Delineation of prototypical degradation mechanism, characterization of unknown degradation impurities by liquid chromatography-quadrupole-time-of-flight-tandem mass spectrometry and stability-indicating analytical method of selumetinib.

Selumetinib (SELU) was recently approved by the US Food and Drug Administration (US FDA) in 2020. However, the degradation impurities of SELU have not been characterized or identified to date. The mechanism for impurity formation and the degradation behavior have not been previously studied. This study aims to elucidate the prototypical degradation mechanism of SELU. Furthermore, the degradation impurities have been identified using LC-quadrupole-time-of-flight tandem mass spectrometry and are reported in this article for the first time. In addition, a stability-indicating analytical method (SIAM) has been developed for this drug. Forced degradation studies revealed the degradation of SELU under various stress conditions, including hydrolytic stress (acid and base), oxidative stress, and photolytic stress (ultraviolet and visible). Three degradation impurities were identified. This article presents the first validated SIAM, capable of accurately quantifying SELU in the presence of its degradation impurities. Furthermore, we have proposed the degradation pathway for SELU and its degradation impurities, a first in the field. The developed SIAM can find applications in process development and quality assurance of SELU in both research laboratories and pharmaceutical industries. Moreover, the identified degradation impurities may serve as impurity standards for quality control testing in pharmaceutical industries.

Phytosynthesis of Silver Nanoparticles Using Oscimum sanctum Leaf Extract and Studies on Its Antidiabetic, Antioxidant, and Antibacterial Properties.

The green synthesis of plasmonic metal nanoparticles (NPs) has gained considerable attention among researchers as it is cost-effective, environmentally friendly, energy-saving, and nontoxic. We have synthesized silver NPs (Ag NPs) with Oscimum sanctum (holy Tulsi) medicinal plant leaf extract by green synthesis methods. Further, we investigate the antibacterial, antioxidant, and antidiabetic activities of the synthesized Ag NPs. Oscimum sanctum leaf extract has secondary metabolites such as phenolic and flavonoid compounds, which play a significant role in the synthesis of Ag NPs. Subsequently, these bioactive molecules get adsorbed on the large surfaces of the synthesized NPs. Spectroscopic techniques such as X-ray diffraction (XRD), UV-visible absorption, Fourier-transform infrared, and scanning electron microscopy have been used to study and characterize the phytosynthesized Ag NPs. The XRD pattern confirms the formation of crystalline Ag NPs with a high degree of intensity. UV-visible absorption spectra confirm the surface plasmon resonance peak in the range of 440-450 nm. A scanning electron microscopy picture reveals homogeneous growth of Ag NPs with particle sizes of 200-400 nm; however, crystallite size along different planes has been estimated in the range of 18-23 nm. We have found that these Ag NPs synthesized with Oscimum sanctum leaf extract show inhibitory activity against α-amylase and α-glucosidase enzymes in vitro. Our findings further reveal that these Ag NPs are more effective in inhibiting the growth of Salmonella typhi bacteria as compared to other bacterial strains.

Refinement of safety and efficacy of anti-cancer chemotherapeutics by tailoring their site-specific intracellular bioavailability through transporter modulation.

Low intracellular bioavailability, off-site toxicities, and multi drug resistance (MDR) are the major constraints involved in cancer chemotherapy. Many anticancer molecules fail to become a good lead in drug discovery because of their poor site-specific bioavailability. Concentration of a molecule at target sites is largely varied because of the wavering expression of transporters. Recent anticancer drug discovery strategies are paying high attention to enhance target site bioavailability by modulating drug transporters. The level of genetic expression of transporters is an important determinant to understand their ability to facilitate drug transport across the cellular membrane. Solid carrier (SLC) transporters are the major influx transporters involved in the transportation of most anti-cancer drugs. In contrast, ATP-binding cassette (ABC) superfamily is the most studied class of efflux transporters concerning cancer and is significantly involved in efflux of chemotherapeutics resulting in MDR. Balancing SLC and ABC transporters is essential to avoid therapeutic failure and minimize MDR in chemotherapy. Unfortunately, comprehensive literature on the possible approaches of tailoring site-specific bioavailability of anticancer drugs through transporter modulation is not available till date. This review critically discussed the role of different specific transporter proteins in deciding the intracellular bioavailability of anticancer molecules. Different strategies for reversal of MDR in chemotherapy by incorporation of chemosensitizers have been proposed in this review. Targeted strategies for administration of the chemotherapeutics to the intracellular site of action through clinically relevant transporters employing newer nanotechnology-based formulation platforms have been explained. The discussion embedded in this review is timely considering the current need of addressing the ambiguity observed in pharmacokinetic and clinical outcomes of the chemotherapeutics in anti-cancer treatment regimens.

Utilisation of immunoglobulin in New Zealand.

BACKGROUND: Immunoglobulin is an expensive and scarce resource and usage is increasing worldwide. Immunoglobulin is used to treat a variety of clinical conditions, particularly primary and acquired immunodeficiencies and immune-mediated neurological disorders. As immunoglobulin usage continues to increase, plasma collection must increase accordingly in order to sustain immunoglobulin production. The New Zealand Blood Service (NZBS) is the provider of immunoglobulin in New Zealand (NZ). Information regarding national immunoglobulin usage warrants analysis given the rise in usage. AIMS: To review immunoglobulin usage in NZ with a focus on the trend in the amount used, number of patients, clinical indications and compliance with international guidelines. A comparison with international immunoglobulin usage was performed. The impact on national plasma collection was reviewed. METHODS: Data on immunoglobulin usage, number of patients and plasma collection over the past decade were obtained from the NZBS Tableau database. Data from international literature were reviewed. RESULTS: Immunoglobulin usage in NZ has been increasing over the past decade, with an annual growth rate of 6.4%. The three main indications for immunoglobulin are primary immunodeficiency disorders, chronic inflammatory demyelinating polyneuropathy (CIDP) and acquired hypogammaglobulinaemia secondary to haematological malignancies. Prominent growth in usage is evident for CIDP and acquired hypogammaglobulinaemia. Immunoglobulin usage in NZ is low compared with other countries, such as Australia and the United States. There has been a marked increase in plasma donations in order to keep up with immunoglobulin demand. CONCLUSIONS: Immunoglobulin is a strategic resource and appropriate usage is critical to regulate demand.

Advancement in Analytical Strategies for Quantification of Biomarkers with a Special Emphasis on Surrogate Approaches.

Accurate quantification of biomarkers has always been a challenge for many bioanalytical scientists due to their endogenous nature and low concentration in biological matrices. Different analytical approaches have been developed for quantifying biomarkers including enzyme-linked immunosorbent assay, immunohistochemistry, western blotting, and chromatographic techniques assisted with mass spectrometry. Liquid chromatography-tandem mass spectrometry-based quantification of biomarkers has gained more attention over other traditional techniques due to its higher sensitivity and selectivity. However, the primary challenge lies with this technique includes the unavailability of a blank matrix for method development. To overcome this challenge, different analytical approaches are being developed including surrogate analyte and surrogate matrix approach. Such approaches include quantification of biomarkers in a surrogate matrix or quantification of an isotopically labeled surrogate analyte in an authentic matrix. To demonstrate the authenticity of the surrogate approach, it is mandatory to establish quantitative parallelism through validation employing respective surrogate analytes and surrogate matrices. In this review, different bioanalytical approaches for biomarker quantification and recent advancements in the field aiming for improvement in the specificity of the techniques have been discussed. Liquid chromatography-tandem mass spectrometry-based surrogate approaches for biomarker quantification and significance of parallelism establishment in both surrogate matrix and surrogate analyte-based approaches have been critically discussed. In addition, different methods for demonstrating parallelism in the surrogate method have been explained.

Preventive and Therapeutic Aspects of Migraine for Patient Care: An Insight.

BACKGROUND: Migraine is a common neurological condition marked by frequent mild to extreme headaches that last 4 to 72 hours. A migraine headache may cause a pulsing or concentrated throbbing pain in one part of the brain. Nausea, vomiting, excessive sensitivity to light and sound, smell, feeling sick, vomiting, painful headache, and blurred vision are all symptoms of migraine disorder. Females are more affected by migraines in comparison to males. OBJECTIVE: The present review article summarizes preventive and therapeutic measures, including allopathic and herbal remedies for the treatment of migraine. RESULTS: This review highlights the current aspects of migraine pathophysiology and covers an understanding of the complex workings of the migraine state. Therapeutic agents that could provide an effective treatment have also been discussed. CONCLUSION: It can be concluded that different migraines could be treated based on their type and severity.

Haemochromatosis: evaluating the effectiveness of a novel patient self-management approach to venesection as blood donation.

AIM: We set out to evaluate the effectiveness of a new model of self management of haemochromatosis, whereby patients with stable ferritin control were discharged from the New Zealand Blood Service (NZBS) therapeutic venesection clinic and educated to manage their own venesection by regular blood donation and annual serum ferritin check by their general practitioner. METHOD: Data regarding the frequency of blood donation and serum ferritin level were collected from the NZBS and Concerto records of haemochromatosis patients in the Wellington region who had been discharged back to the care of their general practitioner between January 2014 and June 2015. RESULTS: Of the 107 patients, 93% continued to donate blood after discharge. A serum ferritin level was checked in 78% of patients by their general practitioner. The mean number of blood donations per year decreased after discharge, with a corresponding rise in the average ferritin level (difference 28 mcg/L; range 13-43 mcg/L; p<0.005). CONCLUSION: The new model of self management was effective for the majority of patients who were discharged from the therapeutic venesection clinic. Longer follow up is required to assess the overall pattern of ferritin control in patients who self manage their haemochromatosis by regular blood donation.