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Exposure of active pharmaceutical compounds (APCs) to the environment during human use is of potential importance in the emergence of drug resistance, changing soil microbiota and their residual effect on living organisms. Thus, this study aimed to assess the extent of exposure of APCs in the hydrologic cycle in and around New Delhi. This study analyzed the presence of 28 drugs from different classes in the surface water (river Yamuna) and aquifers collected from 48 places in Delhi (within the radius of 40 km). The collected water samples were quantified for APCs content using LC-MS/MS. This study revealed that aquifers are extensively affected in most areas based on the accumulation of APCs in water resources to the levels > 0.01 μg/L. Interestingly, a geographical plot of total APCs studied indicated clustering in aquifers with such high levels closer to an unscientific landfill. This 30-year-old un-segregated landfill is found to drain leachate into surface water that had high APCs. This study further revealed that apart from therapeutic usage, the main source of ecological exposure could be due to the disposal of unused and expired pharmaceutical compounds into landfills. For the first time, this study revealed the existence of antimicrobial agents and other APCs in the aquifers of Delhi with levels > 0.1 μg/L, which is a matter of serious concern in terms of multi-drug resistance and other environmental perils. This study warrants the enforcement of regulations for the disposal of unused/expired APCs in high-density population areas.

To evade the possible toxicity associated with the formation of quinone-imine metabolite in amodiaquine (AQ), the para-hydroxyl group was replaced with a −F atom, and the resulting 4′-fluoro-amodiaquine (FAQ) was hybridized with substituted pyrimidines. The synthesized FAQ− pyrimidines displayed better in vitro potency than chloroquine (CQ) against the resistant P. falciparum strain (Dd2), exhibiting up to 47.3-fold better activity (IC 50 : 4.69 nM) than CQ (IC 50 : 222 nM) and 2.8-fold better potency than artesunate (IC 50 : 13.0 nM). Twelve compounds exhibited better antiplasmodial activity than CQ against the CQ-sensitive (NF54) strain. Two compounds were evaluated in vivo against a P. berghei-mouse malaria model. Mechanistic heme-binding studies, computational docking studies against Pf-DHFR and in vitro microsomal stability studies were performed for the representative molecules of the series to assess their antimalarial efficacy.

The time course of pathogenesis of fructose mediated hepatic insulin resistance (HepIR) is not well-delineated and we chronicle it here from post-weaning to adulthood stages. Weaned rats were provided for either 4 or 8 weeks, i.e., upto adolescence or adulthood, chow + drinking water, chow + fructose, 15% or chow + fructose, 15% + hydroalcoholic extract of leaves of Aegle marmelos (AM-HM, 500 mg/kg/d, po) and assessed for feed intake, fructose intake, body weight, fasting blood sugar, oral glucose tolerance test, HOMA-IR, insulin tolerance test and lipid profile. Activities of enzymes (glucose-6-phosphatase, hexokinase, phosphofructokinase, aldehyde dehydrogenase), hormones (leptin, ghrelin, insulin), insulin signaling molecules (Akt-PI3k, AMPK, JNK) hallmarks of inflammation (TNF-α), angiogenesis (VEGF), hypoxia (HIF-1), lipogenesis (mTOR) and regulatory nuclear transcription factors of de novo lipogenesis and hepatic insulin resistance gene (SREBP-1, FoxO1) that together govern the hepatic fructose metabolism, were also studied. The effect of fructose-rich environment on metabolic milieu of hepatocytes was confirmed using (human hepatocellular carcinoma) HepG2 cells. Using in vitro model, fructose uptake and glucose output from isolated murine hepatocytes were measured to establish the HepIR under fructose environment and delineate the effect of AM-HM. The leaves from the plant Aegle marmelos (L) Correa were extracted, fractionated and validated for rutin content using LC-MS/MS. The rutin content of extract was quantified and correlated with oral pharmacokinetic parameters in rat. The outcomes of the study suggest that the molecular and metabolic markers of fructose induced HepIR in developing and adult rats are distinct. Further, AM-HM exerts a multi-pronged attack by raising insulin secretion, augmenting insulin action, improving downstream signaling of insulin, reducing overall requirement of insulin and modulating hepatic expression of glucose transporter (Glut2). The butanol fraction of AM-HM holds promise for future development.

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