pharmaceuticals can greatly affect the environment, the soil and organisms in it and pollute aquatic ecosystems. Since it has been used for only a few decades, knowledge of their fate and behaviour in the environment is still limited. Because of that, the aim of this study was to experimentally determine the Kd values of nitrofurantoin in seven different natural soil and seven different sediment samples with different physico-chemical properties. Sorption phenomena were described with Linear, Freundlich and Dubinin-Radushkevich sorption isotherms. Obtained sorption coefficients (Kd) ranged from 3.967 to 5.121 mLg-1 for sediment samples and 3.634-43.06 mL g-1 for soil samples. The influence of ionic strength and pH of the nitrofurantoin solution and kinetics of the sorption and desorption process were also investigated. Results show that an increase in ionic strength and pH reduces the values of sorption coefficient while the mechanism of nitrofurantoin sorption is the best described with the kinetic model of pseudo-second order.

Fate of febantel in the aquatic environment-the role of abiotic elimination processes.

Febantel is widely used anthelmintic drug active against a range of gastrointestinal parasites in animals. Despite the fact that it has been detected in the aquatic environment, there is no information on its environmental fate. Therefore, abiotic elimination processes of febantel in the aquatic environment have been studied. The results of direct and indirect photodegradation experiments showed that febantel was persistent against solar radiation. Kinetics of hydrolytic elimination was pH and temperature dependent with half-lives in the range from 210 min to 99 days. Febantel metabolites, fenbendazole and fenbendazole sulfone, were found as major degradation products using high-resolution mass spectrometry. The proposed hydrolytic degradation pathway consisted of the base catalyzed hydrolysis followed by consecutive oxidative cyclization to the five-membered ring of the benzo-imidazole derivative. Aquatic toxicity of febantel and its hydrolytic mixture were evaluated toward the luminescence bacteria Vibrio fischeri. Investigation of febantel sorption onto river sediments showed that the best agreement was obtained with the linear model (R2 > 0.99), while the rate of sorption is the best described with the kinetic model of pseudo-second order. The organic carbon-normalized sorption coefficient, KOC, ranged from 1490 to 3894 L kg-1 for five sediment samples. The results of this research demonstrate that febantel persist in the natural waters and potentially could travel far from the source.

Sorption of albendazole in sediments and soils: Isotherms and kinetics.

Albendazole is a broad-spectrum anthelmintic drug effective against gastrointestinal parasites in humans and animals. Despite the fact that it has been detected in environment (water, sediment and soil), there is no information on its fate in the environment. So, in order to understand the sorption process of albendazole in environment, the sorption mechanism and kinetic properties were investigated through sorption equilibrium and sorption rate experiments. For that purpose, batch sorption of albendazole on five sediment samples and five soil samples from Croatia's region with different physico-chemical properties was investigated. Except physico-chemical properties of used environmental solid samples, the effects of various parameters such as contact time, initial concentration, ionic strength and pH on the albendazole sorption were studied. The Kd parameter from linear sorption model was determined by linear regression analysis, while the Freundlich and Langmuir sorption models were applied to describe the equilibrium isotherms. The estimated Kd values varied from 29.438 to 104.43 mLg-1 at 0.01 M CaCl2 and for natural pH value of albendazole solution (pH 6.6). Experimental data showed that the best agreement was obtained with the linear model (R2 > 0.99), while the rate of albendazole sorption is the best described with the kinetic model of pseudo-second-order. Obtained results point to a medium or even strong sorption of albendazole for soil or sediment particles, which is particularly dependent on the proportion of organic matter, pH, copper and zinc in them.

Forced degradation of nepafenac: Development and validation of stability indicating UHPLC method.

This paper presents stability study of the nonsteroidal anti-inflammatory drug (NSAID) nepafenac. In order to investigate stability of nepafenac, it was subjected to forced degradation under different stress conditions: acid and base hydrolysis, oxidation, humidity, heat and light. A novel stability indicating reverse phase ultra high performance liquid chromatographic (UHPLC) method coupled to ultraviolet detector has been developed to separate nepafenac and all related compounds (2-aminobenzophenone, Cl-thionepafenac, thionepafenac, Cl-nepafenac, hydroxy-nepafenac, and cyclic-nepafenac). Efficient chromatographic separation was achieved on a Waters Acquity BEH C18 stationary phase with a gradient elution. Quantification was carried out at 235 nm at a flow rate of 0.6 mL/min(-1). The resolution between nepafenac and six potential impurities is found to be greater than 2.0. The developed method was validated with respect to specificity, LOD, LOQ, linearity, precision, accuracy and robustness. The r(2) values for nepafenac and six potential impurities were all greater than 0.999. The developed method is capable to detect impurities of nepafenac at a level of 0.005% with respect to test concentration of 1.0mg/mL. Significant degradation is observed in acid, base and oxidative degradation conditions and degradation products (DPs) were identified using mass spectrometry analysis; two of them were found to be a known process related impurities (hydroxy- and cyclic-nepafenac) whereas four degradation products were identified as new degradation impurities. The forced degradation samples were assayed against a qualified reference standard and the mass balance was found to be close to 99.5%.

Albendazolesulphoxide concentrations in plasma and hydatid cyst and prediction of parasitological and clinical outcomes in patients with liver hydatidosis caused by Echinococcus granulosus.

AIM: To investigate the relationship between plasma and cyst concentrations of albendazolesulphoxide (ASO) and their effects on parasitological findings and disease recurrence in patients with liver hydatidosis. METHODS: The study was conducted at the University Hospital for Infectious Diseases Dr. Fran Mihaljevic, Zagreb, Croatia, between August 2006 and January 2011. Consecutive patients (N=48, age 6-77 years) were treated with albendazole (3×5 mg/kg/d) over 28 days before surgical cyst removal (n=34) or percutaneous evacuation (PAIR) (n=14). Plasma ASO was determined on days 10 and 28 of treatment and cyst concentrations at surgery/PAIR. RESULTS: Disease recurred in 3 surgically treated patients. Variability of ASO concentrations was substantial. Plasma concentrations on day 10 were higher than on day 28 (geometric means ratio [GMR] 2.00; 95%CI 1.38-2.91, P<0.001) and higher than cyst concentrations at the time of treatment (GMR=1.58, 1.01-2.34, P=0.045). Higher cyst (but not plasma) concentrations were independently associated with lower odds of protoscolex motility (OR=0.23, 0.01-0.70, P<0.001) and higher odds of protoscolex destruction (OR=1.17, 1.04-1.46, P<0.001). With adjustment for age and protoscolex motility, higher day 10 plasma concentrations (but not cyst concentrations) were associated with lower odds of disease recurrence (OR=0.49, 0.09-0.97, P=0.035). Plasma concentrations did not predict cyst concentrations. CONCLUSION: Viability of protoscolices progressively decreased with increasing ASO concentrations in the cyst. Data strongly suggested that higher plasma concentrations reduced the risk of disease recurrence.