Background and purpose: Patients commonly take complementary medicines in conjunction with warfarin yet evidence supporting the safety or the risk of a herb-drug interaction is lacking. The aim of this study was to investigate the possible impact of two commonly used herbal medicines, garlic and cranberry, on the pharmacokinetics and pharmacodynamics of warfarin in healthy male subjects. Experimental approach: An open-label, three-treatment, randomized crossover clinical trial was undertaken and involved 12 healthy male subjects of known CYP2C9 and VKORC1 genotype. A single dose of 25 mg warfarin was administered alone or after 2 weeks of pretreatment with either garlic or cranberry. Warfarin enantiomer concentrations, INR, platelet aggregation and clotting factor activity were measured to assess pharmacokinetic and pharmacodynamic interactions between warfarin and herbal medicines. Key results: Cranberry significantly increased the area under the INR-time curve by 30% when administered with warfarin compared with treatment with warfarin alone. Cranberry did not alter S-or R-warfarin pharmacokinetics or plasma protein binding. Co-administration of garlic did not significantly alter warfarin pharmacokinetics or pharmacodynamics. Both herbal medicines showed some evidence of VKORC1 (not CYP2C9) genotype-dependent interactions with warfarin, which is worthy of further investigation. Conclusions and implications: Cranberry alters the pharmacodynamics of warfarin with the potential to increase its effects significantly. Co-administration of warfarin and cranberry requires careful monitoring.

The treatment of central nervous system (CNS) disorders always remains a challenge for the researchers. The presence of various physiological barriers, primarily the blood–brain barrier (BBB) limits the accessibility of the brain and hinders the efficacy of various drug therapies. Hence, drug targeting to the brain, particularly to the diseased cells by circumventing the physiological barriers is essential to develop a promising therapy for the treatment of brain disorders. Presently, the investigations emphasize the role of different nanocarrier systems or surface modified target specific novel carrier system to improve the efficiency and reduce the side effects of the brain therapeutics. Such approaches supposed to circumvent the BBB or have the ability to cross the barrier function and thus increases the drug concentration in the brain. Although the efficacy of novel carrier system depends upon various physiological factors like active efflux transport, protein corona of the brain, stability, and toxicity of the nanocarrier, physicochemical properties, patient-related factors and many more. Hence, to develop a promising carrier system, it is essential to understand the physiology of the brain and BBB and also the other associated factors. Along with this, some alternative route like direct nose-to-brain drug delivery can also offer a better means to access the brain without exposure of the BBB. In this review, we have discussed the role of various physiological barriers including the BBB and blood-cerebrospinal fluid barrier (BCSFB) on the drug therapy and the mechanism of drug transport across the BBB. Further, we discussed different novel strategies for brain targeting of drug including, polymeric nanoparticles, lipidic nanoparticles, inorganic nanoparticles, liposomes, nanogels, nanoemulsions, dendrimers, quantum dots, etc. along with the intranasal drug delivery to the brain. We have also illustrated various factors affecting the drug targeting efficiency of the developed novel carrier system.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Echinacea and policosanol are commonly used herbal medicines which may be ingested by patients receiving warfarin. Echinacea has been implicated in interacting with drug metabolizing enzymes and policosanol has been shown to decrease platelet aggregation. The potential interaction of echinacea and policosanol with warfarin has not previously been investigated. WHAT THIS STUDY ADDS • Concomitant treatments with echinacea increased the apparent clearance of S‐warfarin but did not have a clinically significant effect on warfarin pharmacodynamics in healthy subjects. Policosanol did not significantly affect warfarin pharmacokinetics or pharmacodynamics. AIMS This study investigated the pharmacokinetic and pharmacodynamic interactions of echinacea and policosanol with warfarin in healthy subjects. METHODS This was an open‐label, randomized, three‐treatment, cross‐over, clinical trial in healthy male subjects (n= 12) of known CYP2C9 and VKORC1 genotype who received a single oral dose of warfarin alone or after 2 weeks of pre‐treatment with each herbal medicine at recommended doses. Pharmacodynamic (INR, platelet activity) and pharmacokinetic (warfarin enantiomer concentrations) end points were evaluated. RESULTS The apparent clearance of (S)‐warfarin (90% CI of ratio; 1.01, 1.18) was significantly higher during concomitant treatment with echinacea but this did not lead to a clinically significant change in INR (90% CI of AUC of INR; 0.91, 1.31). Policosanol did not significantly affect warfarin enantiomer pharmacokinetics or warfarin response. Neither echinacea nor policosanol had a significant effect on platelet aggregation after 2 weeks of pre‐treatment with the respective herbal medicines. CONCLUSION Echinacea significantly reduced plasma concentrations of S‐warfarin. However, neither echinacea nor policosanol significantly affected warfarin pharmacodynamics, platelet aggregation or baseline clotting status in healthy subjects.

The review article explores the various problems associated with hydrolysis which occurs during formulation and the various solutions of it. The moisture content either the drug or the excipients affect the formulation, by hydrolysis, thus it is important to find out ways to prevent it and thus protect the formulation and provide a greater stability under processing and storage condition. The common moisture interactions which occur are water-solid interactions, water-amorphous solid interactions, drug-excipient interactions and the change in the crystal habit of the solids. The science behind the hydrolysis is due to the moisture sensitive functional group of the ingredient, and the other freely moveable living groups. Amides, lactams, esters, lactones, chloride are the functional groups most susceptible to hydrolysis. The hydrolysis of excipients, including both polymeric and non-polymeric also show great impact on the stability of the drugs. The excipients used in the form of sweeteners, plasticizers, solvents, surfactants, wetting agents, emollients, antioxidants, lubricants, preservatives, and etc. have effects on the drug stability. As a result, several solutions are found to prevent unwanted hydrolysis in different dosage forms. The main parameters which are likely to solve this issue are pH, buffers, surfactants, non-aqueous solutions, suspensions, lyophilization, packaging and an adequate proportion of the desiccant use.

Despite the introduction of directly acting antivirals (DAAs), for the treatment of hepatitis C virus (HCV) infection, their cost, patient compliance, and viral resistance are still important issues to be considered. Here, we describe the generation of a novel JFH1-based HCV subgenomic replicon double reporter cell line suitable for testing different antiviral drugs and therapeutic interventions. This cells line allowed a rapid and accurate quantification of cell growth/viability and HCV RNA replication, thus discriminating specific from unspecific antiviral effects caused by DAAs or cytotoxic compounds, respectively. By correlating cell number and virus replication, we could confirm the inhibitory effect on the latter of cell over confluency and characterize an array of lentiviral vectors expressing single, double, or triple cassettes containing different combinations of short hairpin (sh)RNAs, targeting both highly conserved viral genome sequences and cellular factors crucial for HCV replication. While all vectors were effective in reducing HCV replication, the ones targeting viral sequences displayed a stronger antiviral effect, without significant cytopathic effects. Such combinatorial platforms as well as the developed double reporter cell line might find application both in setting-up anti-HCV gene therapy approaches and in studies aimed at further dissecting the viral biology/pathogenesis of infection.