Polyhydroxylated derivatives of fullerene C60, named fullerenols (C60OHn), have stimulated great interest because of their potent antioxidant properties in various chemical and biological systems, ...which enable them to be used as a new promising pharmaceutical for the future treatment of oxidative stress-related diseases, but the details remain unknown. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a principal transcription factor that regulates expression of several antioxidant genes via binding to the antioxidant response element and plays a crucial role in cellular defence against oxidative stress. In this study we investigated whether activation of the Nrf2/antioxidant response element pathway contributes to the cytoprotective effects of C60(OH)24. Our results showed that C60(OH)24 enhanced nuclear translocation of Nrf2 and upregulated expression of phase II antioxidant enzymes, including heme oxygenase-1 (HO-1), NAD(P)H: quinine oxidoreductase 1, and γ-glutamate cysteine ligase in A549 cells. Treatment with C60(OH)24 resulted in phosphorylation of p38 mitogen-activated protein kinases (p38 MAPK), extracellular signal-regulated kinases, and c-Jun-N-terminal kinases. By using inhibitors of cellular kinases, we showed that pretreatment of A549 cells with SB203580, a specific inhibitor of p38 MAPK, abolished nuclear translocation of Nrf2 and induction of HO-1 protein induced by C60(OH)24, indicating an involvement of p38 MAPK in Nrf2/HO-1 activation by C 60(OH)24. Furthermore, pretreatment with C60(OH)24 attenuated hydrogen peroxide-induced apoptotic cell death in A549 cells, and knockdown of Nrf2 by small interfering ribonucleic acid diminished C60(OH)24-mediated cytoprotection. Taken together, these findings demonstrate that C60(OH)24 may attenuate oxidative stress-induced apoptosis via augmentation of Nrf2-regulated cellular antioxidant capacity, thus providing insights into the mechanisms of the antioxidant properties of C60(OH)24.
The BCS, BDDCS, and Regulatory Guidances Chen, Mei-Ling; Amidon, Gordon L.; Benet, Leslie Z. ...
Pharmaceutical research,
07/2011, Letnik:
28, Številka:
7
Journal Article
Recenzirano
The BCS (Biopharmaceutics Classification System), based on aqueous solubility and intestinal permeability, has been widely used since 1995 to predict drug absorption during the course of ...pharmaceutical development. However, when the BCS concepts were initiated, now more than 15 years ago, the term intestinal permeability was used interchangeably with both measures of rate and extent of absorption, believing from the data available at that time that permeability/absorption rate and extent are correlated.
A 59-year-old woman presented with fever for 2 weeks. The patient had end-stage renal disease and was undergoing dialysis therapy for 10 years. Plain radiographs revealed extensive calcification in ...the subcutaneous tissues of the shoulders, thighs, and hips. In this case, TC-MDP bone scan detected all sites of subcutaneous metastatic calcification in one sweep. Ga-citrate scintigraphy was also performed and showed similar uptake at the same locations as those revealed by the bone scan, suggesting the existence of an inflammatory process at the sites of metastatic calcification.
For decades, the establishment of bioequivalence has generally relied on the comparison of population averages between the test and reference formulations. In the early 1990s, individual ...bioequivalence was proposed to ensure that an individual could be switched from the reference product to the test product with unchanged efficacy and safety. Since 1997, the US Food and Drug Administration (FDA) has published three guidance documents on the proposed criterion and statistical methodology for the individual bioequivalence approach. From a scientific stand-point, the individual bioequivalence criterion appears to offer several advantages for some drug products compared with the average criterion. It allows comparison of intraindividual variances, scaling the bioequivalence criterion to the reference variability and detection of an important subject-by-formulation interaction if it exists. Based on these considerations, the FDA has recently recommended replicate study designs for modified release dosage forms and highly variable drug products. The new criterion also promotes inclusion of a heterogeneous population of volunteers in bioequivalence studies. Despite all the advantages of the individual bioequivalence approach, questions remain on the optimal use of replicate study designs and the proposed criterion for evaluation of bioequivalence between formulations. In the finalised guidance documents, therefore, the FDA maintains the average bioequivalence criterion while allowing other criteria under certain circumstances. Collection and analysis of bioequivalence data from replicate study designs may permit further assessment and resolution of these questions.
Traditional treatment therapies for tracheal stenosis often cause severe post-operative complications. To solve the current difficulties, novel and more suitable long-term treatments are needed. A ...whole-segment tissue-engineered trachea (TET) representing the native goat trachea was 3D printed using a poly(caprolactone) (PCL) scaffold engineered with autologous auricular cartilage cells. The TET underwent mechanical analysis followed by in vivo implantations in order to evaluate the clinical feasibility and potential. The 3D-printed scaffolds were successfully cellularized, as observed by scanning electron microscopy. Mechanical force compression studies revealed that both PCL scaffolds and TETs have a more robust compressive strength than does the native trachea. In vivo implantation of TETs in the experimental group resulted in significantly higher mean post-operative survival times, 65.00 ± 24.01 days (n = 5), when compared with the control group, which received autologous trachea grafts, 17.60 ± 3.51 days (n = 5). Although tracheal narrowing was confirmed by bronchoscopy and computed tomography examination in the experimental group, tissue necrosis was only observed in the control group. Furthermore, an encouraging epithelial-like tissue formation was observed in the TETs after transplantation. This large animal study provides potential preclinical evidence around the employment of an orthotopic transplantation of a whole 3D-printed TET.
A 73-year-old man presented with acute renal failure after 3-month standard antituberculosis therapy with rifampicin for pulmonary tuberculosis. Previously undiagnosed human immunodeficiency virus ...(HIV) infection was found at the same time. A kidney biopsy showed crescentic glomerulonephritis and tubulointerstitial nephritis. Furthermore, endothelial tubuloreticular inclusions were seen on electron microscopy. Rifampicin was stopped because it was considered as the most possible cause responsible for the rapidly progressive glomerulonephritis (RPGN). Immunosuppressive therapy was not carried out because of the risk of aggravation of underlying infectious diseases including tuberculosis and HIV. Fortunately, renal function recovered 1 month after discontinuation of rifampicin. This case presented a clinical challenge in the differential diagnosis of the cause for RPGN in such a complex condition and the therapeutic dilemma regarding the use of immunosuppressive drugs.
We report an 89-year-old retired farmer with prolonged bradycardia and hypotension after pyrethroid insecticides ingestion in a suicidal attempt. This patient also had a clinical manifestation ...mimicking organophosphate poisoning, included confusion, lacrimation and salivation. He required intensive care support, atropine and inotrope infusions treatments. Only metabolites of synthetic pyrethroid insecticides (3-phenoxybenzoic acid and 3-phenoxybenzaldehyde) were detected in the urine sample. In the serum toxicology screening, specific analysis for organophosphate pesticides was negative. He eventually recovered without major sequela.
Cumulative oxidative damages to cell constituents are considered to contribute to aging and age-related diseases. The enzyme peptide methionine sulfoxide reductase A (MSRA) catalyzes the repair of ...oxidized methionine in proteins by reducing methionine sulfoxide back to methionine. However, whether MSRA plays a role in the aging process is poorly understood. Here we report that overexpression of the msrA gene predominantly in the nervous system markedly extends the lifespan of the fruit fly Drosophila. The MSRA transgenic animals are more resistant to paraquat-induced oxidative stress, and the onset of senescence-induced decline in the general activity level and reproductive capacity is delayed markedly. The results suggest that oxidative damage is an important determinant of lifespan, and MSRA may be important in increasing the lifespan in other organisms including humans.
Incense burning is a very popular activity in daily life among many parts all over the world. A growing body of both epidemiological and experimental evidences has reported the negative effects of ...incense use on human well-being, posing a potential threat at public significance. This work is a comprehensive review that covers the latest findings regarding the adverse impact of incense smoke on our health, providing a panoramic visualization ranging from mechanisms to implications. The toxicities of incense smoke come directly from its harmful constituents and deposition capacity in the body. Besides, reactive oxygen species-driven oxidative stress and associated inflammation seem to be plausible underlying mechanisms, eliciting various unfavorable responses. Although our current knowledge remains many gaps, this issue still has some important implications.
Brucine was encapsulated into stealth liposomes using the ammonium sulfate gradient method to improve therapeutic index.
Four brucine stealth liposomal formulations were prepared, which were made ...from different phosphatidylcholines (PCs) with different phase transition temperatures (T(m)). The PCs used were soy phosphatidylcholine (SPC), dipalmitoyl phosphatidylcholine (DPPC), hydrogenated soy phosphatidylcholine (HSPC), and distearoyl phosphatidylcholine (DSPC). The stabilities, pharmacokinetics, and toxicities of these liposomal formulations were evaluated and compared.
Size, zeta potential, and entrapment efficiency of brucine-loaded stealth liposomes (BSL) were not influenced by PC composition. In vitro release studies revealed that drug release rate increased with decreased T(m) of PCs, especially with the presence of rat plasma. After intravenous administration, the area under the curve (AUC) values of BSL-SPC, BSL-DPPC, BSL-HSPC, and BSL-DSPC in plasma were 7.71, 9.24, 53.83, and 56.83-fold as large as that of free brucine, respectively. The LD(50) values of brucine solution, BSL-SPC, BSL-DPPC, BSL-HSPC, and BSL-DSPC following intravenous injection were 13.17, 37.30, 37.69, 51.18, and 52.86 mg/kg, respectively. It was found in calcein retention experiments that the order of calcein retention in rat plasma was SPC < DPPC << HSPC < DSPC stealth liposomes.
PC composition could exert significant influence on the stabilities, pharmacokinetics, and toxicities of brucine-loaded stealth liposomes. DSPC or HSPC with T(m) above 50°C should be used to prepare the stealth liposomal formulation for the intravenous delivery of brucine. However, it was found in the present paper that the pharmacokinetics and toxicity of BSL were not influenced by the PC composition when the T(m) of the PC was in the range of -20°C to 41°C.
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