Bioanalytical HPLC method with fluorescence detector for determination of Entresto™ when co-administered with ibuprofen and fexofenadine: a pharmacokinetic study.

Entresto™ (LCZ696) has been approved globally for heart failure management. However, its lifelong use alongside over-the-counter (OTC) drugs like ibuprofen (IBU) and fexofenadine (FEX) necessitates an in-depth investigation of potential pharmacokinetic interactions, as they share the same metabolic and elimination pathways. This study aimed to develop a bioanalytical HPLC method with a fluorescence detector (FLD) to quantify LCZ696 analytes (valsartan, VAL; sacubitril, SAC; and sacubitril active metabolite, LBQ657) in rat plasma. Additionally, an in vivo study was performed to investigate the pharmacokinetic interactions of LCZ696 with IBU and FEX. Utilizing HPLC with a gradient-mode mobile phase of acetonitrile and 0.025 M phosphate buffer (pH 3), the study demonstrated a significant increase in the bioavailability of LCZ696 analytes (VAL and LBQ657) when co-administered with IBU (C max 0.23 ± 0.07 and 0.53 ± 0.21 µg mL-1, respectively) compared to the control (0.17 ± 0.03 and 0.33 ± 0.14 µg mL-1). A more significant increase in C max was noticed with FEX (0.38 ± 0.01 and 0.77 ± 0.18 µg mL-1, respectively). Moreover, a decrease in the clearance (Cl/F) of VAL and LBQ657 was observed (18.05 ± 1.94 and 12.42 ± 2.97 L h-1 kg, respectively) with a more pronounced effect in the case of FEX (30.87 ± 4.29 and 33.14 ± 9.57 L h-1 kg, respectively) compared to the control (49.99 ± 7.31 and 51.19 ± 9.12 L h-1 kg, respectively). In conclusion, our study underscores the importance of cautious administration and appropriate dose spacing of IBU and FEX in patients treated with LCZ696 to prevent elevated serum concentrations and potential toxicity. The novelty of this work lies in its dual contribution: developing a highly sensitive HPLC-FLD method and comprehensively elucidating significant pharmacokinetic interactions between LCZ696 and common OTC drugs.

Nicorandil reduces morphine withdrawal symptoms, potentiates morphine antinociception, and ameliorates liver fibrosis in rats.

AIMS: Chronic liver disease (CLD) is a serious medical condition affecting patients globally and pain management poses a unique challenge. ATP-sensitive potassium channels (KATP) are expressed in nociceptive neurons and hepatic cells. We tested the hypothesis whether morphine and nicorandil, KATP channel opener, alone and in combination possess hepatoprotective, antinociceptive effect and alter morphine physical dependence. MAIN METHODS: Intraperitoneal injection (i.p.) of carbon tetrachloride (CCl4) induced liver fibrosis in male Wistar rats. Nicorandil (15 mg/kg/day) was administered per os for two weeks. Morphine (3.8, 5, 10 mg/kg, i.p.) was administered prior to antinociception testing in tail flick and formalin tests. Morphine physical dependence following naloxone injection, fibrotic, oxidative stress markers, and liver histopathology were assessed. KEY FINDINGS: Morphine alone, produced insignificant changes of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), hepatic hydroxyproline (Hyp), malondialdehyde (MDA), and superoxide dismutase (SOD) levels and exerted significant antinociception in the pain models. Nicorandil alone protected against liver damage (decreased serum ALT, AST, HA, hepatic Hyp, MDA, increased SOD levels, improved fibrosis scores). Nicorandil/morphine combination produced remarkable hepatoprotection and persistent analgesia compared to morphine alone as evidenced by reduced (EC50) of morphine. Nicorandil augmented morphine analgesia and markedly decreased withdrawal signs in morphine-dependent rats. SIGNIFICANCE: The data showed for the first time, the hepatoprotection and augmented antinociception mediated by nicorandil/morphine combination in liver fibrosis via antioxidant and antifibrotic mechanisms. Nicorandil ameliorated withdrawal signs in morphine dependence in CLD. Thus, combining nicorandil/morphine provides a novel treatment strategy to ameliorate hepatic injury, potentiate antinociception and overcome morphine-induced physical dependence in liver fibrosis.

Nicorandil/ morphine crosstalk accounts for antinociception and hepatoprotection in hepatic fibrosis in rats: Distinct roles of opioid/cGMP and NO/KATP pathways.

Previous report indicated that nicorandil potentiated morphine antinociception and attenuated hepatic injury in liver fibrotic rats. Herein, the underlying mechanisms of nicorandil/morphine interaction were investigated using pharmacological, biochemical, histopathological, and molecular docking studies. Male Wistar rats were injected intraperitoneally (i.p.) with carbon tetrachloride (CCl4, 40%, 2 ml/kg) twice weekly for 5 weeks to induce hepatic fibrosis. Nicorandil (15 mg/kg/day) was administered per os (p.o.) for 14 days in presence of the blockers; glibenclamide (KATP channel blocker, 5 mg/kg, p.o.), L-NG-nitro-arginine methyl ester (L-NAME, nitric oxide synthase inhibitor, 15 mg/kg, p.o.), methylene blue (MB, guanylyl cyclase inhibitor, 2 mg/kg, i.p.) and naltrexone (opioid antagonist, 20 mg/kg, i.p.). At the end of the 5th week, analgesia was evaluated using tail flick and formalin tests along with biochemical determinations of liver function tests, oxidative stress markers and histopathological examination of liver tissues. Naltrexone and MB inhibited the antinociceptive activity of the combination. Furthermore, combined nicorandil/morphine regimen attenuated the release of endogenous peptides. Docking studies revealed a possible interaction of nicorandil on µ, κ and δ opioid receptors. Nicorandil/morphine combination protected against liver damage as evident by decreased liver enzymes, liver index, hyaluronic acid, lipid peroxidation, fibrotic insults, and increased superoxide dismutase activity. Nicorandil/morphine hepatoprotection and antioxidant activity were inhibited by glibenclamide and L-NAME but not by naltrexone or MB. These findings implicate opioid activation/cGMP versus NO/KATP channels in the augmented antinociception, and hepatoprotection, respectively, of the combined therapy and implicate provoked cross talk by nicorandil and morphine on opioid receptors and cGMP signaling pathway. That said, nicorandil/morphine combination provides a potential multitargeted therapy to alleviate pain and preserve liver function.

3D-Printed Microfluidics Potential in Combating Future and Current Pandemics (COVID-19).

Coronavirus disease (COVID-19) emerged in China in December 2019. In March 2020, the WHO declared it a pandemic leading to worldwide lockdowns and travel restrictions. By May, it infected 4,789,205 and killed 318,789 people. This led to severe shortages in the medical sector besides devastating socio-economic effects. Many technologies such as artificial intelligence (AI), virtual reality (VR), microfluidics, 3D printing, and 3D scanning can step into contain the virus and hinder its extensive spread. This article aims to explore the potentials of 3D printing and microfluidic in accelerating the diagnosis and monitoring of the disease and fulfilling the shortages of personal protective equipment (PPE) and medical equipment. It highlights the main applications of 3D printers and microfluidics in providing PPE (masks, respirators, face shields, goggles, and isolation chambers/hoods), supportive care (respiratory equipment) and diagnostic supplies (sampling swabs & lab-on-chip) to ease the COVID-19 pressures. Also, the cost of such technology and regulation considerations are addressed. We conclude that 3D printing provided reusable and low-cost solutions to mitigate the shortages. However, safety, sterility, and compatibility with environmental protection standards need to be guaranteed through standardization and assessment by regulatory bodies. Finally, lessons learned from this pandemic can also help the world prepare for upcoming outbreaks.