Effects of excessive alcohol drinking on nicotine biotransformation in rats

Alcohol and nicotine (tobacco smoke) are often used together, and taking both addictive substances is associated with an increased risk of certain diseases. It is extremely important to understand the pharmacodynamic and pharmacokinetic mechanisms of the interaction between nicotine and ethanol, which are still not fully understood. The study aimed to evaluate the influence of chronic alcohol consumption on nicotine biotransformation in ethanol-preferring and non-preferring male and female rats. Rats were divided into four groups depending on their alcohol preferences and gender. Nicotine, nornicotine, nicotine N-oxide, cotinine, trans-3'-hydroxycotinine, and cotinine N-oxide in rats plasma were determined by LC–MS/MS after five days of exposure to tobacco smoke. A non-compartmental analysis of nicotine and its metabolites was used for pharmacokinetic parameters calculation. Our experimental results showed that the rate of nicotine elimination depends on gender, regardless of alcohol preferences (significantly slower in females than in males). Mean residence timeof nornicotine, cotinine, and trans-3'-hydroxycotinine were significantly higher in alcohol-preferring male rats than in alcohol preferring female rats. In non-alcohol preferring female rats compared to ethanol-preferring female rats, significantly more nicotine N-oxide (fivefold) and trans-3'-hydroxycotinine (twofold) reached the general circulation unchanged. Drinking ethanol influenced the elimination of nornicotine and cotinine in male rats. Ethanol consumption was identified as a modifier of nicotine pharmacokinetics and this was gender-dependent

Pseudothecial maturation and ascospore release of Leptosphaeria maculans and L. biglobosa in south-east Poland

Stem canker of brassicas is a severe disease of oilseed rape in Australia, Canada and Europe, including Poland. The disease is caused by Leptosphaeria maculans and L. biglobosa - two pathogens belonging to the class Dothideomycetes. The species differ in pathogenicity, but they have identical shape and size of fruiting bodies and spores of the generative and vegetative stages. Both pathogens are often found together in infected tissues of oilseed rape plants. The main goal of the experiments was to measure the rate of pseudothecial maturation and to monitor ascospore concentration of L. maculans and L. biglobosa in air samples. The paper is the first investigation on the generative stage development of these two species in south-east Poland. The studies were done for three consecutive years (2005-2007), for six most important months in pathogen development and plant infection, including 3 months in the spring (March - May) and 3 months in the autumn (September - November). The stage of pseudothecial maturation was assessed visually, based on the development of asci and ascospores. Monitoring of spore concentration in the air was performed using a Hirst-type 7-day volumetric trap. It was proved that differences in pseudothecial maturation rate in south-east Poland, encompassing the climatic regions of the Carpathian Foothills and Cracow, do not exceed two weeks within one season. The first and the highest ascospore concentration dates depended on weather conditions in a particular season. The total number of spores during the studied seasons varied from 9 to 12 spores/m3, which was from 70 to 90 times lower than the average from five other monitoring sites around Poland. The short exposition to spore showers and very small concentrations of L. maculans and L. biglobosa ascospores in air samples were the most probable reasons for relatively small damage of oilseed rape crops by stem canker in the south-east part of Poland

The development of new methodology for determination of vincristine (VCR) in human serum using LC-MS/MS-based method for medical diagnostics

In this article, we have presented the development and validation of a rapid and sensitive reversed-phase liquid chromatography with tandem mass spectrometry (LC-MS/MS) method for the determination of vincristine (VCR) in patient serum samples. Chromatographic separation was achieved on a Kinetex(®) (Singapore) column using a mobile phase consisting of 25 mM acetic acid and 0.3% formic acid (A) and methanol (B) in a gradient elution mode at a flow rate of 0.3 mL/min. The VCR and internal standard (vinblastine) were monitored using the multiple reaction monitoring mode under positive electrospray ionization. The lower limit of quantification (LLOQ) was 0.67 ng/mL, and the upper limit of quantification (ULOQ) was 250 ng/mL for VCR. The calculated values of LOD and LOQ for VCR were 0.075 and 0.228 ng/mL, respectively. The calibration curve was linear over the VCR concentration range of 1.0–250 ng/mL in serum. The intra- and inter-day precision and precision were within the generally accepted criteria for the bioanalytical method (<15%). The method was successfully applied to the analysis of serum samples in clinical practice

Risk factors for dementia in Parkinson’s Disease — the overuse of anticholinergic drugs

Aim of the study. To determine the risk factors for dementia in a group of patients with Parkinson’s Disease (PD), especially the effect of the anticholinergic burden assessed according to the Anticholinergic Cognitive Burden scale (ACB) and the CRIDECO Anticholinergic Load Scale (CALS). Clinical rationale for the study. To provide information about factors associated with Parkinson’s Disease dementia (PDD), especially the anticholinergic burden and testing the effect of both scales in an assessment of the anticholinergic burden in this group of patients. Material and methods. A retrospective and cross-sectional analysis of medical records of patients with Parkinson’s Disease admitted to the Neurology Department of the Medical University of Silesia, Katowice, Poland between 2019 and 2021 was performed. We found 418 patients with a diagnosis of PD, but 80 were excluded due to lack of a cognitive function assessment. Based on MMSE score, the remaining 338 patients were divided into two groups of patients with, and without, PDD. Next, demographic and clinical data was collected. The anticholinergic burden was assessed using the ACB and the CALS scales. According to the authors of these scales, : if a scale score is of three or more points, this should be considered as a significant anticholinergic burden. Multiple logistic regression with backward elimination was used to assess factors significantly related to the presence of dementia, and two different models were used for both scales assessing the anticholinergic burden. Results. 62 (18.3%) patients were diagnosed with PDD. Overall significant anticholinergic burden (≥ 3 points) was found in 31.95% of patients using CALS and in 18.93% using ACB. Anticholinergic burden was higher in patients with dementia (CALS 50 vs. 27.90%, p &lt; 0.001, ACB 43.5 vs. 13.41%, p &lt; 0.001). According to both models, the factors significantly related to dementia were: age (ACB OR 1,114 (1.062–1.170), p &lt; 0.001, CALS OR 1.123 (1.070–1.178), p &lt; 0.001), significant anticholinergic burden (ACB OR 3.433 (1.746–6.750), p &lt; 0.001, CALS OR 2.166 (1.157–4.055), p = 0.016) disease severity in the Hoehn-Yahr scale (ACB OR 1.752 (1.197–2.565), p = 0.004, CALS OR 1.831 (1.256–2.670), p = 0.002) and atrial fibrillation (ACB OR 5.593 (1.417–22.083), p = 0.014, CALS OR 5.159 (1.314–20.254), p = 0.016). Conclusions and clinical implications. The anticholinergic burden is larger in PDD patients compared to PD patients without dementia. CALS or ACB scales are helpful in this risk assessment and might be crucial to avoid the development of PDD, especially in older PD patients with multimorbidities

STX140, but not paclitaxel, inhibits mammary tumour initiation and progression in C3(1)/SV40 T/t-antigen transgenic mice.

Despite paclitxael's clinical success, treating hormone-refractory breast cancer remains challenging. Paclitaxel has a poor pharmacological profile, characterized by a low therapeutic index (TIX) caused by severe dose limiting toxicities, such as neutropenia and peripheral neuropathy. Consequently, new drugs are urgently required. STX140, a compound previously shown to have excellent efficacy against many tumors, is here compared to paclitaxel in three translational in vivo breast cancer models, a rat model of peripheral neuropathy, and through pharmacological testing. Three different in vivo mouse models of breast cancer were used; the metastatic 4T1 orthotopic model, the C3(1)/SV40 T-Ag model, and the MDA-MB-231 xenograft model. To determine TIX and pharmacological profile of STX140, a comprehensive dosing regime was performed in mice bearing MDA-MD-231 xenografts. Finally, peripheral neuropathy was examined using a rat plantar thermal hyperalgesia model. In the 4T1 metastatic model, STX140 and paclitaxel significantly inhibited primary tumor growth and lung metastases. All C3(1)/SV40 T-Ag mice in the control and paclitaxel treated groups developed palpable mammary cancer. STX140 blocked 47% of tumors developing and significantly inhibited growth of tumors that did develop. STX140 treatment caused a significant (P<0.001) survival advantage for animals in early and late intervention groups. Conversely, in C3(1)/SV40 T-Ag mice, paclitaxel failed to inhibit tumor growth and did not increase survival time. Furthermore, paclitaxel, but not STX140, induced significant peripheral neuropathy and neutropenia. These results show that STX140 has a greater anti-cancer efficacy, TIX, and reduced neurotoxicity compared to paclitaxel in C3(1)/SV40 T-Ag mice and therefore may be of significant benefit to patients with breast cancer