Simultaneous identification of prednisolone and its ten metabolites in human urine by high performance liquid chromatography-tandem mass spectrometry

The use of prednisolone and prednisone is prohibited by the World Anti‐Doping Agency (WADA) due to their performance‐enhancing effect. The purpose of the present work was to explore the possibility of identification and detection of various metabolites of prednisolone by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) in excretion study samples. Ten metabolites of prednisolone could be identified namely prednisone (11‐oxo metabolite) [M‐1], 6‐β‐OH‐prednisolone [M‐2], 20‐β‐OH‐prednisolone [M‐3], 20‐α‐OH‐prednisolone [M‐4], 20‐α‐OH‐prednisone [M‐5], 20‐β‐OH‐prednisone [M‐6], 2 tetrahydro epimers of 20‐β‐OH‐prednisolone [M‐7], 2 tetrahydro epimers of 20‐α‐OH‐prednisolone [M‐8], 2 tetrahydro epimers of 20‐β‐OH‐prednisone [M‐9], and 2 tetrahydro epimers of 20‐α–OH‐prednisone [M‐10]. Prednisolone was administered in 10‐, 20‐, and 40‐mg dosage to healthy volunteers to study detection of various metabolites. The parent, M‐1, M‐2, and M‐3 could be detected up to 72 h while rest of the metabolites were detectable up to 24 h after drug administration. The detection of newer metabolites of the drug can further be used for confirmatory purposes. Copyright © 2012 John Wiley & Sons, Ltd.     

2D, 3D-QSAR and docking studies of 1,2,3-thiadiazole thioacetanilides analogues as potent HIV-1 non-nucleoside reverse transcriptase inhibitors

ABSTRACT: BACKGROUND: The discovery of clinically relevant inhibitors of HIV-RT for antiviral therapy has proven to be a challenging task. To identify novel and potent HIV-RT inhibitors the quantitative structure-activity relationship (QSAR) approach became very useful and largely widespread technique for ligand based drug design. METHODS: We perform the two- and three-dimensional (2D and 3D) QSAR studies of a series of 1,2,3-Thiadiazole thioacetanilides Analogues to elucidate the structural properties required for HIV-RT inhibitory activity. RESULTS: The 2D-QSAR studies were performed using multiple linear regression method (MLR), giving r2 = 0.97 and q2 = 0.94. The 3D-QSAR studies were performed using the stepwise variable selection k-nearest neighbor molecular field analysis approach; a leave-one-out cross-validated correlation coefficient q2=0.89 and a non-cross-validated correlation coefficient r2=0.97 were obtained. Docking analysis suggests the new series have comparable binding affinity with the standard compounds. CONCLUSIONS: This approach showed that hydrophobic & electrostatic effects dominantly determine binding affinities which will further useful for development of new NNRTIs.     

Cerebrospinal fluid profile of amyloid β42 (Aβ42), hTau and ubiquitin in North Indian Alzheimer's disease patients

Alzheimer's disease (AD) is the most common form of dementia, and is characterized by the degeneration of neurons and their synapses, and a higher number of amyloid plaques and neurofibrillary tangles (NFTs) compared with that found in non-demented individuals. Amyloid-β-peptides (Aβ) are major components of amyloid plaques in AD brain whereas NFTs are composed of Tau and associated with ubiquitin. The aim of the present study was to analyze the levels of Aβ42, hTau (total Tau) and ubiquitin in CSF of North Indian population. CSF Aβ42, Tau and ubiquitin were measured in CSF of AD patients as well as controls using ELISA assays. Here we report low Aβ42 levels in AD patients (324.24 ± 76.38 pg/ml) as compared to those in non-AD (NAD) (668.34 ± 43.13 pg/ml), neurological controls (NCs) (727.28 ± 46.49 pg/ml) and healthy controls (HCs) (976.47 ± 124.46 pg/ml). In contrast, hTau and ubiquitin levels were significantly high (568.65 ± 48.89 pg/ml and 36.82 ± 4.34 ng/ml, respectively) in AD patients compared to those in NAD, NC and HC. The hTau levels were 267.37 ± 36.64 pg/ml, 167.34 ± 44.27 pg/ml and 107.62 ± 24.27 pg/ml in NAD, NC and HC, respectively. Similarly, ubiquitin levels were 23.57 ± 2.32 ng/ml, 19.76 ± 3.64 ng/ml and 13.24 ± 4.56 ng/ml in NAD, NC and HC, respectively. In conclusion, low Aβ42 and high Tau–ubiquitin levels were found in North Indian AD patients.     

Opioid-prescribing Practices in Chronic Cancer Pain in a Tertiary Care Pain Clinic

Introduction:

Under treatment of pain is a recognized global issue. Opioid analgesic medication is the mainstay of treatment in cancer patients as per the World Health Organization (WHO) pain relief ladder, yet 50% of cancer patients worldwide do not receive adequate pain relief or are undertreated.

Aim:

The aim of this study was to audit the ongoing opioid-prescribing practices in our tertiary cancer pain clinic during January–June 2010.

Materials & Methods:

The prescribed type of opioid, dose, dosing interval, and laxatives details were analyzed.

Results:

Five hundred pain files were reviewed and 435 were found complete for audit. Three hundred forty-eight (80%) patients were prescribed opioids. Two hundred fifty-nine (74.4%) received weak opioids while 118 (33.9%) received strong opioids. A total of 195 (45%) patients had moderate and 184 (42%) had severe pain. Ninety-three (26.7%) patients received morphine; however, only 31.5% (58 of 184) in severe pain received morphine as per the WHO pain ladder. Only 73 of 93 (78.4%) patients received an adequate dose of morphine with an adequate dosing interval and only 27 (29%) were prescribed laxatives with morphine.

Conclusion:

This study shows that the under treatment of pain and under dosing of opioids coupled with improper side effect management are major issues.     

The tug-of-war between dendritic cells and human chronic viruses

The human immune system is under constant challenge from many viruses, some of which the body is successfully able to clear. Other viruses have evolved to escape the host immune responses and thus persist, leading to the development of chronic diseases. Dendritic cells are professional antigen-presenting cells that play a major role in both innate and adaptive immunity against different pathogens. This review focuses on the interaction of different chronic viruses with dendritic cells and the viruses' ability to exploit this critical cell type to their advantage so as to establish persistence within the host.     

Weak or absent evidence for the association of HLA-DR antigens with risk of thyroid carcinoma: a meta-analysis of observational studies

Inconsistent reports of associations between human leukocyte antigen (HLA)-DR and thyroid cancers exist. We conducted a comprehensive search of the PubMed, Scopus and Web of Science databases. Using random-effects modeling, subgroup analyses, meta-regression and prediction interval (PI) estimation, we combined the existing evidence from 13 studies (977 cases of thyroid cancer and 3735 controls). Only HLA-DR1 and HLA-DR11 were significantly associated; however, the evidence for HLA-DR11 came from only three studies while that for HLA-DR1 had large between-study heterogeneity. All the PIs estimated in the study straddled unity. Therefore, current evidence for the studied association is incomplete as well as uncertain. Attempts to include HLA-DR typing as a prognostic or therapeutic marker may be premature at this time.