Audiometric Outcomes of Ventilation Drainage Treatment for Otitis Media with Effusion in Children: Implications for Speech Development and Hearing Loss.

BACKGROUND Otitis media with effusion is the most commonly recognized condition in childhood. Chronic otitis media with accompanying hearing loss is particularly unfavorable in the first years of the child's life because it can not only permanently damage the structure of the middle ear, but also adversely affect speech development and intellectual abilities in the child. MATERIAL AND METHODS This study, from a single center in Poland, included 201 children (372 ears) requiring surgical treatment due to otitis media with effusion. The condition was diagnosed by an ear, nose, and throat specialist, and each patient had a hearing test performed. The control group consisted of 21 patients (42 ears) with negative outcomes following an audiological interview. RESULTS Among all of the patients enrolled in the study, a normal tympanometry result was found in 60.6% of ears, and otoemission occurred in 63.3% of ears. The average hearing threshold in the study group was 22.01 Hz in the 500 Hz frequency range, while they were 16.76 Hz, 12.72 kHz, and 14.78 kHz for the corresponding 1 kHz, 2 kHz, and 4 kHz ranges, respectively. CONCLUSIONS Ventilation drainage is an effective treatment for otitis media with effusion. The presence of genetic disease has the greatest impact on the course of otitis media. These patients most often require reinsertion of a ventilation tube.

Adenoid hypertrophy in children: a narrative review of pathogenesis and clinical relevance.

Adenoids (nasopharyngeal tonsils), being part of Waldeyer's ring, are masses of lymphoid tissues located at the junction of the roof and the posterior wall of the nasopharynx. Adenoids play an important role in the development of the immune system and serve as a defence against infections, being the first organs that come into contact with respiratory and digestive antigens. The causes of adenoid hypertrophy are not fully known. They are most likely associated with aberrant immune reactions, infections, environmental exposures and hormonal or genetic factors. The aim of this review is to summarise the current knowledge of adenoid hypertrophy in children and associated diseases. Adenoid hypertrophy has many clinical manifestations that are frequent in the paediatric population and is accompanied by various comorbidities.

An Evaluation of Health-Related Quality of Life in Children with Nasal Septum Deviation.

BACKGROUND: From the 1950s, the quality of life criterion came to be studied in earnest, originally forming a part of measurement of human development in Western Europe and the USA. The present study aims to compare the health-related quality of life (HRQL) between children with nasal septum deviation and healthy children controls. MATERIALS AND METHODS: Subjects were children suffering from nasal septum deviation, one of the commonest chronic diseases of the upper respiratory tract. Controls were randomly recruited from kindergarten, primary and secondary schools (junior high school & high school). All schools and subjects were randomly selected. The CHQ-PF50 questionnaire was used and outcome scores were calculated by an algorithm for the 13 tested HRQL variables. RESULTS: Means for all outcome scores in the test subjects (i.e., children with deviated nasal septums) varied between 3.65-89.27 with a standard deviation between 0.83-25.66 and a median between 3.4-100 (n = 101). Those for the controls (n = 102) were 3.78-97.11, 0.86-14.21 and 4.40-100, respectively. Test subjects showed significant scoring declines in Physical Fitness, Role/Social-Emotional/Behavioral, Role/Social-Physical, Mental Health, Self-esteem, General Health Perceptions, Parental Impact Emotional and Time and Family Limitations in Activities. CONCLUSIONS: 1. The well-being of children with nasal septum deviation was found to be chiefly limited by their physical fitness, effects of physical condition on social behavior/interaction and how health is perceived. 2. Parents considered their children's health to be paramount, as demonstrated by assessing the HRQL.

Comparison of Lipid Properties and Cadmium and Lead Content in Red Deer (Cervus elaphus) Meat from Three Feeding Grounds.

The aim of the study was to compare the properties of lipids and the content of cadmium and lead in the meat of red deer (Cervus elaphus) kept in a forest feeding ground (FFG) and on organic and conventional farms in Poland. Longissimus lumborum (LL) and Musculus semimembranosus (SM) muscles were collected for the study from 36 red deer carcasses in an equal sex and age ratio (3 and 4 years old). From April to October, the animals consumed only the vegetation growing in the feeding grounds. The floristic and phytoncide composition, as well as the fodder value, of the feeding grounds were assessed. Additionally, the intramuscular fat and cholesterol content, the profile, sum, and ratios of fatty acids (FAs), lipid nutraceutical parameters, and cadmium and lead content were determined in LL and SM. The plant composition comprised 116 species in the organic feeding ground (OFG) and 78 species in the conventional feeding ground (CFG). The LL and SM muscles of the red deer from the organic and forest feeding grounds exhibited significantly lower amounts of fat and cholesterol than those from the conventional system. The differences in the fatty acid composition between the three groups were quite small. Differences in intramuscular fat content contributed to a higher percentage of PUFAs in the FFG and OFG, in comparison to the CFG. In all types of feeding ground, the cadmium (0.002 to 0.008 mg/kg) and lead (0.009 to 0.019 mg/kg) content determined in the meat did not pose a threat to consumers.

Physical and Psychosocial Concept Domains Related to Health-Related Quality of Life (HRQL) in 50 Girls and 52 Boys Between 5 and 18 Years Old in Poland Using the Parent-Reported 50-Item Child Health Questionnaire (CHQ-PF50).

BACKGROUND We used the parent-reported 50-item Child Health Questionnaire (CHQ-PF50) to evaluate parental by-proxy responses regarding 102 healthy Polish children and adolescents, aged 5 to 18 years, in 13 physical and psychosocial concept domains linked to health-related quality of life (HRQL) to determine which domains pose the greatest limitations to health. MATERIAL AND METHODS Participants were 50 healthy female and 52 healthy male school children (nursery, primary, junior-high, and high), selected randomly and found eligible from 585 participants originally recruited; participants with diseases/ailments and incomplete questionnaires were excluded. The CHQ-PF50 has 50 questions divided into 13 domains that represent physical and mental well-being; parents gave their retrospective responses from memory. Scores were expressed numerically using a standard algorithm and ranged from 0 to 100; higher scores represented more favorable HRQL outcomes. Summary statistics were performed, and age and sex effects were assessed. RESULTS Mean HRQL domain scores never attained 100 (maximum value). They were lowest (P<0.004) for domains of Family Cohesion (66.57), Parental Emotional (77.21), and General Health Perceptions (75.41), while highest (but still significantly <100, P<0.047) in Physical Functioning (97.11), Role/Social Emotional-Behavioral (96.51), and Role/Social-Physical (96.24). Neither age nor sex significantly affected domain scores. Outcomes were comparable to European and US studies but differed from a previous small-scale Polish study. CONCLUSIONS None of the CHQ-PF50 domain mean values reached the maximum in apparently healthy Polish children. HRQL was lowest in Family Cohesion, Parental Emotional, and General Health Perceptions. Outcomes are considered a useful control baseline in Polish studies on disease.

A review of health-related quality of life issues in children suffering from certain key otolaryngological illnesses.

Background: The health-related quality of life (HRQoL) concept is nowadays increasingly and more broadly used for helping evaluate the effectiveness of medical treatment, superseding the earlier "quality of life" approach. The HRQoL concept likewise applies to otolaryngology and this narrative review study is focused on HRQoL outcomes in four key childhood otolaryngological diseases as reported in the literature. Study aim: To retrospectively evaluate the literature on measuring HRQoL in children suffering from selected otolaryngological illnesses, during treatment. Materials and Methods: Published studies/case reports were searched for in Medline, PubMed, Web of Science, Scopus and ORCID on the quality of life based on paediatric patient questionnaires, whether completed by subjects themselves or by their parents (by proxy). The following key words were used: health quality of life, otolaryngology/ENT, pediatrics/paediatrics. Studies before 1999 were omitted because hitherto, the "quality of life" had been imprecisely defined thus rendering any subsequent comparisions problematic. Results: HRQoL scores and well-being were found to significantly deteriorate in child patients suffering from four important otolaryngological disorders: chronic sinusitis, nasal septum deviation, adenoid hypertrophy and hearing disease. The main problems found were infection, inflammation, disruption to family life and child-parental interaction, fitness-related issues, reduced ENT patencies and apnea. Conclusions: The HRQoL appears to significantly deteriorate in children suffering from otolaryngological diseases. Further such studies are needed for other ENT diseases.

Health-Related Quality of Life Assessed in Children with Chronic Rhinitis and Sinusitis.

INTRODUCTION: Quality of life (QoL) can be simply defined as an area of human life that directly affects people which they consider to be important. This can be defined in greater detail as 'an individual perception of an individual's life position within a cultural context, value system and in relation to their tasks, expectations and standards determined by environmental conditions'. The health-related quality of life (HRQoL) more specifically focuses on how the QoL affects health (including both medical and non-medical issues). Limitations in well-being will, by association, also occur in those children suffering with sinus diseases. STUDY AIM: To compare the quality of life in children-adolescents suffering from some of the most commonly occurring childhood diseases of chronic rhinitis and sinusitis on a group of healthy children-adolescents. Test materials and methods: Subjects were children-adolescents with at least one of the aforementioned conditions afflicting the upper respiratory tract. Admission criteria were: ages 5 to 18 years in the presence of a chronic disease such as chronic rhinitis and paranasal sinusitis. The Child Health Questionnaire-Parent Form 50 CHQ-PF-50 (CHQ-PF50) was used, which is a general-purpose research instrument based on psychometric testing designed for assessing physical and mental well-being in children-adolescents aged 5 to 18 years. RESULTS: Wellbeing significantly deteriorated in sick children within the following areas: current health status of the child (STAND), physical fitness (PF), social functioning resulting from behaviour or emotional state (REB), the impact of physical health on limitations in social functioning (RP), pain and discomfort (BP), behaviour (BE), mental health (MH), self-esteem (SE), general health perception (GH), influence of the child's health condition on parental emotions (PE), limitations on parental leisure time due to the child's health (PT) and restrictions on joint family activities (FA). CONCLUSIONS: The greatest impairment to well-being in children with chronic rhinitis and paranasal sinusitis was on the impact of the child's health status on parents' emotions, pain and discomfort and general perception of health. This study confirms that parents of healthy children attach great importance to their health and health-related quality of life.

Fatty Acids and Nutraceutical Properties of Lipids in Fallow Deer (Dama dama) Meat Produced in Organic and Conventional Farming Systems.

The aim of the study was to assess the fatty acid profile and nutraceutical properties of lipids contained in fallow deer (Dama dama) meat produced in organic and conventional farming systems. Longissimus lumborum (LL) and semimembranosus (SM) muscles from 24 fallow deer carcasses were selected for the study. The fallow deer meat from the organic farming system was characterized by significantly lower intramuscular fat content. The fatty acid profile in the organic meat was characterized by a particularly high proportion (p < 0.0001) of conjugated linoleic acid-CLA (LL-2.29%, SM-2.14%), alpha-linolenic acid-ALA (LL-4.32%, SM-3.87%), and docosahexaenoic acid-DHA (LL-2.83%, SM-2.60%). The organic system had a beneficial effect (p < 0.0001) on the amount of polyunsaturated fatty acids (PUFAs), including n-3 PUFAs, which resulted in a more favorable n-6 PUFA (polyunsaturated fatty acid)/n-3 PUFA ratio. The significantly higher nutritional quality of organic meat lipids was confirmed by such nutraceutical indicators as the thrombogenic index (TI), ∆9-desaturase C16, elongase, and docosahexaenoic acid+eicosapentaenoic acid (DHA+EPA) in the LL and SM and cholesterol index (CI), and the cholesterol-saturated fat index (CSI) indices in the SM. LL was characterized by higher overall quality.

Health-Related Quality of Life Assessed in Children with Adenoid Hypertrophy.

INTRODUCTION: The quality of life issue began to be earnestly studied in the second half of the 20th century. It had originally been used as a criterion for measuring levels of human development in the USA and Western Europe. At first, only objective parameters were assessed, such as material goods; however, later, subjective and non-material parameters were added, such as health, freedom, and happiness. Over time, more and more attention has been paid to the subjective parameters regarding any quality of life assessment. Adenoids are physiological clusters of lymphoid tissue included in Waldeyer's ring, which play an important role in shaping and directing the child's local and systemic lines of defence. Adenoid hypertrophy occurs due to a variety of factors, such as recurring or chronic infections of the upper respiratory tract. STUDY AIM: To assess health status in children with adenoid system hypertrophy compared with a group of healthy children. MATERIALS AND METHODS: The study group consisted of children suffering from adenoid hypertrophy, this being the most common chronic disease of the upper respiratory tract. The control group was composed of children attending nursery school (kindergarten), primary school, middle school, and high school. The study was performed by using the Child Health Questionnaire-Parent Form 50 CHQ-PF-50 (CHQ-PF50), which is a general purpose research tool based on psychometric testing when assessing physical and mental well-being in children aged 5 to 18 years. RESULTS: There were 101 filled out questionnaires for the test group (54 girls and 47 boys), mean age 8.62 years (ranging 5-17), whilst 102 questionnaires for the controls (50 girls and 52 boys), mean age 10.58 years (ranging 5-18). Insignificant differences were found between social functioning resulting from behaviour or emotional state (REB), pain and discomfort (BP), and family cohesion (FC). CONCLUSIONS: Children suffering from adenoid hypertrophy demonstrate the largest decreases in wellbeing in the following areas: behaviour, general perception of health, and mental health.

Content of Selected Macro- and Microelements in the Liver of Free-Living Wild Boars (Sus Scrofa L.) from Agricultural Areas and Health Risks Associated with Consumption of Liver.

The aim of the study was to determine the levels of selected toxic and non-toxic elements in the liver of free-living wild boars from agricultural areas and to assess health risks associated with liver consumption. Samples were collected from 70 wild boars. The animals were divided into three age groups (group I up to one year, group II from one to three years, group III over three to five years). It was shown that wild boar liver is a rich source of mineral compounds (K, Fe, Mg, Ca, Zn, and Cu). The age was found to exert an effect on the concentration of most minerals. The sex significantly determined the content of Fe, Ca, and Cd. The maximum allowable level of Cd in the liver was exceeded in two and three samples from groups I and III, respectively. Therefore, regular monitoring of the content of this element in tissues of game animals is extremely important and advisable to assess the consumer exposure to this metal. From the point of view of human health, the estimation of the non-carcinogenic risk indicated that the intake of individual trace elements through the consumption of the liver was safe, whereas consumption of combined trace elements (only in the case of the consumption of the wild boar liver twice a week) suggested a potential health risk to children.

Meat quality of Pulawska breed pigs and image of longissimus lumborum muscle microstructure compared to commercial DanBred and Naima hybrids.

The objective of this article was the evaluation of selected properties of meat quality including the characteristics of longissimus lumborum (LL) muscle microstructure of Pulawska breed pigs and fatteners of the DanBred and Naima hybrids which are used in national meat production. Three genetic groups of fatteners were studied in the experiment: group I - DanBred hybrid; group II - Naima hybrid; and group III - the Pulawska breed. Pig fattening took place under the same environmental conditions from the starting weight of 30 kg  ±  2 kg to 103-105 kg. For the analysis of muscle fibre characteristics and meat quality from each group, 30 animals were selected (  1 : 1  ). Physico-chemical properties and ultrastructure were evaluated in samples collected from the LL muscle. A statistically significant impact ( P < 0.01 ) of a genetic group on pH 45 , content of water, protein and ash, as well as on the colour of meat, the number of STOs (slow-twitch oxidatives) and the diameter of FTG (fast-twitch glycolytic) muscle fibres, was found. Meat of the Pulawska breed, compared to DanBred and Naima, showed a statistically significant ( P < 0.01 ) higher (by 2.05 % and 2.49 %, respectively) nutritional value expressed as protein content and mineral components. Overall, these results imply better biological properties of Pulawska meat than DanBred and Naima hybrids. The higher STO and lower FTG found in muscles from Pulawska pigs might partially explain meat quality differences found between the breeds in the present study. The data of the current study indicated that meat quality characteristics and muscle microstructure of fatteners showed differences, and these differences may be used for alternative pork meat production for the consumer.

Correction to: Population pharmacokinetic approach for evaluation of treosulfan and its active monoepoxide disposition in plasma and brain on the basis of a rat model.

The original version of this article, published on 30 May 2020 contained a mistake.

Population pharmacokinetic approach for evaluation of treosulfan and its active monoepoxide disposition in plasma and brain on the basis of a rat model.

PURPOSE: Efficacy of treosulfan, used in the treatment of marrow disorders, depends on the activity of its monoepoxy-(EBDM) and diepoxy compounds. The study aimed to describe the pharmacokinetics of treosulfan and EBDM in the rat plasma and brain by means of mixed-effects modelling. METHODS: The study had a one-animal-per-sample design and included ninty-six 10-week-old Wistar rats of both sexes. Treosulfan and EBDM concentrations in the brain and plasma were measured by an HPLC-MS/MS method. The population pharmacokinetic model was established in NONMEM software with a first-order estimation method with interaction. RESULTS: One-compartment pharmacokinetic model best described changes in the concentrations of treosulfan in plasma, and EBDM concentrations in plasma and in the brain. Treosulfan concentrations in the brain followed a two-compartment model. Both treosulfan and EBDM poorly penetrated the blood-brain barrier (ratio of influx and efflux clearances through the blood-brain barrier was 0.120 and 0.317 for treosulfan and EBDM, respectively). Treosulfan plasma clearance was significantly lower in male rats than in females (0.273 L/h/kg vs 0.419 L/h/kg). CONCLUSIONS: The developed population pharmacokinetic model is the first that allows the prediction of treosulfan and EBDM concentrations in rat plasma and brain. These results provide directions for future studies on treosulfan regarding the contribution of transport proteins or the development of a physiological-based model.

Technological and nutritional properties of meat from female wild boars (Sus scrofa scrofa L.) of different carcass weights.

The aim of this work was to assess the technological and nutritional quality of meat from female wild boars. The muscle samples - Musculus longissimus thoracis et lumborum (LTL) and Musculus semimembranosus (SM) - were taken from a total of 40 female wild boar after a hunt. Carcasses were allocated to five groups according to weight (group I - 30 ± 5  kg; group II - 45 ± 4.9  kg; group III - 60 ± 4.7  kg; group IV - 75 ± 5.2  kg; group V - 90 ± 5  kg). Studies that have been carried out have shown that technological and nutritional properties of meat from wild boars depend on the mass of carcasses and the type of muscle. The pH of analyzed wild boar meat proved that there was normal glycolysis and glycogenolysis progress in all groups. The water holding capacity (WHC) of SM muscles from the lowest-weight carcasses was significantly ( P ≤ 0.01 ) lower as compared to the heavier carcasses. There were significant differences ( P ≤ 0.01 ) in the shear force of the LTL muscle between groups I, IV and V. The muscles cut from carcasses of a higher mass represent higher values of this parameter. The higher-mass carcasses were characterized by a darker color, which resulted from the higher concentration of myoglobin. The protein concentration increased with carcass weight. A similar effect of carcass weight on the content of intramuscular fat (IMF) was found. Due to the low calorie content, the meat of young wild boar may be an interesting and attractive component of the diet.

Relationship between exposure to treosulfan and its monoepoxytransformer - An insight from population pharmacokinetic study in pediatric patients before hematopoietic stem cell transplantation.

Treosulfan (TREO), a structural analog of busulfan, is currently studied as a myeloablative agent in conditioning regimens before hematopoietic stem cell transplantation in pediatric patients. High exposure to TREO (>1650 mg∗h/mL) might be related to early toxicity, especially skin toxicity and mucositis. The aim of the present study was to investigate a potential relationship between exposure to TREO and its monoepoxytransformer (S,S-EBDM), as well as variability of the pharmacokinetics of these entities by means of a population pharmacokinetic approach with a non-linear mixed-effects analysis. The study included data from 14 children with malignant and non-malignant diseases treated with TREO in daily doses 10-14 g/m2. The parent-metabolite population pharmacokinetic model was developed in NONMEM 7.3 software. Upon the constructed model, an extensive simulation was performed to assess the correlation between exposure to TREO and S,S-EBDM. It was found that TREO and S,S-EBDM pharmacokinetics was best described with 2-compartmental and 1-compartmental linear models, respectively. The vast majority (>65%) of TREO was transformed to S,S-EBDM. Overall, a considerable interpatient variability of pharmacokinetic parameters was observed, especially the clearance of S,S-EBDM. A weak correlation was found between the exposure to TREO and S,S-EBDM (r = 0.1681, p < 0.0001). Also, patients with an exposure to TREO above 1650 mg∗h/mL were most likely to have also a high exposure to S,S-EBDM (35.38 µM∗h vs. 43.14 µM∗h, p < 0.0001). In summary, a parent-metabolite population pharmacokinetic model for TREO and S,S-EBDM was developed for the first time. It was shown that there is a weak correlation between exposure to TREO and S,S-EBDM. Therefore therapeutic drug monitoring of not only prodrug but also its active epoxide might be needed.

Population pharmacokinetics of treosulfan and development of a limited sampling strategy in children prior to hematopoietic stem cell transplantation.

PURPOSE: There is an increasing interest in use of treosulfan (TREO), a structural analogue of busulfan, as an agent in conditioning regimens prior to hematopoietic stem cell transplantation (HSCT), both in pediatric and adult populations. The aim of this study was to develop a population pharmacokinetic model and to establish limited sampling strategies (LSSs) enabling accurate estimation of exposure to this drug. METHODS: The study included 15 pediatric patients with malignant and non-malignant diseases, undergoing conditioning regimens prior to HSCT including TREO administered as a 1 h or 2 h infusion at daily doses of 10, 12, or 14 g/m2. A population pharmacokinetic model was developed by means of non-linear mixed-effect modeling approach in Monolix® software. Multivariate regression analysis and Bayesian method were used to develop 2- and 3-point strategies for estimation of exposure to TREO. RESULTS: Pharmacokinetics of TREO was best described with a two-compartmental linear model with proportional residual error. Following sampling schedules allowed accurate estimation of exposure to TREO: 1 h and 6 h or 1 h, 2 h, and 6 h for a TREO dose 12 g/m2 in a 1 h infusion, or at 2 h and 6 h or 2 h, 4 h, and 8 h for a TREO dose of 12 g/m2 and 14 g/m2 in a 2 h infusion. CONCLUSIONS: A two-compartmental population pharmacokinetic model of TREO was developed and successfully used to establish 2- and 3-point LSSs for accurate and precise estimation of TREO AUC0→∞.

HBcAg produced in transgenic tobacco triggers Th1 and Th2 response when intramuscularly delivered.

Hepatitis B core Antigen (HBcAg) assembled into Capsid-Like Particles (CLPs) is investigated as a therapeutic vaccine in treatment of chronic hepatitis B (CHB) and in diagnostic tests or as a carrier for various epitopes. While the expression of HBcAg has been thoroughly clarified in E. coli and yeast, it has also been investigated in other expression systems. Stably transformed tobacco expressed HBcAg at a level of 110-250µg/g fresh weight, therefore in view of its large leaf biomass it offers a production platform comparable with transient expression systems regarding the final yield of HBcAg. Several extraction and purification methods were tested and finally the antigen was purified up to 43% using sucrose density gradient centrifugation. The purified HBcAg retained its antigenicity, as confirmed by ELISA and western blot, while maintaining its CLP-structure as observed in TEM. In mice HBcAg intramuscularly delivered at 2×10µg triggered a significant response (serum anti-HBc titre around 150,000), being statistically equivalent to that induced by the reference antigen. Among anti-HBc IgG isotypes, IgG2a and then IgG1 were increasing during immune response. However IgG2b and IgG3 were also induced, especially in mice immunised with the plant-derived antigen. Analysis of the isotype profile indicates mainly Th1 polarisation, but completed with Th2 response. Obtained results indicate a considerable potential of plant-derived HBcAg as a therapeutic vaccine, since a mixed immune response with a stronger Th1 component is particularly required for treatment of CHB.

Disposition of treosulfan and its active monoepoxide in a bone marrow, liver, lungs, brain, and muscle: Studies in a rat model with clinical relevance.

For the recent years, the application of treosulfan (TREO)-based conditioning prior to hematopoietic stem cell transplantation (HSCT) has been increasing as an alternative to busulfan-based therapy, especially for patients presenting high risk of developing hepato-, pulmo-, and neurotoxicity. So far, the penetration of TREO and its epoxy-derivatives into central nervous system and aqueous humor of the eye has been investigated. However, lacking knowledge on the compounds distribution into the other key tissues precludes comprehensive understanding and assessment of TREO clinical efficacy and toxicity. In this paper, the disposition of TREO and its active monoepoxide (S,S-EBDM) in a bone marrow, liver, lungs, brain, and quadriceps femoris was studied in an animal model. Male and female adult Wistar rats (n=48/48) received an intraperitoneal injection of TREO at the dose of 500mg/kg b.w. Concentrations of TREO and S,S-EBDM in tissues were determined with a validated HPLC-MS/MS method. Pharmacokinetic calculations were performed in WinNonlin using a noncompartmental analysis. Mean values of the maximal concentrations of TREO and S,S-EBDM in the organs were sex-independent and ranged from 61 to 1650µM and 25-105µM, respectively. No quantifiable levels of S,S-EBDM were found in the liver. Average tissue/plasma area under the curve (AUC) ratio for unbound TREO increased in the sequence: brain (0.10)

Determination of prodrug treosulfan and its biologically active monoepoxide in rat plasma, liver, lungs, kidneys, muscle, and brain by HPLC-ESI-MS/MS method.

A prodrug treosulfan (TREO) is currently investigated in clinical trials for conditioning prior to hematopoietic stem cell transplantation. Bioanalysis of TREO and its active derivatives, monoepoxide (S,S-EBDM) and diepoxide, in plasma and urine underlay the pharmacokinetic studies of these compounds but cannot explain an organ pharmacological action or toxicity. Recently, distribution of TREO and S,S-EBDM into brain, cerebrospinal fluid, and aqueous humor of the eye has been investigated in animal models and the obtained results presented clinical relevance. In this paper, a selective and rapid HPLC-ESI-MS/MS method was elaborated and validated for the studies of disposition of TREO and S,S-EBDM in rat plasma, liver, lungs, kidneys, muscle, and brain. The two analytes and codeine, internal standard (IS), were isolated from 50µL of plasma and 100µL of supernatants of the tissues homogenates using ultrafiltration Amicon vials. Chromatographic resolution was accomplished on C18 column with isocratic elution. The limits of quantitation of TREO and S,S-EBDM in the studied matrices ranged from 0.11 to 0.93µM. The HPLC-MS/MS method was adequately precise and accurate within and between runs. The IS-normalized matrix effect differed among the tissues and was the most pronounced in a liver homogenate supernatant (approximately 0.55 for TREO and 0.35 for S,S-EBDM). Stability of the analytes in experimental samples was also established. The validated method for the first time enabled determination of TREO and S,S-EBDM in the six life-important tissues in rats following administration of the prodrug.

Ocular disposition of treosulfan and its active epoxy-transformers following intravenous administration in rabbits.

Treosulfan (TREO) has an established position in chemotherapy of advanced ovarian cancer but has been also applied in uveal melanoma patients. Moreover, it is used as an orphan drug for a myeloablative conditioning prior to stem cell transplantation. In this paper, biodistribution of prodrug TREO and its active monoepoxide (S,S-EBDM) and diepoxide (S,S-DEB) into aqueous humor of the eye was studied for the first time. For that purpose, alone TREO and the mixture of TREO, S,S-EBDM and S,S-DEB were administered intravenously to New Zealand White rabbits. The three analytes were determined in plasma and aqueous humor by validated HPLC methods and pharmacokinetic calculations were performed in WinNonlin. After the infusion of TREO, the aqueous humor/plasma Cmax ratio and area under the curve ratio amounted 0.04 and 0.10 for TREO, and 1.1 and 2.2 for S,S-EBDM, respectively. Following the bolus injection of the mixture of the prodrug and its epoxides, the aqueous humor/plasma Cmax ratios for TREO, S,S-EBDM and S,S-DEB were 0.05, 0.66, and 4.0, respectively. The presented results indicate a poor penetration of TREO into the eye, which may impair systemic treatment of ocular tumors but is beneficial in terms of a lack of clinically relevant ophthalmic adverse effects.