Antiproliferative effects of LY-2183240 combined with various chemotherapeutic drugs in an isobolographic in vitro model of malignant melanoma.

Despite a great progress in identifying treatment options for patients with malignant melanoma, novel therapies tend to be costly and, in some cases, produce adverse effects forcing the melanoma patients to withdraw drugs. There is a strong need for less expensive drugs with a more favorable spectrum of anticancer actions. This study was designed to assess whether LY-2183240 (a potent inhibitor of both, anandamide cellular reuptake and fatty acid amide hydrolase (FAAH), an enzyme that degrades anandamide) has antiproliferative and cytotoxic effects on various human malignant melanoma cell lines (primary A375 and FM55P, metastatic SK-MEL28 and FM55M2) when administered alone or in combination with docetaxel, paclitaxel, mitoxantrone and cisplatin via the MTT assay. The MTT, LDH and BrdU assays were used to evaluate the potency and safety of LY-2183240, whereas isobolographic analysis of interactions was applied to characterize the interactions of LY-2183240 with the studied chemotherapeutics (docetaxel, paclitaxel, mitoxantrone and cisplatin). The isobolography confirmed that the combinations of LY-2183240 with docetaxel, paclitaxel and mitoxantrone produced additive interactions in all the tested melanoma cell lines. Only two antagonistic interactions for LY-2183240 combined with cisplatin in the A375 and FM55P cell lines were observed by the MTT assay. In conclusion, LY-2183240 can be considered an add-on drug for the treatment of melanoma, when combined with docetaxel, paclitaxel, or mitoxantrone, but not with cisplatin.

Acceptance of euthanasia by students of selected study disciplines at universities in Lublin, Poland.

BACKGROUND: In the context of discussions between supporters and opponents of euthanasia, and legal regulations regarding this type of practices, the attitude of young people with respect to this phenomenon is a very interesting issue. According to Polish law, euthanasia is prohibited. The aim of this study was to determine the degree of acceptance of euthanasia among students from Polish universities across three different fields of study: psychology, medicine, and economic-technical disciplines, and to identify the factors associated with the acceptance of this phenomenon. METHODS: The study included 627 persons studying in Lublin, Poland: medicine (280), psychology (170), and economic-technical studies (177). The study was conducted as a survey using questionnaire containing items concerning students' attitudes towards euthanasia. The analysis of the collected data was conducted using the SPSS software (version 29) with the following methods: Chi2, Student's t-test, Phi test, Cramer's V test, Kolmogorov-Smirnov test, one-way ANOVA with Dunnett's post hoc test, linear regression analysis, and categorical regression analysis using optimal scaling (CATREG). RESULTS: Nearly half of the students participating in the study (45.9%) rated the practice of euthanasia as decidedly negative. The highest number of strongly negative evaluations was found among psychology students, and the least among students of economic-technical disciplines. The level of acceptance of euthanasia is significantly associated with religious involvement and studying psychology. Being religious and being a psychology student both contribute to lower acceptance of euthanasia and a lower willingness to consent to euthanasia. Consent to euthanasia is more commonly declared by individuals with experience of living with elderly people. CONCLUSIONS: Although nearly half of the respondents expressed a negative attitude towards euthanasia, considering the secularization process among Polish youth, it can be assumed that the level of acceptance of euthanasia in this social group will increase. The lower level of acceptance of euthanasia among psychology and medical students compared to students of economic-technical disciplines suggests that the curricula of these studies present alternative solutions to the problems of terminally ill patients other than euthanasia.

AM1172 (a hydrolysis-resistant endocannabinoid analog that inhibits anandamide cellular uptake) reduces the viability of the various melanoma cells, but it exerts significant cytotoxic effects on healthy cells: an in vitro study based on isobolographic analysis.

BACKGROUND: Despite great advances in our understanding of the impact of cannabinoids on human organism, many of their properties still remain undetermined, including their potential antineoplastic effects. This study was designed to assess the anti-proliferative and cytotoxic effects of AM1172 (a hydrolysis-resistant endocannabinoid analog that inhibits anandamide cellular uptake) administered alone and in combinations with docetaxel (DOCX), paclitaxel (PACX), mitoxantrone (MTX) and cisplatin (CDDP) on various human malignant melanoma A375, FM55P, SK-MEL 28 and FM55M2 cell lines. MATERIALS: In the MTT, LDH, and BrdU assays, the potency and safety of AM1172 when administered alone and in combinations with DOCX, PACX, MTX, and CDDP were determined. RESULTS: The isobolographic analysis revealed that combinations of AM1172 with PACX, DOCX, MTX, and CDDP exerted additive interactions, except for a combination of AM1172 with PACX in primary melanoma A375 cell line, for which synergy was observed (*p<0.05). Nevertheless, AM1172 when administered alone produced cytotoxic effects on healthy human melanocytes (HEMa-LP) and human keratinocytes (HaCaT), which unfortunately limits its potential therapeutic utility. CONCLUSIONS: AM1172 cannot be used separately as a chemotherapeutic drug, but it can be combined with PACX, DOCX, MTX, and CDDP, offering additive interactions in terms of the anti-proliferative effects in various malignant melanoma cell lines.

Imperatorin interacts additively with novel antiseizure medications in the mouse maximal electroshock-induced seizure model: an isobolographic transformation.

BACKGROUND: Anticonvulsant effects of imperatorin (IMP) have been experimentally confirmed earlier, but no information is available on the interaction profiles of this naturally occurring coumarin when combined with novel antiseizure medication (ASMs). This study aimed to determine the effects of IMP on the anticonvulsant effects of lacosamide (LCM), oxcarbazepine (OXC), pregabalin (PGB), and topiramate (TPM) in the maximal electroshock-induced seizure (MES) model in mice. METHODS: The anticonvulsant effects exerted by novel ASMs (LCM, OXC, PGB, and TPM) when combined with constant doses of IMP (25 and 50 mg/kg) underwent isobolographic transformation to precisely classify the observed interactions in the mouse MES model. Total brain concentrations of ASMs were measured with high-pressure liquid chromatography to exclude the pharmacokinetic nature of interactions among IMP and the tested ASMs. RESULTS: IMP (50 mg/kg) significantly enhanced (p < 0.01) the anticonvulsant potency of LCM, OXC, PGB, and TPM in the mouse MES model. IMP (25 mg/kg) mildly potentiated the anticonvulsant action of LCM, OXC, PGB, and TPM, but no statistical significance was reported for these combinations. The isobolographic transformation of data from the MES test revealed that the interactions of novel ASMs with IMP were additive. Moreover, IMP (50 mg/kg) did not affect the total brain content of any of the novel ASMs in experimental mice. CONCLUSIONS: The additive interactions of IMP with LCM, OXC, PGB, and TPM in the mouse MES model accompanied by no pharmacokinetic changes in the total brain content of ASMs are worthy of recommendation for further studies.

Anticonvulsant effects of isopimpinellin and its interactions with classic antiseizure medications and borneol in the mouse tonic-clonic seizure model: an isobolographic transformation.

BACKGROUND: Overwhelming evidence indicates that some naturally occurring coumarins and terpenes are widely used in folk medicine due to their various therapeutic effects affecting the brain. Antiseizure medications (ASMs) are the principal treatment option for epilepsy patients, although some novel strategies based on naturally occurring substances are intensively investigated. This study was aimed at determining the influence of isopimpinellin (ISOP-a coumarin) when administered either separately or in combination with borneol (BOR-a monoterpenoid), on the antiseizure potencies of four classic ASMs (carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB), and valproate (VPA)) in the mouse model of maximal electroshock-induced (MES) tonic-clonic seizures. MATERIALS: Tonic-clonic seizures were evoked experimentally in mice after systemic (ip) administration of the respective doses of ISOP, BOR, and classic ASMs. Interactions for two-drug (ISOP + a classic ASM) and three-drug (ISOP + BOR + a classic ASM) mixtures were assessed isobolographically in the mouse MES model. RESULTS: ISOP (administered alone) had no impact on the anticonvulsant potencies of four classic ASMs. Due to the isobolographic transformation of data, the combination of ISOP + VPA exerted an antagonistic interaction, whereas the two-drug mixtures of ISOP + CBZ, ISOP + PHT, and ISOP + PB produced additive interactions in the mouse MES model. The three-drug combinations of ISOP + BOR with CBZ and PHT produced additive interactions, while the three-drug combinations of ISOP + BOR with PB and VPA exerted synergistic interactions in the mouse MES model. CONCLUSIONS: The most intriguing interaction was that for ISOP + VPA, for which the addition of BOR evoked a transition from antagonism to synergy in the mouse MES model.

Evaluation of the quality of life of older people with diabetes.

INTRODUCTION AND OBJECTIVE: Diabetes is commonly classified as a chronic disease of affluence due to the frequency of its incidence and the rate of its spreading. The aim of the study was to evaluate the quality of life of geriatric patients with type 2 diabetes. MATERIAL AND METHODS: 294 seniors diagnosed with type 2 diabetes living in the Lower Silesian Province in south-western Poland took part in the study. The study used a self-developed questionnaire collecting clinical and socio-demographic data, the WHOQOL-Bref questionnaire, Acceptance of Illness Scale (AIS), Self-Care of Diabetes Inventory (SCODI) and the Geriatric Depression Scale (GDS). RESULTS: Significant relationships of QoL with BMI, level of education and place of residence, were observed. BMI was significantly negatively correlated with the psychological domain of functioning and the environmental functioning, the level of education was correlated with physical health, psychological and environmental functioning, while the place of residence was correlated with the perception of the QoL and environmental functioning. Acceptance of illness was positively correlated with the perception of QoL and one's physical health. The results of regression analyses in predicting QoL in all domains showed that all models were a good fit for the data (p < 0.001), and the single predictor was maintenance of self-care. The level of depression was negatively correlated to a statistically significant degree with the perception of QoL and one's health condition. CONCLUSIONS: BMI, level of education and place of residence had the highest impact on the quality of life of the participants. The quality of life of the participants improved with the increase in the acceptance of their illness. The higher the level of depression exhibited by the participants, the poorer they evaluated their quality of life.

Euthanasia in opinions of students of medicine.

INTRODUCTION AND OBJECTIVE: Euthanasia assumes the deliberate deprivation of life of another human being for the good of that person. At present, euthanasia is legally practiced in Holland, Belgium, Luxemburg, Columbia and Canada. In Poland, euthanasia is strictly prohibited. The aim of this work is to present the opinions of medical students about euthanasia. An anonymous questionnaire was conducted among first-year students of medicine at the Medical University of Lublin, Poland. MATERIAL AND METHODS: The anonymous questionnaire consisted of 35 questions that concerned three components of euthanasia attitude: knowledge, evaluation, and acceptance of its use. The study included 281 students of medicine (77.6% of all first-year students). RESULTS: Although euthanasia in Poland is legally prohibited, almost one-fifth of students of medicine expressed a positive attitude towards euthanasia, and over a quarter of students opted for its legalization. Only two independent variables, i.e., family size (number of children) and religious involvement of the respondents, differentiated both the overall assessment of euthanasia and the level of acceptance for its legalization. Non-religious people more often (43.3%) than religiously engaged people (6.4%) expressed positive opinions about euthanasia. CONCLUSIONS: The attitudes of students towards euthanasia are often inconsistent. There is a need to evaluate medical study programmes in the context of creating the right attitudes of future doctors towards euthanasia.

Assessment of functional capacity of the elderly.

INTRODUCTION AND OBJECTIVE: Ageing is a continuous, progressive process of functional reserve loss. Physical fitness and mental state have a significant impact on the functionality level of the elderly population. Assessing the degree elderly people's of independence regarding self-care is an important aspect of the Comprehensive Geriatric Assessment (CGA). The aim of the study was to assess the functional capacity of people over 65 years of age. MATERIAL AND METHODS: The study involved 312 patients in hospital wards across Lower Silesia, south-west Poland. The criteria for participation were as follows: providing informed consent to participate in the study, intellectual capacity to be interviewed, and age over 65. The study applied the diagnostic survey method, together with the use of the VAS, Barthel, IADL and GDS scales. RESULTS: Among the respondents, 59.94% were in a moderately severe condition according to the Barthel scale, average IADL score - 20.56 points; according to the GDS scale, 58.97% had no symptoms of depression. Respondents suffered from multiple chronic diseases, the most common of which were hypertension (71.47%); they also reported some medical issues, mainly back pain (47.44). Assessment of the correlation of the Barthel and GDS scales, as well as the IADL and GDS, revealed a significant and negative correlation at -0.49 and -0.50. Assessment of the correlation between the number of diseases and the Barthel scale was -0.49, the number of symptoms and the Barthel scale -0.4; pain severity and the Barthel scale -0.41, number of diseases and IADL -0.58, and number of symptoms and IADL -0.52. CONCLUSIONS: The greater the seniors' independence regarding instrumental activities of daily living, the weaker the symptoms of depression. Multimorbidity and experiencing pain impaired independence among the elderly.

Impact of isolation on the biopsychosocial functioning of older people with COVID-19.

INTRODUCTION: COVID-19 is a highly contagious coronavirus disease that has had a significant impact on the functioning of society. On 11 March 2020, due to the rapid spread of the virus, the WHO declared a global pandemic. By the end of 2021, 5 variants of SARS-CoV-2 had been identified since the beginning of the pandemic. The course of the disease varied depending on the age of the patients and the presence of possible comorbidities. Most patients were asymptomatic or sparsely symptomatic of the infection; however, in about 6% of cases, the course of the disease was critical. Typical symptoms of COVID-19 include: fever, muscle pain and headache, lack of smell and taste, cough, dyspnea, diarrhoea and nausea. According to epidemic guidelines, infected patients were subjected to isolation, which harmed their mental state, especially the elderly. OBJECTIVE: The aim of the study was to assess the impact of isolation on the biopsychosocial functioning of elderly patients with COVID-19. MATERIAL AND METHODS: The study was conducted among 360 elderly patients in hospital wards operating as a unit in a hospital complex dedicated to patients infected with the SARS-CoV-2 virus. Data were collected using standardized questionnaires: ADL Scale, IADL, GDS, SF-36 Quality of Life Scale, Multidimensional Scale of Perceived Social Support, and supplementary questions about, among others, the oxygen therapy provided, length of stay in the unit, and the support received from relatives. RESULTS: Almost half (48%) of the subjects received oxygen therapy, and 36% had a length of disease of 7-14 days. A correlation was observed between the quality of life and the above-mentioned factors. Correlations of quality of life indicators with the length of illness were moderate (except for the level of pain) and positive, meaning that the longer the patients were ill, the lower their quality of life. Correlations of disease severity were moderate for pain, vitality, and emotional limitations, while vital for physical functioning and limitations and general and mental health. The intensity of oxygen therapy was moderately correlated with physical and emotional limitations and general health and strongly correlated with physical functioning, vitality and mental health. Correlations between functional status and mental status of elderly patients were also studied. Analysis of variance showed that the constructed model was an excellent fit to the data, F = 37.14; p < 0.001, explaining 42% of the variance in the dependent variable (R2= 0.42). As many as 80% of the respondents felt that isolation harmed their well-being. Examining the impact of quality of life on their well-being showed that most of the associations tested were statistically significant, and all were positive. Associations of moderate strength were shown for physical functioning, physical limitations and general health, while strong associations were shown for vitality, emotional limitations and mental health. Pain complaints were associated with changes in well-being at the level of statistical trend (p = 0.055). This means that the lower the patients' quality of life, especially in terms of vitality and mental health, the more significant the impact of isolation on their well-being. The study also investigated the effect of social support on mental state. The model proved to be an excellent fit to the data, F = 5.91, p = 0.002, and explained 23% of the variance in the dependent variable (Adjusted R² = 0.23). At the same time, support from friends turned out to be the only significant predictor (Beta = 0.53), and this means that the more support the subjects received from them, the lower the level of depression they manifested. CONCLUSIONS: 1) The better the functional state of a senior and the support received from relatives, the lower the severity of depression. 2) The lower the quality of a senior's life, especially in terms of mental state, the greater the negative impact on his/her well-being in isolation. 3) The low quality of life of a senior increased the likelihood of depression. 4) The quality of life of older Covid-19 patients was higher in those without chronic disease. 5) The quality-of-life level was lower in patients with a more severe course of COVID-19, and longer duration of disease and oxygen therapy.

Comparison of the Anticancer Effects of Arvanil and Olvanil When Combined with Cisplatin and Mitoxantrone in Various Melanoma Cell Lines-An Isobolographic Analysis.

Due to the unique structures of arvanil and olvanil, the drugs combine certain properties of both cannabinoids and vanilloids, which makes them able to stimulate both TPRV1 and CB1 receptors and causes them to be interesting agents in the setting of carcinoma treatment. The aim of this study was to investigate the cytotoxic and anti-proliferative effects of arvanil and olvanil when administered alone and in combination with cisplatin (CDDP) and mitoxantrone (MTX), using various primary (A375, FM55P) and metastatic (SK-MEL 28, FM55M2) human malignant melanoma cell lines. The results indicate that both arvanil and olvanil inhibited (dose-dependently) the viability and proliferation of various malignant melanoma cells, as demonstrated by MTT and BrdU assays. The safety profile of both arvanil and olvanil tested in human keratinocytes (HaCaT) and normal human melanocytes (HEMa-LP) revealed that neither arvanil nor olvanil caused significant cytotoxicity in HaCaT and HEMa-LP cell lines in LDH and MTT assays. Isobolographically, it was found that both arvanil and olvanil exerted additive interactions with MTX and antagonistic interactions with CDDP in the studied malignant melanoma cell lines. In conclusion, the combinations of arvanil or olvanil with MTX may be considered as a part of melanoma multi-drug therapy; however, the combination of these compounds with CDDP should be carefully considered due to the antagonistic interactions observed in the studied malignant melanoma cell lines.

Effectiveness of the Functional Movement Screen for assessment of injury risk occurrence in football players.

The aim of the study was to determine whether the Functional Movement Screen (FMS) test carried out among young boys practising football training identifies previous injuries. Sixty-five boys aged 12-13 years, who had regularly practised football in an academy for at least 3 years, were recruited and divided into two groups: an injured group (IG), consisting of players who had experienced at least one injury in the past (n + 25, age 12.32 ± 0.48) and a non-injured group (non-IG), a control group, made up of athletes with no injuries to the musculoskeletal system (n = 40, age 12.25 ± 0.49). Seven FMS tests were used to rate the functional fitness level as a part of the FMS tool. Significant differences between the total scores of the FMS tests (p < 0.001, r = 0.54) were documented. Higher scores in the FMS test were observed in the control group (M = 16.58, SD = 2.04) than in the study group (M = 14.20, ± SD = 1.96). The FMS test is an effective diagnostic tool to identify previous injuries among young football players.

Cannabidiol Interacts Antagonistically with Cisplatin and Additively with Mitoxantrone in Various Melanoma Cell Lines-An Isobolographic Analysis.

The medical application of cannabidiol (CBD) has been gathering increasing attention in recent years. This non-psychotropic cannabis-derived compound possesses antiepileptic, antipsychotic, anti-inflammatory and anxiolytic properties. Recent studies report that it also exerts antineoplastic effects in multiple types of cancers, including melanoma. In this in vitro study we tried to reveal the anticancer properties of CBD in malignant melanoma cell lines (SK-MEL 28, A375, FM55P and FM55M2) administered alone, as well as in combination with mitoxantrone (MTX) or cisplatin (CDDP). The effects of CBD on the viability of melanoma cells were measured by the MTT assay; cytotoxicity was determined in the LDH test and proliferation in the BrdU test. Moreover, the safety of CBD was tested in human keratinocytes (HaCaT) in LDH and MTT tests. Results indicate that CBD reduces the viability and proliferation of melanoma-malignant cells and exerts additive interactions with MTX. Unfortunately, CBD produced antagonistic interaction when combined with CDDP. CBD does not cause significant cytotoxicity in HaCaT cell line. In conclusion, CBD may be considered as a part of melanoma multi-drug therapy when combined with MTX. A special attention should be paid to the combination of CBD with CDDP due to the antagonistic interaction observed in the studied malignant melanoma cell lines.

Ageing policy in Poland during the COVID-19 pandemic.

INTRODUCTION AND OBJECTIVE: Poland is engaged in the implementation of activation programmes for seniors at governmental as well as non-governmental levels. Among these programmes may be mentioned, 'Active+', 'Senior+', 'Care 75+', and 'Senior Caritas'. The COVID-19 pandemic highlighted the need for the inclusion of seniors into social life, and concern about their health. An important challenge for social and ageing policy is the provision of proper standards of care and health protection, especially during an increased sanitary regime. The aim of the study was analysis of the ageing policy strategy and the quality of life of seniors before and during the COVID-19 pandemic. REVIEW METHODS: The study was conducted by the method of analysis of data in the area of national initiatives concerning activation programmes for seniors implemented during 2020-2021. The starting point was the well-established definition of the quality of life by the WHO. ABBREVIATED DESCRIPTION OF THE STATE OF KNOWLEDGE: The analysis performed showed a multitude of factors determining the needs of seniors at the time of the pandemic, which often differed from those observed earlier. The latest studies of the quality of life of the elderly in Poland demonstrated that nearly 60% of respondents assessed their psychological condition as worse than before the pandemic. Another problem was the issue of physical activity, which was limited by more than 62% of seniors, and difficulties with access to health care system services. SUMMARY: It seems necessary to implement forms of assistance which could be adjusted to the changing epidemiological conditions, in order to improve the quality of life of persons who, in the near future, will constitute a considerable percentage of Polish society.

Interactions among Lacosamide and Second-Generation Antiepileptic Drugs in the Tonic-Clonic Seizure Model in Mice.

Combination therapy with two or three antiseizure medications (ASMs) is sometimes a preferred method of treatment in epilepsy patients. (1) Background: To detect the most beneficial combination among three ASMs, a screen test evaluating in vivo interactions with respect to their anticonvulsant properties, was conducted on albino Swiss mice; (2) Methods: Classification of interactions among lacosamide (LCM) and selected second-generation ASMs (lamotrigine (LTG), pregabalin (PGB), oxcarbazepine (OXC), and topiramate (TPM)) was based on the isobolographic analysis in the mouse maximal electroshock-induced seizure (MES) model. Interactions among LCM and second-generation ASMs were visualized using a polygonogram; (3) Results: In the mouse MES model, synergy was observed for the combinations of LCM + TPM + PGB and LCM + OXC + PGB. Additivity was reported for the other combinations tested i.e., LCM + LTG + TPM, LCM + LTG + PGB, LCM + LTG + OXC, and LCM + OXC + TPM in this seizure model. No adverse effects associated with triple ASM combinations, containing LCM and second-generation ASMs were observed in mice; (4) Conclusions: The combination of LCM + TPM + PGB was the most beneficial combination among the tested in this study, offering synergistic suppression of tonic-clonic seizures in mice subjected to the MES model. Both the isobolographic analysis and polygonogram method can be recommended for experimental epileptology when classifying interactions among the ASMs.

Determinants of primary healthcare patients' dissatisfaction with the quality of provided medical services.

INTRODUCTION: The quality of medical services and health care are complex problems with a number of various definitions, conceptual approaches, measurement tools and techniques. The most important influence on quality in primary health care has the (immaterial) human factor, the relationship between patient and doctor, medical personnel and the primary health care institution, and the skill to use new technologies to improve quality in health care. OBJECTIVE: The aim of the study is to discover the determinants of primary health care patients' dissatisfaction with the quality of medical services. MATERIAL AND METHODS: Patients with medical appointments on the day of the survey and gave their consent to participate were included in the study. A total of 901 patients of primary health care institutions [591 (65.59%) women and 310 (34.41%) men] in the Swietokrzyskie Province took part. The diagnostic poll method based on a questionnaire examining the patients' satisfaction with the quality of health services was used. Logistic regression identified the determinants of dissatisfaction of the patients. RESULTS: The determinants that mostly affected the patients' dissatisfaction with medical services were: rudeness of the doctor (p=0.0001), rudeness of the rest of medical staff (p=0.0001), non-comprehensibility of information about health by the patient (p=0.004), no clear identification of the patient in the health care system (p=0.01), and difficult access to information regarding the health condition (medical documentation) (p=0.018). CONCLUSIONS: Primary health care patients who participated in the study pointed to the attitude of the doctor towards a patient during a visit, and the attitude of the remaining medical personnel among the determinants of dissatisfaction with medical services.

Synergy, Additivity, and Antagonism between Cisplatin and Selected Coumarins in Human Melanoma Cells.

(1) Cisplatin (CDDP) is used in melanoma chemotherapy, but it has many side effects. Hence, the search for natural substances that can reduce the dose of CDDP, and CDDP-related toxicity, is highly desired. Coumarins have many biological properties, including anticancer and antiproliferative effects. (2) An in vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay on two human melanoma cell lines (FM55P and FM55M2) examined the antitumor properties of CDDP and five naturally occurring coumarins (osthole, xanthotoxin, xanthotoxol, isopimpinellin, and imperatorin). The antiproliferative effects produced by combinations of CDDP with the coumarins were assessed using type I isobolographic analysis. (3) The most potent anticancer properties of coumarins were presented by osthole and xanthotoxol. These compounds were characterized by the lowest median inhibitory concentration (IC50) values relative to the FM55P and FM55M2 melanoma cells. Isobolographic analysis showed that for both melanoma cell lines, the combination of CDDP and osthole exerted synergistic and additive interactions, while the combination of CDDP and xanthotoxol exerted additive interactions. Combinations of CDDP with xanthotoxin, isopimpinellin, and imperatorin showed antagonistic and additive interactions in two melanoma cell lines. (4) The combination of CDDP and osthole was characterized by the most desirable synergistic interaction. Isobolographic analysis allows the selection of potential candidates for cancer drugs among natural substances.

Polygonogram with isobolographic synergy for three-drug combinations of phenobarbital with second-generation antiepileptic drugs in the tonic-clonic seizure model in mice.

BACKGROUND: Combination therapy consisting of two or more antiepileptic drugs (AEDs) is usually prescribed for patients with refractory epilepsy. The drug-drug interactions, which may occur among currently available AEDs, are the principal criterion taken by physicians when prescribing the AED combination to the patients. Unfortunately, the number of possible three-drug combinations tremendously increases along with the clinical approval of novel AEDs. AIM: To isobolographically characterize three-drug interactions of phenobarbital (PB) with lamotrigine (LTG), oxcarbazepine (OXC), pregabalin (PGB) and topiramate (TPM), the maximal electroshock-induced (MES) seizure model was used in male albino Swiss mice. MATERIALS AND METHOD: The MES-induced seizures in mice were generated by alternating current delivered via auricular electrodes. To classify interactions for 6 various three-drug combinations of AEDs (i.e., PB + TPM + PGB, PB + OXC + TPM, PB + LTG + TPM, PB + OXC + PGB, PB + LTG + PGB and PB + LTG + OXC), the type I isobolographic analysis was used. Total brain concentrations of PB were measured by fluorescent polarization immunoassay technique. RESULTS: The three-drug mixtures of PB + TPM + PGB, PB + OXC + TPM, PB + LTG + TPM, PB + OXC + PGB, PB + LTG + PGB and PB + LTG + OXC protected the male albino Swiss mice from MES-induced seizures. All the observed interactions in this seizure model were supra-additive (synergistic) (p < 0.001), except for the combination of PB + LTG + OXC, which was additive. It was unable to show the impact of the studied second-generation AEDs on total brain content of PB in mice. CONCLUSIONS: The synergistic interactions among PB and LTG, OXC, PGB and TPM in the mouse MES model are worthy of being transferred to clinical trials, especially for the patients with drug resistant epilepsy, who would benefit these treatment options.

A subjective sense of the quality of life in adolescents from the Swietokrzyskie Voivodship.

OBJECTIVES: The measurement of the health-related quality of life (HRQOL) is one of the most important methods for self-assessment of health, which makes it possible to identify irregularities in the physical, mental and social functioning. The aim of the research was to determine HRQOL using the Health Related Quality of Life Questionnaire for Children and Young People (the KIDSCREEN-52 questionnaire) - the instrument recommended by the World Health Organization - which makes it possible to distinguish groups of adolescents with a diversified subjective sense of the quality of life. MATERIAL AND METHODS: The study involved a group of 871 adolescents, 411 boys and 460 girls, aged 13-16 years, residing in the Swietokrzyskie Voivodship. The method of a diagnostic survey was used in the research. The KIDSCREEN-52 questionnaire, which is an instrument for examining the HRQOL of adolescents, was employed in the study. The k-means clustering method was applied, which made it possible to establish 3 groups of adolescents with a different subjective sense of the quality of life. RESULTS: Three groups of adolescents with a diversified subjective sense of the quality of life (high, average, low) were identified using the KIDSCREEN-52 questionnaire. The subjective quality of life in the majority of the respondents was high, in particular in those living in rural areas. The surveyed boys with a high subjective quality of life showed a significantly higher self-esteem, acceptance and peer support than the surveyed girls. CONCLUSIONS: The KIDSCREEN-52 questionnaire is an accurate and sensitive tool for assessing HRQOL. It allows identifying 3 groups of adolescents with a diversified subjective sense of the quality of life. It can form the basis for further diagnosis of the bio-psycho-social functioning of adolescents. Int J Occup Med Environ Health. 2021;34(3):415-25.

Anticonvulsant Effectiveness and Neurotoxicity Profile of 4-butyl-5-[(4-chloro-2-methylphenoxy)methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (TPL-16) in Mice.

Protective (antiseizure) effects of 4-butyl-5-[(4-chloro-2-methylphenoxy)-methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (TPL-16) and acute neurotoxic effects were determined in the tonic-clonic seizure model and rotarod test in mice. The interaction profile of four classic antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) with TPL-16 was also determined in the tonic-clonic seizure model in mice. The protective effects of TPL-16 from tonic-clonic seizures (as ED50 values) and acute neurotoxic effects of TPL-16 (as TD50 values) were determined in 4 pretreatment times (15, 30, 60 and 120 min after its i.p. administration), in adult male albino Swiss mice. The interaction profile of TPL-16 with carbamazepine, phenobarbital, phenytoin and valproate in the tonic-clonic seizure model was determined with isobolographic analysis. Total concentrations of carbamazepine, phenobarbital, phenytoin and valproate were measured in the mouse brain homogenates. The candidate for novel antiepileptic drug (TPL-16) administered separately 15 min before experiments, has a beneficial profile with protective index (as ratio of TD50 and ED50 values) amounting to 5.58. The combination of TPL-16 with valproate produced synergistic interaction in the tonic-clonic seizure model in mice. The combinations of TPL-16 with carbamazepine, phenobarbital and phenytoin produced additive interaction in terms of protection from tonic-clonic seizures in mice. None of the total brain concentrations of classic AEDs were changed significantly after TPL-16 administration in mice. Synergistic interaction for TPL-16 with valproate and the additive interaction for TPL-16 with carbamazepine, phenobarbital and phenytoin in the tonic-clonic seizures in mice allows for recommending TPL-16 as the promising drug for further experimental and clinical testing.

Sub-additive (antagonistic) interaction of lacosamide with lamotrigine and valproate in the maximal electroshock-induced seizure model in mice: an isobolographic analysis.

BACKGROUND: Launching polytherapy with two or three antiseizure drugs (ASDs) in patients with epilepsy is still problematic. The choice of ASDs to combine them together is usually based on clinicians' experience and it requires knowledge about mechanisms of action of the studied ASDs and their drug-drug interactions, whose nature may be favorable, neutral or unfavorable. To characterize three-drug interaction among lacosamide (LCM), lamotrigine (LTG) and valproate (VPA), the type I isobolographic analysis was used. The antiseizure effects of three-drug combination were analyzed in a model of maximal electroshock-induced seizures (MES) in albino Swiss mice. MATERIALS AND METHODS: The seizure activity in mice was evoked by alternating current stimulation (25 mA, 500 V, 50 Hz, 0.2 s). Both, the type I isobolographic analysis and the test of parallelism of dose-response effects of the ASDs were used so as to properly classify interaction among three ASDs, administered in a fixed ratio combination of 1:1:1. RESULTS: The three-drug mixture of LCM, LTG and VPA at the fixed ratio of 1:1:1 protected the experimental mice from MES-induced seizures; however, the reported interaction was sub-additive (antagonistic; p < 0.01) with isobolography. CONCLUSION: The antagonistic pharmacodynamic interaction among LCM, LTG and VPA in the MES test in mice cannot be transferred to clinical settings and this unfavorable combination should not be recommended for patients with epilepsy.