Publications by authors named "Shruti Rastogi"

14 Publications

  • Page 1 of 1

Severe cutaneous adverse reactions in Asians: Trends observed in culprit anti-seizure medicines using VigiBase®.

Seizure 2021 Oct 13;91:332-338. Epub 2021 Jul 13.

Postgraduate Institute of Medical Education & Research, Chandigarh 160012, India.

Purpose: Diverse ethnic genetic populations display variability in the risk regarding anti-seizure medicine (ASM)-induced severe cutaneous adverse reactions (SCARs). However, clinical and epidemiological data on ASM-induced SCARs in Asians is limited.

Methods: We conducted a retrospective, post-market study until April 30, 2020 using VigiBase® for demographic characteristics, causative ASMs, complications and mortality. The study included adverse events as classified by Standardized Medical Dictionary for Regulatory Activities (MedDRA) queries of SCARs, mainly Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), and SJS/TEN overlap reported for ASMs.

Results: A total of 694,811 adverse events were reported across the world while using ASMs. Of this, skin and subcutaneous tissue adverse events were 122,885 (17.6%). Among ASM-induced skin and subcutaneous tissue adverse events, SJS, TEN, DRESS and SJS/TEN overlap represented 11,181 (9.1%), 3,645 (3.0%), 5,106 (4.1%) and 6 (0.004%) cases, respectively. Female SJS/TEN/DRESS patients were 54.1%, and 75% of them were adults (>18Y). Nearly 64% of the ASM-induced SCARs were serious and culminated in death (3.5%), life-threatening conditions (11.5%), and hospitalization/prolonged hospitalization (43.5%) of patients on ASM therapy. Carbamazepine (31.6%), phenytoin (29.6%), lamotrigine (24.3%), valproic acid (6.4%) and phenobarbital (5.7%) are the most commonly used ASMs linked with SCARs. ASMs associated with significantly higher risk of SCARs in Asians were carbamazepine [n = 3265, ROR 3.55 (95% CI 3.38-3.72, P < 0.0001)], lamotrigine [n = 1253, ROR 3.90 (95% CI 3.63-4.18, P < 0.0001)], gabapentin [n = 85, ROR 3.58 (95% CI 2.79-4.60, P < 0.0001)], pregabalin [n = 68, ROR 3.16 (95% CI 2.40-4.16, P < 0.0001)], clonazepam [n = 53, ROR 3.19 (95% CI 2.31-4.41, P < 0.0001)], lorazepam [n = 31, ROR 3.07 (95% CI 2.06-4.59, P < 0.0001)] and acetazolamide [n = 28, ROR 3.90 (95% CI 2.45-6.21, P < 0.0001)].

Conclusion: Based on our study, carbamazepine, lamotrigine, gabapentin, pregabalin, clonazepam, lorazepam, and acetazolamide are the most common causative ASMs for SCARs in the Asian population.
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http://dx.doi.org/10.1016/j.seizure.2021.07.011DOI Listing
October 2021

Drug delivery device for the inner ear: ultra-sharp fully metallic microneedles.

Drug Deliv Transl Res 2021 Feb;11(1):214-226

Department of Mechanical Engineering, Columbia University, 500 West 120th Street, New York, NY, 10027, USA.

Drug delivery into the inner ear is a significant challenge due to its inaccessibility as a fluid-filled cavity within the temporal bone of the skull. The round window membrane (RWM) is the only delivery portal from the middle ear to the inner ear that does not require perforation of bone. Recent advances in microneedle fabrication enable the RWM to be perforated safely with polymeric microneedles as a means to enhance the rate of drug delivery from the middle ear to the inner ear. However, the polymeric material is not biocompatible and also lacks the strength of other materials. Herein we describe the design and development of gold-coated metallic microneedles suitable for RWM perforation. When developing microneedle technology for drug delivery, we considered three important general attributes: (1) high strength and ductility material, (2) high accuracy and precision of fabrication, and (3) broad design freedom. We developed a hybrid additive manufacturing method using two-photon lithography and electrochemical deposition to fabricate ultra-sharp gold-coated copper microneedles with these attributes. We refer to the microneedle fabrication methodology as two-photon templated electrodeposition (2PTE). We demonstrate the use of these microneedles by inducing a perforation with a minimal degree of trauma in a guinea pig RWM while the microneedle itself remains undamaged. Thus, this microneedle has the potential literally of opening the RWM for enhanced drug delivery into the inner ear. Finally, the 2PTE methodology can be applied to many different classes of microneedles for other drug delivery purposes as well the fabrication of small scale structures and devices for non-medical applications. Graphical Abstract Fully metallic ultra-sharp microneedle mounted at end of a 24-gauge stainless steel blunt syringe needle tip: (left) Size of microneedle shown relative to date stamp on U.S. one-cent coin; (right) Perforation through guinea pig round window membrane introduced with microneedle.
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http://dx.doi.org/10.1007/s13346-020-00782-9DOI Listing
February 2021

PGE deficiency predisposes to anaphylaxis by causing mast cell hyperresponsiveness.

J Allergy Clin Immunol 2020 12 11;146(6):1387-1396.e13. Epub 2020 May 11.

Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. Electronic address:

Background: Reduced levels of prostaglandin E (PGE) contribute to aspirin-induced hypersensitivity. COX inhibitors are also frequent cofactors in anaphylaxis. Whether alterations in the PGE system contribute to anaphylaxis independently of COX inhibitor intake is unclear.

Objective: Our aim was to test the hypothesis that relative PGE deficiency predisposes to anaphylaxis.

Methods: Sera from 48 patients with anaphylaxis and 27 healthy subjects were analyzed for PGE levels and correlated against severity; 9α,11β-PGF and PGI metabolites were measured for control purposes. PGE stabilization by 15-hydroxyprostaglandin dehydrogenase inhibitor or EP2 or EP4 receptor agonists were used in a murine model of passive systemic anaphylaxis. FcεRI-triggered mediator release was determined in bone marrow-derived cultured mast cells (MCs) and human skin-derived MCs. Signaling was studied by Western blot analysis.

Results: Patients with anaphylaxis were characterized by markedly reduced PGE levels vis-à-vis healthy subjects, whereas prostacyclin metabolite levels were diminished only weakly, and 9α,11β-PGF levels conversely increased. PGE was negatively correlated with severity. Lower PGE levels and higher susceptibility to anaphylaxis were also found in C57BL/6 mice vis-à-vis in Balb/c mice. Stabilization of PGE level by 15-hydroxyprostaglandin dehydrogenase inhibitor protected mice against anaphylaxis. Exogenous PGE attenuated bone marrow-derived cultured MC activation through EP2 and EP4 receptors. EP2 and EP4 agonism also curbed FcεRI-mediated degranulation of human MCs. Mechanistically, PGE interfered with the phosphorylation of phospholipase C gamma-1 and extracellular signal-regulated kinase.

Conclusions: Homeostatic levels of PGE attenuate MC activation via EP2/EP4 and protect against anaphylaxis. Relative deficiency of PGE predisposes to anaphylaxis in humans and mice, whereas PGE stabilization protects against anaphylactic reactions.
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http://dx.doi.org/10.1016/j.jaci.2020.03.046DOI Listing
December 2020

Towards a comprehensive safety understanding of granulocyte-colony stimulating factor biosimilars in treating chemotherapy associated febrile neutropenia: Trends from decades of data.

Toxicol Appl Pharmacol 2020 05 25;395:114976. Epub 2020 Mar 25.

Indian Pharmacopoeia Commission, Ministry of Health & Family Welfare, Government of India, Sector-23, Raj Nagar, Ghaziabad 201002, Uttar Pradesh, India.

Filgrastim, a biopharmaceutical listed on WHO model list of essential medicines, was approved in USA in 1991 for patients with non-myeloid malignancies associated with severe neutropenia and fever. Several filgrastim biosimilars have now been approved in USA, Europe and elsewhere since 2008, based on the reference product which has lost patent exclusivity; however their immunogenicity and safety is controversial. We conducted a retrospective, post market study between 1991 and May 2018 using VigiBase®. The study included all adverse events with case reports ≥150. Overall, 11,183 adverse drugs reaction reports were identified during observation period; of which 5764; 51.5% reports concerned to Neupogen®, the originator, and rest consists of Leucostim® (N = 680), Zarzio® (N = 622), Grasin® (N = 545), Nivestim® (N = 359) and Tevagrastim® (N = 152) biosimilars. When compared with the originator, Grasin® was associated with higher reporting of pyrexia (11.5% vs 7.9%, ROR 1.52, IC 1.12), myalgia (37% vs 2.2%, ROR 25.94, IC 2.11) and back pain (11.3% vs 4%, ROR 3.09, IC 2.32). Zarzio® was associated with increased reporting of arthralgia (4.5% vs 2.9%, ROR 1.59, IC 1.25) and neutropenia (11.4% vs 4%, ROR 2.59, IC 3.07). Bone pain was reported more often with Nivestim® (14.4% vs 8.3%, ROR 1.87, IC 5.30). Drug ineffectiveness was reported in cases with Zarzio® (35.9%), Nivestim® (19.4%) and Tevagrastim® (42.2%). Authors observed significant differences among originator and biosimilars in particular to efficacy, adverse events reported and time to onset of occurrences. Large epidemiologic studies are needed to further confirm these finding and provide additional insights.
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http://dx.doi.org/10.1016/j.taap.2020.114976DOI Listing
May 2020

Peptide-based therapeutics: quality specifications, regulatory considerations, and prospects.

Drug Discov Today 2019 01 6;24(1):148-162. Epub 2018 Oct 6.

Analytical Research & Development, Indian Pharmacopoeia Commission, Ministry of Health & Family Welfare, Government of India, Sector-23, Raj Nagar, Ghaziabad 201002, UP, India; Medical Devices & Materiovigilance, Indian Pharmacopoeia Commission, Ministry of Health & Family Welfare, Government of India, Sector-23, Raj Nagar, Ghaziabad 201002, UP, India; Biologics, Indian Pharmacopoeia Commission, Ministry of Health & Family Welfare, Govt. of India, Sector-23, Raj Nagar, Ghaziabad 201002, UP, India; Indian Pharmacopoeia Commission, Ministry of Health & Family Welfare, Government of India, Sector-23, Raj Nagar, Ghaziabad 201002, UP, India.

Exquisite selectivity, remarkable efficacy, and minimal toxicity are key attributes inherently assigned to peptides, resulting in increased research interest from the pharmaceutical industry in peptide-based therapeutics (PbTs). Pharmacopoeias develop authoritative standards for PbT by providing standard specifications and test methods. Nevertheless, a lack of harmonization in test procedures adopted for PbT in the latest editions of Pharmacopoeias has been observed. Adoption of a harmonized monograph could increase further the interest of the global pharmaceutical industry in PbTs. Here, we provide an overview of pharmacopoeial methodologies and specifications commonly observed in PbT monographs and highlight the main differences among the pharmacopoeias in terms of the active pharmaceutical ingredients that they focus on. We also address the prospects for PbTs to mature as a new therapeutic niche.
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http://dx.doi.org/10.1016/j.drudis.2018.10.002DOI Listing
January 2019

Veterinary herbal medicines in India.

Pharmacogn Rev 2015 Jul-Dec;9(18):155-63

Department of Phytopharmaceuticals, Indian Pharmacopoeia Commission, Ministry of Health and Family Welfare, Ghaziabad, Uttar Pradesh, India.

India has a rich and diversified flora. It is seen that synthetic drugs could pose serious problems, are toxic and costly. In contrast to this, herbal medicines are relatively nontoxic, cheaper and are eco-friendly. Moreover, the people have used them for generations. They have also been used in day-to-day problems of healthcare in animals. 25% of the drugs prescribed worldwide come from plants. Almost 75% of the medicinal plants grow naturally in different states of India. These plants are known to cure many ailments in animals like poisoning, cough, constipation, foot and mouth disease, dermatitis, cataract, burning, pneumonia, bone fractures, snake bites, abdominal pains, skin diseases etc. There is scarce review of such information (veterinary herbals) in the literature. The electronic and manual search was made using various key words such as veterinary herbal, ethno-veterinary medicines etc. and the content systematically arranged. This article deals with the comprehensive review of 45 medicinal plant species that are official in Indian Pharmacopoeia (IP) 2014. The botanical names, family, habitat, plant part used and pharmacological actions, status in British Pharmacopoeia 2014, USP 36 are mentioned. Also, a relationship between animal and human dose, standardization and regulatory aspects of these selected veterinary herbals are provided.
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http://dx.doi.org/10.4103/0973-7847.162140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4557239PMC
September 2015

Implementing the Principle of the 3 Rs Through the Indian Pharmacopoeia.

Ther Innov Regul Sci 2015 Sep;49(5):750-755

1 Indian Pharmacopoeia Commission, Ministry of Health and Family Welfare, Government of India, Ghaziabad, India.

Quality and safety tests are required for regulatory approval of drugs and pharmaceuticals in the country to guarantee minimum safety standards, and most of these tests include animal usage. In the case of biological medicines, these safety and quality tests have to be performed on a batch-to-batch basis and require a large number of animals. Russell and Burch's 1959 principle of the 3 Rs- replacement, reduction, and refinement-is now being increasingly adopted worldwide, and various national and international pharmacopoeias have taken initiatives to safeguard animals. This article details the Indian Pharmacopoeia Commission's initiative to implement the 3 Rs through the Indian Pharmacopoeia. Explored are the deletion of animal tests, such as the abnormal toxicity test at final lot for biologicals; the replacement of in vivo methods by in vitro methods; the reduction in the number of animals used where deletion of the animal test is not possible; and the refinement of tests to cause minimal suffering to the animals. In Indian Pharmacopoeia 2014, pyrogen testing using rabbits has been replaced by the bacterial endotoxin test in the majority of biological monographs-keeping in view international trends and, especially for vaccine monographs, validated in vitro tests such as the bacterial endotoxin test as an alternative to the pyrogen test where justified and authorized. Steps are taken for introducing a single-dilution assay for the potency testing of diphtheria and tetanus vaccine (adsorbed) with the aim of minimizing number of animals used. The justified and authorized use of animals in drug manufacturing, analytic laboratories, and research will not only help in the expedited development/production of drugs but also be useful in protecting and promoting animal health.
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http://dx.doi.org/10.1177/2168479015572371DOI Listing
September 2015

Biotechnology in the realm of history.

J Pharm Bioallied Sci 2011 Jul;3(3):321-3

Amity Institute of Biotechnology, Amity University, Uttar Pradesh, Sector-125, NOIDA- 201303, (UP), India E-mail:

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http://dx.doi.org/10.4103/0975-7406.84430DOI Listing
July 2011

LocDB: experimental annotations of localization for Homo sapiens and Arabidopsis thaliana.

Nucleic Acids Res 2011 Jan 11;39(Database issue):D230-4. Epub 2010 Nov 11.

Department of Biochemistry and Molecular Biophysics, Columbia University, 701 West, 168th Street, New York, NY 10032, USA.

LocDB is a manually curated database with experimental annotations for the subcellular localizations of proteins in Homo sapiens (HS, human) and Arabidopsis thaliana (AT, thale cress). Currently, it contains entries for 19,604 UniProt proteins (HS: 13,342; AT: 6262). Each database entry contains the experimentally derived localization in Gene Ontology (GO) terminology, the experimental annotation of localization, localization predictions by state-of-the-art methods and, where available, the type of experimental information. LocDB is searchable by keyword, protein name and subcellular compartment, as well as by identifiers from UniProt, Ensembl and TAIR resources. In comparison to other public databases, LocDB as a resource adds about 10,000 experimental localization annotations for HS proteins and ∼900 for AS proteins. Over 40% of the proteins in LocDB have multiple localization annotations providing a better platform for development of new multiple localization prediction methods with higher coverage and accuracy. Links to all referenced databases are provided. LocDB will be updated regularly by our group (available at: http://www.rostlab.org/services/locDB).
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http://dx.doi.org/10.1093/nar/gkq927DOI Listing
January 2011

Bioinformatics predictions of localization and targeting.

Methods Mol Biol 2010 ;619:285-305

Department of Biochemistry and Molecular Biophysics, Columbia University and Columbia University Center for Computational Biology and Bioinformatics (C2B2), New York, NY, USA.

One of the major challenges in the post-genomic era with hundreds of genomes sequenced is the annotation of protein structure and function. Computational predictions of subcellular localization are an important step toward this end. The development of computational tools that predict targeting and localization has, therefore, been a very active area of research, in particular since the first release of the groundbreaking program PSORT in 1991. The most reliable means of annotating protein structure and function remains homology-based inference, i.e. the transfer of experimental annotations from one protein to its homologs. However, annotations about localization demonstrate how much can be gained from advanced machine learning: more proteins can be annotated more reliably. Contemporary computational tools for the annotation of protein targeting include automatic methods that mine the textual information from the biological literature and molecular biology databases. Some machine learning-based methods that accurately predict features of sorting signals and that use sequence-derived features to predict localization have reached remarkable levels of performance. Sustained prediction accuracy has increased by more than 30 percentage points over the last decade. Here, we review some of the most recent methods for the prediction of subcellular localization and protein targeting that contributed toward this breakthrough.
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http://dx.doi.org/10.1007/978-1-60327-412-8_17DOI Listing
July 2010

Characterizing positive and negative selection and their phylogenetic effects.

Gene 2008 Jul 8;418(1-2):22-6. Epub 2008 Apr 8.

Department of Molecular Biology, University of Wyoming, Laramie, WY 82071, USA.

Total evidence and the use of large datasets to overcome uncertainty are the state of the art in systematic analysis. This assumes that the only true phylogenetic signal is ancestry and that functional, structural, and other factors will not add an alternative signal. Using gene families, where individual codon positions were sorted into bins based upon average-pairwise dN/dS ratio, we show that standard, common phylogenetic methods that were designed for stochastic, neutral, site-independent processes, generate less robust phylogenetic signal for bins with strong negative or positive selection. This was true for phylogenetic reconstruction with parsimony, distance, and likelihood methods. Further, we present a case for the potential existence of systematic functional or structural signal that competes with ancestral signal. For the example of positive selection, we simulate the evolution of sequences through three dimensional lattice constructs with folding constraint and changing binding functionality and show that total evidence for these lattice genes presents trees with functional signal, but that the neutral synonymous sites in these genes show the true ancestral signal. In this case, sequence convergence is promoted by functional convergence.
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http://dx.doi.org/10.1016/j.gene.2008.03.017DOI Listing
July 2008

Evolution after gene duplication: models, mechanisms, sequences, systems, and organisms.

J Exp Zool B Mol Dev Evol 2007 Jan;308(1):58-73

Department of Molecular Biology, University of Wyoming, Laramie, Wyoming 82071, USA.

Gene duplication is postulated to have played a major role in the evolution of biological novelty. Here, gene duplication is examined across levels of biological organization in an attempt to create a unified picture of the mechanistic process by which gene duplication can have played a role in generating biodiversity. Neofunctionalization and subfunctionalization have been proposed as important processes driving the retention of duplicate genes. These models have foundations in population genetic theory, which is now being refined by explicit consideration of the structural constraints placed upon genes encoding proteins through physical chemistry. Further, such models can be examined in the context of comparative genomics, where an integration of gene-level evolution and species-level evolution allows an assessment of the frequency of duplication and the fate of duplicate genes. This process, of course, is dependent upon the biochemical role that duplicated genes play in biological systems, which is in turn dependent upon the mechanism of duplication: whole genome duplication involving a co-duplication of interacting partners vs. single gene duplication. Lastly, the role that these processes may have played in driving speciation is examined.
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http://dx.doi.org/10.1002/jez.b.21124DOI Listing
January 2007

Evaluation of models for the evolution of protein sequences and functions under structural constraint.

Biophys Chem 2006 Nov 22;124(2):134-44. Epub 2006 Jun 22.

Department of Molecular Biology, University of Wyoming, Laramie, WY 82071, USA.

In the field of evolutionary structural genomics, methods are needed to evaluate why genomes evolved to contain the fold distributions that are observed. In order to study the effects of population dynamics in the evolved genomes we need fast and accurate evolutionary models which can analyze the effects of selection, drift and fixation of a protein sequence in a population that are grounded by physical parameters governing the folding and binding properties of the sequence. In this study, various knowledge-based, force field, and statistical methods for protein folding have been evaluated with four different folds: SH2 domains, SH3 domains, Globin-like, and Flavodoxin-like, to evaluate the speed and accuracy of the energy functions. Similarly, knowledge-based and force field methods have been used to predict ligand binding specificity in SH2 domain. To demonstrate the applicability of these methods, the dynamics of evolution of new binding capabilities by an SH2 domain is demonstrated.
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http://dx.doi.org/10.1016/j.bpc.2006.06.008DOI Listing
November 2006

Subfunctionalization of duplicated genes as a transition state to neofunctionalization.

BMC Evol Biol 2005 Apr 14;5:28. Epub 2005 Apr 14.

Computational Biology Unit, BCCS, University of Bergen, 5020 Bergen, Norway.

Background: Gene duplication has been suggested to be an important process in the generation of evolutionary novelty. Neofunctionalization, as an adaptive process where one copy mutates into a function that was not present in the pre-duplication gene, is one mechanism that can lead to the retention of both copies. More recently, subfunctionalization, as a neutral process where the two copies partition the ancestral function, has been proposed as an alternative mechanism driving duplicate gene retention in organisms with small effective population sizes. The relative importance of these two processes is unclear.

Results: A set of lattice model genes that fold and bind to two peptide ligands with overlapping binding pockets, but not a third ligand present in the cell was designed. Each gene was duplicated in a model haploid species with a small constant population size and no recombination. One set of models allowed subfunctionalization of binding events following duplication, while another set did not allow subfunctionalization. Modeling under such conditions suggests that subfunctionalization plays an important role, but as a transition state to neofunctionalization rather than as a terminal fate of duplicated genes. There is no apparent selective pressure to maintain redundancy.

Conclusion: Subfunctionalization results in an increase in the preservation of duplicated gene copies, including those that are neofunctionalized, but never represents a substantial fraction of duplicate gene copies at any evolutionary time point and ultimately leads to neofunctionalization of those preserved copies. This conclusion also may reflect changes in gene function after duplication with time in real genomes.
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http://dx.doi.org/10.1186/1471-2148-5-28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1112588PMC
April 2005
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