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The everted rat intestinal‐sac model was utilized to assess the effect of post‐prandial conditions on the stereoselective intestinal metabolism of halofantrine to its active metabolite desbutylhalofantrine. Everted intestinal sacs were incubated with (±)‐halofantrine HCl in the presence of simulated bile solution (containing lecithin, lipase and cholesterol) and lipids to mimic post‐prandial conditions in the small intestine. The halofantrine enantiomer concentrations in intestinal sacs were relatively constant in the presence of bile, but decreased significantly on addition of lipids to the incubation media. Formation of desbutylhalofantrine enantiomers was inversely proportional to bile concentration whereas addition of lipids in the presence of bile caused a significant decrease in desbutylhalofantrine:halofantrine ratio of (?) enantiomers. Pre‐treatment of rats with peanut oil had no significant effect on desbutylhalofantrine formation in the incubated sacs or microsomal preparations, nor did it affect the expression of intestinal cytochrome P450. Addition of extra cholesterol to the bile incubations caused a significant increase in tissue halofantrine and desbutylhalofantrine concentrations, which as for lower cholesterol, were diminished on addition of other lipids. The results were consistent with previous in vivo evaluations showing that the desbutylhalofantrine to halofantrine ratio was decreased by the ingestion of a high fat meal. Chirality, 2010. © 2009 Wiley‐Liss, Inc. 相似文献
64.
Hesham Salem Noha Abdal-Karim Bahaa Omran Abdel-Rahman Abdel-Gayed Mazen Atef Mahmoud Abdelgaleel 《Luminescence》2022,37(4):656-664
An approved, straightforward, fast, and delicate spectrofluorimetric strategy was developed for the estimation of tepotinib (TEPO), sotorasib (SOTO), and darolutamide (DARO) as new antineoplastic drugs. The spectrofluorimetric strategy was based on quantitative fluorescence quenching of MER at 538 nm after being excited at 350 nm by the addition of the cited drugs in the presence of acetate buffer (pH 3.5). The degree of fluorescence quenching was directly proportional to the concentrations of the cited drugs within the concentration range of 0.5–10.0, 0.2–10, and 0.4–10.0 μg ml−1 for TEPO, SOTO, and DARO, respectively. Mean ± standard deviation (SD) were calculated for the studied drugs as follows; 99.9 ± 0.87, 99.72 ± 1.08, and 100.21 ± 1.44, for TEPO, SOTO, and DARO, respectively. Limit of detection (LOD) values were 0.16, 0.05, and 0.11 μg ml−1, whereas limit of quantitation (LOQ) values were 0.5, 0.15, and 0.36 μg ml−1 for TEPO, SOTO, and DARO, respectively. Statistical comparison through detailed strategies produced greater understanding and found that there were no noteworthy contrasts in exactness and exactness between strategies. The proposed strategy was used effectively to analyze the measurement of different forms of the examined drugs. Moreover, the recommended fluorimetric strategy was used for examination of TEPO, SOTO, and DARO in human plasma and urine tests. 相似文献
65.
The solubilizing and absorption enhancer properties towards nimesulide (ND) of tromethamine (Tris) and polyvinylpyrrolidone
(PVP) have been investigated. Solid binary systems were prepared at various drug-polymer ratios by mixing or coprecipitation,
characterized by differential scanning calorimetry, X-ray diffractometry, and Fourier transform infrared spectroscopy, and
tested for dissolution behavior. Both carriers improved drug dissolution and their performance depended on concentration of
the hydrophilic carrier in coprecipitates. Tris was more effective than PVP, despite the amorphizing power of PVP as revealed
by solid state analyses. Complete drug amorphiztion was attained at 1∶3 (wt/wt) drug: PVP, 25% (wt/wt) ND in PVP. According
to thermal behavior of ND and Tris, ND-Tris systems present a eutectic behavior. The eutectic composition was 30% ND-70% Tris
at ∼129°C. Amorphous ND-PVP and eutectic ND-Tris mixtures showed an improvement of 5.55 and 6.6 times of drug dissolution
efficiency, respectively. In vivo experiments in mice demonstrated that administration of 60 mg/kg of drug coprecipitated
with PVP or Tris resulted, respectively, in a 50% and 94% reduction of acetic acid-induced writhings in comparison with pure
drug, which, instead, was statistically ineffective as compared with the control group. Moreover, the eutectic mixture of
ND-Tris demonstrated antiwrithing potency 1.88 times higher than amorphous ND-PVP coprecipitate. Thus, the solubilizing power,
dissolution-enhancing effect, and analgesic effect enhancer ability toward the drug make Tris particularly suitable for developing
a reduced-dose, fast-release solid oral dosage form of nimesulide.
Published: August 10, 2007 相似文献
66.
Yasir Alhamdi Daniel R. Neill Simon T. Abrams Hesham A. Malak Reham Yahya Richard Barrett-Jolley Guozheng Wang Aras Kadioglu Cheng-Hock Toh 《PLoS pathogens》2015,11(5)
Streptococcus pneumoniae accounts for more deaths worldwide than any other single pathogen through diverse disease manifestations including pneumonia, sepsis and meningitis. Life-threatening acute cardiac complications are more common in pneumococcal infection compared to other bacterial infections. Distinctively, these arise despite effective antibiotic therapy. Here, we describe a novel mechanism of myocardial injury, which is triggered and sustained by circulating pneumolysin (PLY). Using a mouse model of invasive pneumococcal disease (IPD), we demonstrate that wild type PLY-expressing pneumococci but not PLY-deficient mutants induced elevation of circulating cardiac troponins (cTns), well-recognized biomarkers of cardiac injury. Furthermore, elevated cTn levels linearly correlated with pneumococcal blood counts (r=0.688, p=0.001) and levels were significantly higher in non-surviving than in surviving mice. These cTn levels were significantly reduced by administration of PLY-sequestering liposomes. Intravenous injection of purified PLY, but not a non-pore forming mutant (PdB), induced substantial increase in cardiac troponins to suggest that the pore-forming activity of circulating PLY is essential for myocardial injury in vivo. Purified PLY and PLY-expressing pneumococci also caused myocardial inflammatory changes but apoptosis was not detected. Exposure of cultured cardiomyocytes to PLY-expressing pneumococci caused dose-dependent cardiomyocyte contractile dysfunction and death, which was exacerbated by further PLY release following antibiotic treatment. We found that high PLY doses induced extensive cardiomyocyte lysis, but more interestingly, sub-lytic PLY concentrations triggered profound calcium influx and overload with subsequent membrane depolarization and progressive reduction in intracellular calcium transient amplitude, a key determinant of contractile force. This was coupled to activation of signalling pathways commonly associated with cardiac dysfunction in clinical and experimental sepsis and ultimately resulted in depressed cardiomyocyte contractile performance along with rhythm disturbance. Our study proposes a detailed molecular mechanism of pneumococcal toxin-induced cardiac injury and highlights the major translational potential of targeting circulating PLY to protect against cardiac complications during pneumococcal infections. 相似文献
67.
68.
Glutathione transferase (GST) is a phase II detoxifying enzyme that plays a protective mechanism against oxidizing substances and toxic contaminants. Among these contaminants, heavy metals and polycyclic and halogenated aromatic hydrocarbons (PHAHs) have been shown to exert their toxic effects through the modulation of detoxifying enzymes, including the GSTs. Recently, we showed that heavy metals particularly Hg2+, Pb2+, and Cu2+ modulate the expression of phase II detoxifying enzymes such as NAD(P)H:quinone oxidoreductase 1 and Gsta1 in a concentration- and time-dependent manner. However, the effect of heavy metals and their potential interactions with aryl hydrocarbon receptor (AhR) ligands, PHAHs, on total Gst activity is still unknown. In the current study, we have investigated the effects of Hg2+, Pb2+, and Cu2+ in the absence and presence of four AhR ligands on the total Gst activity and reactive oxygen species (ROS) production in wild-type and AhR-deficient Hepa 1c1c7 cells. Our results showed that Hg2+ and Cu2+, but not Pb2+, significantly induced Gst activity in wild-type cells, whereas all metals induced the Gst activity in AhR-deficient cells. The induction of Gst activity by heavy metals was strongly correlated with an increase in the ROS production in wild-type, but not in AhR-deficient cells. Co-administration of heavy metals with AhR ligands differentially modulated Gst activity, in that co-exposure to Hg2+ plus AhR ligands could be beneficial in protecting against cytotoxicity as demonstrated by the increase in Gst activity with a proportional decrease in ROS production. Whereas co-exposure to Cu2+ plus AhR ligands was more toxic in that a decrease in Gst activity and an increase in oxidative stress of the cell were observed. We concluded that heavy metals differentially modulate the Gst activity through oxidative stress- and AhR-mediated mechanisms. 相似文献
69.
Gyöngyi Kenesi Hesham M. Shafik Attila W. Kovács Sándor Herodek Mátyás Présing 《Hydrobiologia》2009,623(1):191-202
The aim of this research was to test whether NH4
+ and NO3
− affect the growth, P demand, cell composition and N2 fixation of Cylindrospermopsis raciborskii under P limitation. Experiments were carried out in P-limited (200 μg l−1 PO4-P) chemostat cultures of C. raciborskii using an inflowing medium containing either 4,000 μg l−1 NH4-N, 4,000 μg l−1 NO3-N or no combined N. The results showed the cellular N:P and C:P ratios of C. raciborskii decreased towards the Redfield ratio with increasing dilution rate (D) due to the alleviation of P limitation. The cellular C:N and carotenoids:chlorophyll-a ratios also decreased with D, predominantly as a result of an increase in the chlorophyll-a and N content. The NH4
+ and NO3
− supply reduced the P maintenance cell quota of C. raciborskii. Consequently, the biomass yield of the N2-grown culture was significantly lower. The maximum specific growth rate of N2-grown culture was also the lowest observed. It is suggested that these differences in growth parameters were caused by the
P and energy requirement for heterocyte formation, nitrogenase synthesis and N2 fixation. N2 fixation was partially inhibited by NO3
− and completely inhibited by NH4
+. It was probably repressed through the high N content of cells at high dissolved N concentrations. These results indicate
that C. raciborskii is able to grow faster and maintain a higher biomass under P limitation where a sufficient supply of NH4
+ or NO3
− is maintained. Information gained about the species-specific nutrient and pigment stoichiometry of C. raciborskii could help to access the degree of nutrient limitation in water bodies.
Handling editor: Luigi Naselli-Flores 相似文献
70.
Xiaoying Zhang Ajay Bommareddy Wei Chen Sherief Khalifa Radhey S Kaushik Hesham Fahmy Chandradhar Dwivedi 《Translational oncology》2009,2(1):21-30
Sarcophine-diol (SD), a structural modifications of sarcophine, has shown chemopreventive effects on 7,12-dimethylbenz(a)anthracene-initiated and 12-O-tetradecanoylphorbol-13-acetate-promoted skin tumor developments in mice. Tumorigenesis is associated with uncontrolled cell growth and loss of apoptosis. In the present study, the effects of SD on cell growth and apoptosis in human epidermoid carcinoma A431 cells were determined to assess whether SD could inhibit cell growth and/or induce apoptosis, thus elucidating possible mechanism of action. MTT assay was used for cell viability; bromodeoxyuridine incorporation assay was used for cell proliferation; fluorescence-activated cell sorting analysis of annexin V/propidium iodide staining and TUNEL assay were used for determining apoptotic cells; Western blot analysis was used for determining the expression of caspase-3 and colorimetric caspase activity assays were used for determination of caspase-3, -8, and -9 activity. The results showed that SD treatment at concentration of 200 to 600 µM resulted in a concentration-dependent decrease in cell viability and cell proliferation in A431 cells, which largely inhibited cell growth. Sarcophine-diol treatment induced a strong apoptosis and significantly (P < .05) increased DNA fragmentation in A431 cells. Furthermore, SD treatment significantly (P < .05) increased the activity and expression of caspase-3 through activation of upstream caspase-8 in A431 cells rather than the activation of caspase 9. Sarcophine-diol treatment is relatively much less cytotoxic in monkey kidney normal CV-1 cells. These results suggest that SD decreases cell growth and induces apoptosis through caspase-dependent extrinsic pathway in A431 cells, and this may contribute to its overall chemopreventive effects in mouse skin cancer models. 相似文献