- Antiretroviral drug resistance mutations among patients failing first-line treatment in Hanoi, Vietnam. [Journal Article]
- IDInfect Drug Resist 2019; 12:1237-1242
- CONCLUSIONS: Drug resistance mutations in patients with first-line ART failure had a high prevalence of NNRTI and NRTI resistance but still susceptible to PIs.
- Evaluation of a library of FDA-approved drugs for their ability to potentiate antibiotics against multidrug resistant Gram-negative pathogens. [Journal Article]
- AAAntimicrob Agents Chemother 2019 Jun 03
- The Prestwick library was screened for antibacterial activity or 'antibiotic-resistance breaking' (ARB) potential against four species of Gram-negative pathogens. Discounting known antibacterials, th…
The Prestwick library was screened for antibacterial activity or 'antibiotic-resistance breaking' (ARB) potential against four species of Gram-negative pathogens. Discounting known antibacterials, the screen identified very few ARB hits, which were strain/drug specific. These ARB hits included antimetabolites (zidovudine, floxuridine, didanosine, gemcitabine), anthracyclines (daunorubicin, mitoxantrone, epirubicin) and psychoactive drugs (gabapentin, fluspirilene, oxethazaine). This suggests that there are few approved drugs which could be directly repositioned as adjunct-antibacterials and these will need robust testing to validate efficacy.
- Bile duct ligation enhances AZT CNS toxicity partly by impairing the expression and function of BCRP in rat brain. [Journal Article]
- APActa Pharmacol Sin 2019 May 29
- Breast cancer resistance protein (BCRP) is one of ATP-binding cassette (ABC) transporters in brain microvessel endothelial cells that transport their substrates from brain to blood, thus limiting sub…
Breast cancer resistance protein (BCRP) is one of ATP-binding cassette (ABC) transporters in brain microvessel endothelial cells that transport their substrates from brain to blood, thus limiting substrates to crossing into brain through blood-brain barrier. Our previous works show that bile duct ligation (BDL) impairs expression and function of brain BCRP in rats. Since zidovudine (AZT) is BCRP substrate, we investigated whether impaired expression and function of BCRP increased brain distribution and toxicity of AZT in BDL-D7 rats. After administration of AZT (10 mg/kg, i.v.), BDL markedly increased brain AZT concentrations, compared with sham-operated (SO) rats. The ratio of AZT brain-to-plasma area under concentration curve (AUC) in BDL rats was increased to 1.6-folds of SO rats. After treatment with AZT (100 mg/kg every day, i.v.) for 7 days, BDL significantly impaired cognitive functions compared with SO rats, evidenced by the significantly decreased percentage of alternation in Y-maze test and prolonged escaped latency in two-way passive avoidance trial. Furthermore, AZT treatment caused significant decrease in copies of mitochondrial DNA and mitochondrial membrane potential in hippocampus of BDL rats. Moreover, AZT treatment caused a significant decrease of cortex microtubule-associated protein 2 and hippocampus synaptophysin levels in BDL rats. AZT-induced CNS adverse alterations in BDL rats were not observed in SO rats treated with AZT. In conclusion, BDL decreases the function and expression of brain BCRP in rats, leading to increased brain distribution of AZT, which in turn enhances AZT CNS toxicity, leading to mitochondrial dysfunction, neuronal damage, and ultimately cognitive dysfunction.
- Evaluation of the inhibition risk of shikonin on human and rat UDP-glucuronosyltransferases (UGT) through the cocktail approach. [Journal Article]
- TLToxicol Lett 2019 Sep 15; 312:214-221
- Shikonin, a natural red colorant, is widely used for food garnishment and cosmetic ingredient in the world. Shikonin also possesses a variety of pharmacological actions, including anti-inflammation a…
Shikonin, a natural red colorant, is widely used for food garnishment and cosmetic ingredient in the world. Shikonin also possesses a variety of pharmacological actions, including anti-inflammation and anti-cancer activities. However, little is known about its effects on the UDP-glucuronosyltransferases (UGT) activity. Therefore, the aim of this study was to evaluate the effect of shikonin on the UGT1A1, UGT1A3, UGT1A6, UGT1A9 and UGT2B7 activities via the human and rat liver microsomal assay and cocktail approach. The results showed shikonin inhibited human and rat liver microsomal UGT activity only in a dose-dependent manner. The further enzyme kinetic studies demonstrated that shikonin was not only a competitive inhibitor of human UGT1A1, UGT1A9, and UGT2B7, but also presented competitive inhibition on rat UGT1A1 and AZTG reactions. In conclusion, shikonin as a reversible inhibitor of UGT enzyme has a high-risk potential to cause the possible toxicity, especially drug-drug or food-drug interactions.
- Neurodevelopmental effects of ante-partum and post-partum antiretroviral exposure in HIV-exposed and uninfected children versus HIV-unexposed and uninfected children in Uganda and Malawi: a prospective cohort study. [Journal Article]
- LHLancet HIV 2019 May 20
- CONCLUSIONS: Maternal triple antiretroviral exposure during both the ante-partum and post-partum phases did not result in greater developmental risks for the mothers' HIV-exposed and uninfected children through age 60 months, compared with children who were HIV-unexposed and uninfected. This might be because ante-partum triple antiretroviral protection of the health of mothers with HIV during pregnancy might be neuroprotective for the child, and when continued post partum, could enhance the quality of caregiving for the child through better clinical care for the mother.
- Targeting HIV-TB coinfection by developing novel piperidin-4-substituted imines: Design, synthesis, in vitro and in silico studies. [Journal Article]
- APArch Pharm (Weinheim) 2019; 352(6):e1800358
- Tuberculosis is the "Achilles heel" of the human immunodeficiency (HIV) ministration. HIV-positive people are 16-27 times more prone to contract tuberculosis. But the adverse interaction between anti…
Tuberculosis is the "Achilles heel" of the human immunodeficiency (HIV) ministration. HIV-positive people are 16-27 times more prone to contract tuberculosis. But the adverse interaction between antiretroviral drugs and antitubercular drugs has made it necessary to look for a single drug regimen for HIV-TB coinfection. Piperidine derivatives have been reported as anti-HIV and anti-TB agents. This inspired us to design, synthesize, and characterize a series of 3,5-bis(furan-2-ylmethylidene)-piperidin-4-substituted imines (R1-R25) and these were further screened for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv and anti-HIV activity. Molecular docking studies showed energetically favorable binding interactions with both EACP reductase (1ZID.pdb) and reverse-transcriptase (1REV.pdb) targets. The compounds R7, R12, R17, R18, R19, R20 were found to be more potent as anti-TB agents than ethambutol (MIC 3.125 μg/ml). Compound R7 was found to be moderately active with an IC50 of 2.1 ± 0.04 μM in multicycle infection assays, in comparison with the standard drug, zidovudine (IC50 = 5.7 ± 0.04 nM), used as anti-HIV drug. The cytotoxicity assay was done on Vero, MT-2, and TZM-bl cells to assess the safety of these compounds and they were found to be safe. From the above results, R7 seems to be a promising lead for anti-HIV and anti-TB activity.
- Chronic kidney disease and HIV in the era of antiretroviral treatment: findings from a 10-year cohort study in a west African setting. [Journal Article]
- BNBMC Nephrol 2019 May 07; 20(1):155
- CONCLUSIONS: Our findings do not confirm the high risk of CKD reported in previous studies of West Africans with HIV, but support the recommendations for early initiation of ART and close kidney function monitoring in patients with HBP or aged ≥40 yr.
- Nature and prevalence of adverse drug reaction of antiretroviral medications in Halibet National Referral Hospital: a retrospective study. [Journal Article]
- BPBMC Pharmacol Toxicol 2019 May 06; 20(1):24
- CONCLUSIONS: ADRs associated with ART drugs in Halibet hospital were found to be highly prevalent. Furthermore, CD4 count below 200, was identified as a major risk factor that predisposes patients to ADRs. This is burdensome to resource constrained countries such as Eritrea who have limited drug options and high HIV prevalence, therefore these findings will help patients and healthcare professionals understand the nature as well as seriousness of these ADRs and identify the risks involved with ART medications which can help minimize ART associated ADRs early on.
- Risk Factors for Adverse Birth Outcomes in the PROMISE 1077BF/1077FF Trial. [Journal Article]
- JAJ Acquir Immune Defic Syndr 2019 Apr 23
- CONCLUSIONS: ART effects on adverse pregnancy outcomes reported in the randomized PROMISE trial remained strongly significant even after controlling for demographic, baseline clinical and obstetrical risk factors, which were also associated with these outcomes.
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- Reducing Hematologic Toxicity With Short Course Postexposure Prophylaxis With Zidovudine for HIV-1 Exposed Infants With Low Transmission Risk. [Journal Article]
- PIPediatr Infect Dis J 2019; 38(7):727-730
- Using retrospectively collected data from 383 infants born to HIV-1-infected mothers receiving antiretroviral therapy, we compared transmission rates and hematologic toxicity between infants receivin…
Using retrospectively collected data from 383 infants born to HIV-1-infected mothers receiving antiretroviral therapy, we compared transmission rates and hematologic toxicity between infants receiving 2-week (short course) versus longer duration zidovudine postexposure prophylaxis. Short course resulted in lower hematologic toxicity without evidence of increased vertical transmission risk.