- Studying drug-drug interaction through chromatographic analysis of two mixtures offering antimicrobial synergism. [Journal Article]
- JCJ Chromatogr B Analyt Technol Biomed Life Sci 2018 Nov 03; 1104:1-10
- Micellar mobile phase was utilized for the separation and quantification of two antimicrobial mixtures with some analgesics that were found to augment their antimicrobial activity, namely; cefotaxime...
Micellar mobile phase was utilized for the separation and quantification of two antimicrobial mixtures with some analgesics that were found to augment their antimicrobial activity, namely; cefotaxime sodium (CFX) with ibuprofen (IBU) and naproxen (NPX) (mixture Ι), and azithromycin dihydrate (AZT) with diclofenac sodium (DIC) (mixture ΙΙ). Both mixtures were analyzed using a C18 column operated at 50 °C using a mobile phase composed of sodium dodecyl sulphate (SDS), an organic modifier; (1-propanol or acetonitrile), and 0.3% triethylamine (TEA), adjusting pH to the required value with 2 M orthro-phosphoric acid, accompanied with UV detection. The proposed method was subjected to full validation procedure and was applied to determine the concentration of the studied antibiotics in homogenized liver, kidney and heart rat tissue samples, with or without the co-administered non steroidal anti-inflammatory drugs.
- Predictive factors associated with liver fibrosis and steatosis by transient elastography in patients with HIV mono-infection under long-term combined antiretroviral therapy. [Journal Article]
- JIJ Int AIDS Soc 2018; 21(11):e25201
- CONCLUSIONS: Integrated strategies for preventing non-communicable diseases in people with HIV mono-infection are necessary to decrease the burden of liver diseases. Clinical Trial Number: NCT02542020.
- Mitochondrial DNA content of peripheral blood mononuclear cells in ART untreated & stavudine/zidovudine treated HIV-1-infected patients. [Journal Article]
- IJIndian J Med Res 2018; 148(2):207-214
- CONCLUSIONS: mtDNA depletion in PBMCs was evident among HIV-infected individuals on ART. Moreover, as mtDNA content was reduced among the patients symptomatic for toxicity than the asymptomatic in both the HIV-infected groups, the current study supports mtDNA content of PBMCs to serve as a biomarker of mitochondrial dysfunction induced by NRTI and HIV. Longitudinal studies with a large sample need to be done to confirm these findings.
- Azidothymidine produces synergistic activity in combination with colistin against antibiotic-resistant Enterobacteriaceae. [Journal Article]
- AAAntimicrob Agents Chemother 2018 Oct 29
- Bacterial infections remain the leading killer worldwide which is worsened by the continuous emergence of antibiotic resistance. In particular, antibiotic-resistant Enterobacteriaceae is prevalent an...
Bacterial infections remain the leading killer worldwide which is worsened by the continuous emergence of antibiotic resistance. In particular, antibiotic-resistant Enterobacteriaceae is prevalent and extremely difficult to treat. Reusing existing drugs and rejuvenating the therapeutic potential of existing antibiotics represent an attractive novel strategy. Azidothymidine (AZT) is an antiretroviral drug which is used in combination with other antivirals to prevent and to treat HIV/AIDS. AZT is also active against Gram-negative bacteria but has not been developed for that purpose. Here we investigated in vitro and in vivo efficacy of AZT in combination with colistin against antibiotic-resistant Enterobacteriaceae including extended-spectrum beta-lactamase (ESBL), New Delhi metallo-beta-lactamase 1 (NDM) or the mobilized colistin resistance (mcr-1) producing strains. Minimum inhibitory concentration was determined using the broth microdilution method. The combinatory effect of AZT and colistin was examined using the checkerboard method and time-kill analysis. A murine peritoneal infection model was used to test the therapeutic effect of the combination of AZT and colistin. Fractional inhibitory concentration index from checkerboard assay demonstrated that AZT synergized with colistin against 61% and 87% of ESBL-producing Escherichia coli and Klebsiella pneumoniae, respectively, 100% of NDM-1-producing strains and 92% of mcr-1 producing E. coli Time-kill analysis demonstrated significant synergistic activities when AZT was combined with colistin. In the murine peritoneal infection model, AZT in combination with colistin showed augmented activities of both drugs in the treatment of NDM-1 K. pneumoniae and mcr-1 E. coli infections. AZT and colistin combination poses a potential to be used coherently to treat antibiotic-resistant Enterobacteriaceae infections.
- Zidovudine-mediated autophagy inhibition enhances mitochondrial toxicity in muscle cells. [Journal Article]
- AAAntimicrob Agents Chemother 2018 Oct 29
- Nucleoside reverse transcriptase inhibitors (NRTI) such as zidovudine (AZT) are constituents of HIV-1 therapy and prevention of mother to child transmission. Prolonged thymidine analogues exposure ha...
Nucleoside reverse transcriptase inhibitors (NRTI) such as zidovudine (AZT) are constituents of HIV-1 therapy and prevention of mother to child transmission. Prolonged thymidine analogues exposure has been associated with mitochondrial toxicities to heart, liver, and skeletal muscle. We hypothesized that the thymidine analogue AZT might interfere with autophagy in myocytes, a lysosomal degradation pathway implicated in regulation of mitochondrial recycling, cell survival and the pathogenesis of myodegenerative diseases. The impact of AZT and lamivudine (3TC) on C2C12 myocyte autophagy was studied using various methods based on LC3-GFP overexpression or LC3 staining in combination with western blotting, flow cytometry and confocal and electron microscopy. Lysosomal and mitochondrial functions were studied using appropriate staining for lysosomal mass, acidity, cathepsin activity as well as mitochondrial mass and membrane potential in combination with flow cytometry and confocal microscopy. AZT, but not 3TC, exerted a significant dose and time-dependent inhibitory effect on late stages of autophagosome maturation, which was reversible upon mTOR inhibition. Inhibition of late autophagy at therapeutic drug concentrations led to dysfunctional mitochondria accumulation with membrane hyperpolarization and increased ROS generation, and ultimately compromised cell viability. These AZT effects could be readily replicated by pharmacological and genetic inhibition of myocyte autophagy and most importantly rescued by pharmacological stimulation of autophago-lysosomal biogenesis. Our data suggest that the thymidine analogue AZT inhibits autophagy in myocytes, which in turn leads to accumulation of dysfunctional mitochondria with increased ROS generation and compromised cell viability. This novel mechanism could contribute to our understanding of the long-term side effects of antiviral agents.
- Azithromycin-loaded liposomes for enhanced topical treatment of methicillin-resistant Staphyloccocus aureus (MRSA) infections. [Journal Article]
- IJInt J Pharm 2018 Oct 09; 553(1-2):109-119
- Antibiotic delivery via liposomal encapsulation represents a promising approach for the efficient topical treatment of skin infections. The present study aimed to investigate the potential of using d...
Antibiotic delivery via liposomal encapsulation represents a promising approach for the efficient topical treatment of skin infections. The present study aimed to investigate the potential of using different types of azithromycin (AZT)-loaded liposomes to locally treat skin infections caused by methicillin-resistant Staphylococcus aureus (MRSA) strains. Conventional liposomes (CLs), deformable liposomes (DLs), propylene glycol-containing liposomes (PGLs) and cationic liposomes (CATLs) encapsulating AZT were prepared, and their physical characteristics, drug release profiles, ex vivo skin penetration/deposition abilities, in vitro anti-MRSA activities (planktonic bacteria and biofilm) and cell biocompatibilities were assessed. The (phospho)lipid composition and presence of surfactant or propylene glycol affected the physical characteristics of the liposomes, the release profile of AZT, its deposition inside the skin, as well as in vitro antibacterial efficacy and tolerability with the skin cells. All the liposomes retained AZT inside the skin more efficiently than did the control and were biocompatible with keratinocytes and fibroblasts. CATLs, DLs and PGLs efficiently inhibited MRSA strain growth and were superior to free AZT in preventing biofilm formation, exhibiting minimal inhibitory concentrations and minimal biofilm inhibitory concentrations up to 32-fold lower than those of AZT solution, thus confirming their potential for improved topical treatment of MRSA-caused skin infections.
- P2X antagonists inhibit HIV-1 productive infection and inflammatory cytokines IL-10 and IL-1β in a human tonsil explant model. [Journal Article]
- JVJ Virol 2018 Oct 10
- HIV-1 causes a persistent infection of the immune system that is associated with chronic comorbidities. The mechanisms that underlie this inflammation are poorly understood. Emerging literature has i...
HIV-1 causes a persistent infection of the immune system that is associated with chronic comorbidities. The mechanisms that underlie this inflammation are poorly understood. Emerging literature has implicated pro-inflammatory purinergic receptors and downstream signaling mediators in HIV-1 infection. This study probed whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1 stimulated inflammation. A human ex vivo human tonsil histo-culture infection model was developed to support HIV-1 productive infection and stimulated inflammatory cytokine interleukin-1 beta (IL-1β) and immunosuppressive cytokine, interleukin-10 (IL-10). This study tests whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1 stimulated inflammation. The purinergic P2X1 receptor antagonist, NF449, the purinergic P2X7 receptor antagonists, A438079, and azidothymidine (AZT) were tested in HIV-1 infected human tonsil explants to compare inhibition of HIV-1 infection and HIV-stimulated inflammatory cytokine production. All drugs limited HIV-1 productive infection, but P2X-selective antagonists (NF449, and A438079) significantly lowered HIV-stimulated IL-10 and IL-1β. We further observed that P2X1- and P2X7-selective antagonists can act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Our findings highlight the differential effects of HIV-1 on inflammation in peripheral blood as compared to lymphoid tissue. For the first time, we demonstrate that P2X-selective antagonists act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Drugs that block these pathways can have independent inhibitory activities against HIV-1 infection and HIV-induced inflammation.IMPORTANCE:Patients who are chronically infected with HIV-1 experience sequelae related to chronic inflammation. The mechanisms of this inflammation have not been elucidated. Here we describe a class of drugs that target the P2X pro-inflammatory signaling receptors in a human tonsil explant model. This model highlights differences in HIV-1 stimulation of lymphoid tissue inflammation and peripheral blood. These drugs serve to both block HIV-1 infection and production of IL-10 and IL-1β in lymphoid tissue suggesting a novel approach to HIV-1 therapeutics in which both HIV-1 replication and inflammatory signaling are simultaneously targeted.
- Correlation of changes in hemodynamic response as measured by cerebral optical spectrometry with subjective pain ratings in volunteers and patients: a prospective cohort study. [Journal Article]
- JPJ Pain Res 2018; 11:1991-1998
- CONCLUSIONS: Cerebral Optical Spectrometry-based ROPA significantly correlated with subjectively reported pain in volunteers and laboring women, and could be a useful monitor for clinical circumstances where direct assessment is not available, or to complement patient-reported pain scores.
- Novel core-shell dextran hybrid nanosystem for anti-viral drug delivery. [Journal Article]
- MSMater Sci Eng C Mater Biol Appl 2018 Dec 01; 93:864-872
- Zidovudine (AZT) is an antiviral drug extensively used for combating the global pandemic- HIV/AIDS. However, its uses are overshadowed by its short half -life, poor aqueous solubility and inability t...
Zidovudine (AZT) is an antiviral drug extensively used for combating the global pandemic- HIV/AIDS. However, its uses are overshadowed by its short half -life, poor aqueous solubility and inability to cross physiological barriers. This study highlights a nanosystem consisting of dextran and stearic acid for AZT delivery. This hybrid nanoparticle was prepared by double emulsion solvent evaporation method. The morphological analysis of the prepared nanoparticles was carried out by transmission electron microscopy (TEM) and structural analysis through FTIR spectroscopy. Haemolysis, blood cell aggregation and cytotoxicity evaluations were also performed. These biological evaluations indicated that the nanoparticles were compatible and fluorescence microscopy studies demonstrated increased cellular internalization of drug loaded hybrid nanoparticles when compared with free drug molecules. The experimental outcomes indicate that the prepared nanoparticles are highly biocompatible haemocompatible and effective in getting internalized into cells of neural origin. These results highlight the feasibility and efficacy of the hybrid nanoparticles for effective delivery of zidovudine.
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- Safety profile of AZT derivatives: Organoselenium moieties confer different cytotoxic responses in fresh human erythrocytes during in vitro exposures. [Journal Article]
- JTJ Trace Elem Med Biol 2018; 50:240-248
- CONCLUSIONS: The insertion of either chlorophenylseleno or, in a certain way, phenylseleno moietes in the structure of AZT molecule was harmful to erythrocytes and this effect seems to involve a pro-oxidant activity. This was not true for the derivative encompassing methylphenylseleno portion, making it a promising candidate for pharmacological studies.