Drug Challenge Research Articles

Prenatal exposure to morphine impairs attention and impulsivity in adult rats.

An alarming number of neonates born with prenatal exposure to morphine has resulted from the opioid epidemic; however, the long-term effects of prenatal opioid exposure on offspring behavior remain relatively unknown. In this study, we evaluated whether prenatal exposure to the mu opioid receptor agonist, morphine, has enduring effects on cognitive functions in adult life. On embryonic days 11-18 (E11-E18), female pregnant rats were injected subcutaneously with either morphine or saline twice daily. Adult male offspring that was prenatally exposed to saline or morphine was trained in the 5-choice serial reaction time test (5-CSRTT) to test their cognitive abilities under baseline conditions. Next, these rats were treated with saline (1ml/kg), naloxone (1mg/kg), and acute morphine (1, 3, 5mg/kg), subcutaneously, once daily and following drug challenges rats were tested in the 5-CSRTT. Meanwhile, behavioral performance on training days between opioid drug challenges were analyzed to monitor possible drug-induced shifts in baseline performance. As a final experiment in order to investigate subchronic exposure to morphine, rats were injected with 5mg/kg morphine for 5days and then naloxone in the last day of the experiment (day 6). Firstly, during acquisition of a stable baseline in the training phase, rats prenatally exposed to morphine showed delayed learning of the task demands. Furthermore, under baseline responding the rats prenatally exposed to morphine showed declined inhibitory control demonstrated by increased impulsive and compulsive-like responding compared to rats prenatally exposed to saline. Moreover, acute and subchronic morphine challenges in the rats prenatally exposed to morphine caused a deficit in visuospatial attention in comparison with saline treatment as well as the rats prenatally exposed to saline. These effects were abolished by naloxone. The current findings indicate a direct causal effect of prenatal morphine exposure on inhibitory control and task learning later in life, as well as deficits in attention following morphine exposure in adulthood.

Patterns of response and drugs involved in hypersensitivity reactions to beta-lactams in children.

Beta-lactams generate different allergenic determinants that induce selective or cross-reactive drug hypersensitivity reactions (DHRs). We aimed to identify the drugs involved, the selectivity of the response, the mechanism, and the value of the different diagnostic tests for establishing a diagnosis in children evaluated for DHRs to beta-lactams. Prospective study evaluating children aged under 16years reporting DHRs to beta-lactams. Reactions were classified as immediate and non-immediate reactions. The workup included sIgE, skin testing, and drug provocation tests (DPTs) for immediate reactions and patch testing and DPTs for non-immediate ones. Of the 510 children included, 133 were evaluated for immediate reactions and confirmed in 8.3%. Skin test/in vitro IgE contributed to diagnosing half of the cases. Selective reactions occurred with amoxicillin (63%), followed by common penicillin determinants (27%) and cephalosporins (0.9%). Among non-immediate reactions (11.4% of the 377 children evaluated), most required DPTs, 52.7% of which were positive at 6-7days of drug challenge. Selective reactions were identified with amoxicillin (80%), penicillin G (7.5%), cephalosporins (7.5%), and clavulanic acid (5%). Urticaria and maculopapular exanthema were the most frequent entities. There were few confirmed cases of either type of reaction. Skin testing proved less valuable in non-immediate reactions, over half of which would also have been lost in a short DPT protocol. Selective responders to amoxicillin were more likely to have non-immediate reactions, while clavulanic acid selectivity was exclusive to the non-immediate typology. Over half the cases with DPTs required 6-7days of treatment for DHR confirmation.

Drug sensitivity prediction from cell line-based pharmacogenomics data: guidelines for developing machine learning models.

The goal of precision oncology is to tailor treatment for patients individually using the genomic profile of their tumors. Pharmacogenomics datasets such as cancer cell lines are among the most valuable resources for drug sensitivity prediction, a crucial task of precision oncology. Machine learning methods have been employed to predict drug sensitivity based on the multiple omics data available for large panels of cancer cell lines. However, there are no comprehensive guidelines on how to properly train and validate such machine learning models for drug sensitivity prediction. In this paper, we introduce a set of guidelines for different aspects of training gene expression-based predictors using cell line datasets. These guidelines provide extensive analysis of the generalization of drug sensitivity predictors and challenge many current practices in the community including the choice of training dataset and measure of drug sensitivity. The application of these guidelines in future studies will enable the development of more robust preclinical biomarkers.

Chemical peritonitis associated with intraperitoneal vancomycin: A case series

Peritonitis is a serious complication in peritoneal dialysis, usually secondary to an infectious cause. Chemical peritonitis is rarer. No case exclusively attributed to vancomycin has been reported in the last 20 years. Data from 4 consecutive patients diagnosed with culture -negative peritonitis following administration of intraperitoneal vancomycin between May and June 2019 were retrospectively recorded. All patients were treated with 2 grams of intraperitoneal vancomycin after a break in aseptic technique and developed a cloudy effluent. No patient was previously known to be allergic to vancomycin. All had a clear dialysate before vancomycin. All developed an elevated leukocyte count in the dialysate. All had sterile cultures. All resumed a clear effluent with less <100 cells/μL after vancomycin cessation, and in two there were no further administrations. In one, a new drug challenge led to recrudescence of abdominal pain and reappearance of a cloudy sterile effluent. In another, vancomycin from a different lot was administrated 3 days after, no symptoms developed and dialysate cell count remained normal. The pathogenic mechanisms underlying chemical peritonitis are not fully known. The clinical course is typically benign. Management seems to be limited to drug withdrawal. If unrecognized, chemical peritonitis may ultimately lead to unnecessary catheter removal.

Abstract 310: Gut microflora mediated novel oral drug delivery system

Abstract The oral route is the most convenient route of drug administration and almost 80 % of the drugs are administered through this route. Despite many advantages like self-administrable, convenient, economic, pain-free, non-invasive, etc, the oral route is a major challenge for drugs which has low permeability through the GI tract leading to absorption of only 3-10% of the administered dose and reduced bioavailability. Therefore, due to limited half-life (~30 mins) in the stomach and small intestine, to achieve effective response excess of drugs need to be administrated through an oral route which causes many side effects including irritable bowel syndrome, hemorrhoids, gastrointestinal ulcers, and cancer, Cohn's disease, ulcerative colitis, etc. Besides mixing of the un-metabolized drug to the environment like soil and drinking water causes bio-magnifications and infer the development of antibiotic resistance in microorganisms. Therefore, an increase of half-life in the GI tract would be a great solution to solve this problem. Here in this work, we show the use of surface encapsulated mesoporous (2-3 nm) carbohydrate nanoparticles of (15-25 nm in size) on metabolically active Lactobacillus reuteri, a GRAS bacterium, as a drug carrier vehicle suitable for oral administration. We have further demonstrated the use of bacteria mediated drug delivery system for enhancing the potency of 5-fluorouracil against Sarcoma-180 cancer. The bacterial surface encapsulated nanoparticles particles showed 12-15% drug loading capacity of its dry weight. The particles also showed excellent stability up to 48 h in simulated gastric and intestinal fluid. Further, the particles showed sustained release of the drug for up to 16 h, where after an initial blast (release up to 30 %) between 30 min-1 h a steady release of drug was obtained for up to 6.5 to 7 h, where 95% of the drug got released within that window. The pre-clinical study showed anchorage of drug-loaded surface encapsulated microbes to the mice intestinal alveolar regions after feeding through the oral route. Further, a study using murine Sarcoma-180 tumor model showed enhancement of life span and enhanced shrinkage of the Sarcoma-180 solid tumor volume (up to -95%) at optimal dose 50 mg/Kg dose, in comparison with control only ~75% throughout 10 days' treatment. Up to 75 % reduction of tumor volume was also observed in suboptimal dose (25 mg/kg) using the microbial vehicle. Reduction of hepatic and nephrotic toxicity was also evident from the blood parameters analysis and histological analysis was also prominent using this delivery tool. This novel design and development make this system ideal for use in orally administrable drug shaving low solubility or permeability or both. Citation Format: Parmandeep Kaur, Diptiman Choudhury. Gut microflora mediated novel oral drug delivery system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 310.

Sulfonamide Hypersensitivity.

Sulfonamides, particularly antimicrobial sulfonamides, have been implicated as a common cause of a spectrum of hypersensitivity reactions. Immediate IgE-mediated reactions have been reported but are much less common than delayed cutaneous reactions. Delayed cutaneous reactions range from benign exanthems to severe cutaneous reactions such as Stevens Johnson syndrome, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms. Sulfonamides can be subclassified as antimicrobial sulfonamides and non-antimicrobial sulfonamides, which are also distinguished by key structural differences, resulting in very low risk of cross-reactivity between these two subclasses. Immediate and delayed skin testing and in vitro testing remain limited as options in evaluating antimicrobial sulfonamide hypersensitivity. Drug challenges continue to play an important role in the evaluation of both immediate and delayed reactions, with a growing body of evidence for the safety of direct challenges regardless of human immunodeficiency virus infection status. While numerous "desensitization" protocols have been described for the management of antimicrobial sulfonamide hypersensitivity, there is limited evidence that such procedures are successful because of an induction of tolerance.

Allergic Reaction due to Anti-Tuberculosis Drugs, How to Manage?

Tuberculosis (TB) still becomes a significant health problem in Indonesia. The first-line anti-tuberculosis drug (ATD) is still the most effective TB drug, but it can have some side effects. One of them is allergic skin reactions that can affect a patient's compliance. Allergic reactions due to ATD are found in 4-6% of TB cases and are the third most frequent side effect after gastrointestinal and liver function disorder. All first-line ATD can cause allergic reactions. Allergic reactions due to ATD can be mild, such as itching and reddish rashes, to severe and life-threatening rashes, such as anaphylactic shock, Steven Johnson Syndrome (SJS), and Toxic Epidermal Necrotic (TEN). The most important things in the management are identifying and stopping drugs. It includes drug challenge and desensitization of causing drug. Desensitization must be distinguished from drug challenge or provocation tests, which are diagnostic tools. The proper management of ATD allergic reactions can improve compliance and patient's outcomes.

Algorithm to guide re-exposure to penicillin in allergic pregnant women with syphilis: Efficacy and safety

BackgroundGestational syphilis is underdiagnosed and undertreated, leading to stillbirth, prematurity, low birthweight, neonatal death, and congenital syphilis. Most patients who label as allergic to penicillin are misdiagnosed. ObjectiveTo assess the efficacy and safety of an algorithm to guide re-exposure to penicillin in pregnant women with syphilis and reporting allergy to the antibiotic. MethodsWe performed a prospective study assessing pregnant women with syphilis and labeled as allergic to penicillin. Based on clinical history, patients were divided in two groups: high-risk and low-risk to penicillin allergy. Low-risk patients with negative skin testing and negative serum specific IgE to penicillin underwent drug provocation test. The remaining patients underwent desensitization. ResultsNinety-one patients were enrolled. Allergy to penicillin was confirmed in 7.69% of pregnant women with syphilis and clinical history of allergy to penicillin; in all cases the diagnosis was made through intradermal testing, which predicted 100% of the breakthrough reactions observed during rapid drug desensitization (p < 0.001). Risk stratification based on the initial clinical reaction and skin testing to guide penicillin re-introduction through drug challenge or desensitization was safe (97.8%) and effective (97.8%). ConclusionWe developed and showed the efficacy and safety of an algorithm to guide re-exposure to penicillin in pregnant women with syphilis and labeled as allergic to this drug. Intradermal test is an excellent biomarker in the diagnosis of immediate hypersensitivity reaction to penicillin and to predict breakthrough reaction during rapid drug desensitization. Further studies may confirm the greater safety of the intravenous protocol compared to the oral protocol.

Can the COVID-19 Pandemic Disrupt the Current Drug Development Practices?

Therapeutics and vaccines against the COVID-19 pandemic need to be developed rapidly and efficiently, given its severity. To maximize the efficiency and productivity of drug development, the world has adopted disruptive technologies and approaches in various drug development areas. Telehealth, characterized by the heavy use of digital technologies; drug repositioning strategies, aided by computational breakthroughs; and data tracking tool hubs, enabling real-time information sharing, have received much attention. Moreover, drug developers have engaged in open innovation by establishing various types of collaborations, many of which have been carried out across nations and enterprises. Finally, regulatory agencies have attempted to operate on a more flexible review basis than before. Although such disruptive approaches have partly reshaped drug development practices, issues and challenges remain before the completion of this paradigm shift in conventional drug development practices for the post-pandemic era. In this review, we have highlighted the role of a collaborative community of experts in order to figure out how disruptive technologies can be fully integrated into the current drug development practices and improve drug development efficiency for the post-pandemic era.

PET-ABC: fully Bayesian likelihood-free inference for kinetic models

Aims. We describe an intuitive, easy to use method called PET-ABC that enables full Bayesian statistical inference from single subject dynamic PET data. The performance of PET-ABC was compared with weighted non-linear least squares (WNLS) in terms of reliability of kinetic parameter estimation and statistical power for model selection. Methods. Dynamic PET data based on 1-tissue and 2-tissue compartmental models were simulated with 2 noise models and 3 noise levels. PET-ABC was used to evaluate the reliability of parameter estimates under each condition. It was also used to perform model selection for a simulated noisy dataset composed of a mixture of 1- and 2-tissue compartment kinetics. Finally, PET-ABC was used to analyze a non-steady state dynamic [11C] raclopride study performed on a fully conscious rat administered either 2 mg.kg−1 amphetamine or saline 20 min after tracer injection. Results. PET-ABC yielded posterior point estimates for model parameters with smaller variance than WNLS, as well as probability density functions indicating confidence intervals for those estimates. It successfully identified the superiority of a 2-tissue compartment model to fit the simulated mixed model data. For the drug challenge study, the post observation probability of striatal displacement of the PET signal was 0.9 for amphetamine and approximately 0 for saline, indicating a high probability of amphetamine-induced endogenous dopamine release in the striatum. PET-ABC also demonstrated superior statistical power to WNLS (0.87 versus 0.09) for selecting the correct model in a simulated ligand displacement study. Conclusions. PET-ABC is a simple and intuitive method that provides complete Bayesian statistical analysis of single subject dynamic PET data, including the extent to which model parameter estimates and model choice are supported by the data. Software for PET-ABC is freely available as part of the PETabc package https://github.com/cgrazian/PETabc.

Fentanyl conjugate vaccine by injected or mucosal delivery with dmLT or LTA1 adjuvants implicates IgA in protection from drug challenge

Fentanyl is a major contributor to the devastating increase in overdose deaths from substance use disorders (SUD). A vaccine targeting fentanyl could be a powerful immunotherapeutic. Here, we evaluated adjuvant and delivery strategies for conjugate antigen vaccination with fentanyl-based haptens. We tested adjuvants derived from the heat-labile toxin of E. coli including dmLT and LTA1 by intramuscular, sublingual or intranasal delivery. Our results show anti-fentanyl serum antibodies and antibody secreting cells in the bone-marrow after vaccination with highest levels observed with an adjuvant (alum, dmLT, or LTA1). Vaccine adjuvanted with LTA1 or dmLT elicited the highest levels of anti-fentanyl antibodies, whereas alum achieved highest levels against the carrier protein. Vaccination with sublingual dmLT or intranasal LTA1 provided the most robust blockade of fentanyl-induced analgesia and CNS penetration correlating strongly to anti-FEN IgA. In conclusion, this study demonstrates dmLT or LTA1 adjuvant as well as mucosal delivery may be attractive strategies for improving the efficacy of vaccines against SUD.

The cognitive and behavioral effects of D-amphetamine and nicotine sensitization in adult zebrafish

BackgroundZebrafish are growing in use as a model for understanding drug dependence and addiction. Sensitization paradigms have been a useful tool in identifying mechanisms involved in drug-induced behavioral and neurological changes, but in zebrafish have tended to focus on locomotor, rather than cognitive, endpoints.MethodsHere, we used a novel method, the FMP Y-maze, which measures continuous performance through a series of repeated binary choices (L vs R), to establish a model for assessing parameters associated with psychostimulant-induced behavioral and cognitive sensitization in adult zebrafish.ResultsRepeat, intermittent exposure to d-amphetamine (AMPH) for 14 days increased alternations (LRLR) in the maze, suggesting improved working memory, which was enhanced further following drug challenge after a short withdrawal period, suggesting behavioral sensitization. However, this cognitive enhancement coincided with a reduction in the use of other exploration strategies, hypolocomotion, and inhibition of cognitive flexibility. Like AMPH, exposure to nicotine (NIC) increased alternations following drug challenge after chronic treatment. Repeat NIC exposure appeared to induce both cognitive and psychomotor sensitization, as evidenced by increased working memory performance (alternations) and locomotor activity, without negatively impacting other search strategies or cognitive flexibility.ConclusionChronic treatment with AMPH or NIC boosts cognitive performance in adult zebrafish. Cognitive sensitization occurred with both drugs, resulting in enhanced working memory; however, repeat AMPH exposure, following a withdrawal period, resulted in inhibited cognitive flexibility, an effect not evident with repeat NIC exposure. Cognitive and behavioral sensitization paradigms in zebrafish could serve as a useful tool for assessing cognitive states which result in cognitive enhancing or impairing effects of drugs.

The role and histopathology of oral drug challenge in the evaluation of fixed drug eruptions

AbstractThis case series describes the role of oral drug challenge in the diagnosis of fixed drug eruption in the setting of polypharmacy. Practical testing guidelines are provided. The literature describing the histopathology of acute fixed drug reaction is also reviewed and compared with the findings in this series.

P30 Can non-allergy health workers safely delabel reported penicillin allergies using an antibiotic allergy assessment tool? - A multicentre study

BackgroundFalse penicillin allergy labels can be potentially hazardous to patients. Most penicillin allergy labels can be safely removed following risk stratification and formal drug challenge. These de-labelling strategies have been limited to specialist allergy and infectious disease services.AimsTo determine whether non-allergy specialist health-care workers can use an antibiotic allergy assessment tool (AAAT) to correctly phenotype and manage reported penicillin allergy.MethodNon-allergy health-care workers in three UK hospital were emailed online questionnaires and asked to assign the allergy phenotype and management recommendation for eight vignettes of real cases reporting a penicillin allergy using the AAAT. In one hospital participants were randomised into two groups: one group was directed to use the AAAT whilst the second group had no decision tool. Participants were assigned an average score for correct allergy phenotype, management and a major error rate.ResultsUse of the AAAT across the eight vignettes significantly improved the average score for assigning correct phenotype (6.7 vs 5.2 p < 0.001), management choice (7.1 vs 5.7 p < 0.001), and major error rate (0.6 vs 1.6 p < 0.001). Participant performance with the AAAT was generalizable across all three hospitals. Despite use of the AAAT 35-40% of participants made at least one major error.ConclusionThe AAAT significantly improved health worker performance in phenotyping and choosing correct management for reported penicillin. However, even with the AAAT, there remains a risk of potentially hazardous management choices highlighting the need for formal allergy training to expand penicillin allergy assessment services.

Deubiquitinating enzyme inhibitor alleviates cyclin A1-mediated proteasome inhibitor tolerance in mixed-lineage leukemia.

Drug resistance is a significant obstacle to effective cancer treatment. Drug resistance develops from initially reversible drug‐tolerant cancer cells, which offer therapeutic opportunities to impede cancer relapse. The mechanisms of resistance to proteasome inhibitor (PI) therapy have been investigated intensively, however the ways by which drug‐tolerant cancer cells orchestrate their adaptive responses to drug challenges remain largely unknown. Here, we demonstrated that cyclin A1 suppression elicited the development of transient PI tolerance in mixed‐lineage leukemia (MLL) cells. This adaptive process involved reversible downregulation of cyclin A1, which promoted PI resistance through cell‐cycle arrest. PI‐tolerant MLL cells acquired cyclin A1 dependency, regulated directly by MLL protein. Loss of cyclin A1 function resulted in the emergence of drug tolerance, which was associated with patient relapse and reduced survival. Combination treatment with PI and deubiquitinating enzyme (DUB) inhibitors overcame this drug resistance by restoring cyclin A1 expression through chromatin crosstalk between histone H2B monoubiquitination and MLL‐mediated histone H3 lysine 4 methylation. These results reveal the importance of cyclin A1‐engaged cell‐cycle regulation in PI resistance in MLL cells, and suggest that cell‐cycle re‐entry by DUB inhibitors may represent a promising epigenetic therapeutic strategy to prevent acquired drug resistance.

Natural Recovery and Supportive Community Networks

The natural recovery process of “maturing out” appears to be an active process of renewal and growth, leading to transformative growth that involves the individual’s body, mind, and spiritual dimensions. If spontaneous or “maturing out” recovery accounts for about 4 to18% of the alcohol and other drug (AOD) challenges to the field of behavioral health treatment, how does one effectively partner with the other 82% who have alcohol and other drug issues? To answer this concern, we must ask a few more questions. (1) What developmental factors influence growth? (2) What social determinants of health enhance recovery? (3) What is a supportive community network? and (4) What constitutes evidence-based practice? When one only looks at the biological reasons for behavioral health challenges, the assumption is that getting well and overcoming deficiencies is a function of the individual rather than the system of care. This kind of narrow perspective has contributed to a behavioral health delivery system that continually struggles to provide an integrated, comprehensive care model. This restrictive thought process undermines individuals’ confidence to change and is unduly dismissive of community leaders’ efforts.

Unusual case of colorectal carcinoma with sarcoid-like mediastinal adenopathy and near-fatal DPD deficiency

The liver is the commonest site for metastases in colorectal carcinoma; other isolated sites are considered extremely rare. 5-fluorouracil (5-FU) is the backbone of treatment for metastatic colorectal carcinoma (mCRC) and without it survival may be significantly reduced. It is primarily metabolised by dihydropyrimidine dehydrogenase (DPD). Testing for DPD deficiency is not a routine practice and toxicity will only manifest following drug challenge. There are limited standardised treatment guidelines in managing patients with severe drug reactions following 5-FU exposure. We describe a delayed presentation of life-threatening DPD deficiency in a patient with colorectal carcinoma and mediastinal lymphadenopathy. We describe our experience with chemotherapy in this difficult clinical scenario and highlight the importance of histological confirmation in unusual sites of metastatic disease.

Study on pathogenic genes of dwarfism disease by next-generation sequencing.

BACKGROUNDThere are many factors that lead to dwarfism, and the mechanism has not yet been elucidated. Next-generation sequencing may identify candidate-related gene mutations, which may clarify the molecular cause.AIMTo analyze genetic variation by using a constructed panel related to dwarfism by utilizing next-generation sequencing platform sequencing analysis to screen candidate-related gene mutations.METHODSPhysical and laboratory characteristics, including clinical examination, growth hormone drug challenge test, serum insulin-like growth factor-1 (IGF-1), IGF binding protein 3, other related tests, imaging examination, and chromosome karyotyping, were analyzed. Next-generation sequencing was performed to analyze pathogenicity variability.RESULTSIn the 39 dwarfism patients, 10 had pathogenicity variability. Gene variation was found in the OBSL1, SLC26A2, PTPN11, COL27AI, HDAC6, CUL7, FGFR3, DYNC2H1, GH1, and ATP7B genes. Of the 10 patients with pathogenicity variability, the related physical characteristics included double breast development and growth hormone deficiency, enuresis and indirect inguinal hernia on the left, two finger distance of 70.2 cm, head circumference of 49.2 cm, ischium/lower body length of 1.8 cm, weak limb muscles, and partial growth hormone deficiency. After 6 mo of growth hormone therapy, the concentrations of IGF-1 and IGF binding protein 3 increased from 215.2 ± 170.3 to 285.0 ± 166.0 and 3.9 ± 1.4 to 4.2 ± 1.1, respectively.CONCLUSIONOBSL1, SLC26A2, PTPN11, COL27AI, HDAC6, CUL7, FGFR3, DYNC2H1, GH1, and ATP7B genes may be related to the incidence of dwarfism, and more research needs to be performed to elucidate the mechanism.

Metabolic fitness landscapes predict the evolution of antibiotic resistance

Bacteria evolve resistance to antibiotics by a multitude of mechanisms. A central, yet unsolved question is how resistance evolution affects cell growth at different drug levels. Here, we develop a fitness model that predicts growth rates of common resistance mutants from their effects on cell metabolism. The model maps metabolic effects of resistance mutations in drug-free environments and under drug challenge; the resulting fitness trade-off defines a Pareto surface of resistance evolution. We predict evolutionary trajectories of growth rates and resistance levels, which characterize Pareto resistance mutations emerging at different drug dosages. We also predict the prevalent resistance mechanism depending on drug and nutrient levels: low-dosage drug defence is mounted by regulation, evolution of distinct metabolic sectors sets in at successive threshold dosages. Evolutionary resistance mechanisms include membrane permeability changes and drug target mutations. These predictions are confirmed by empirical growth inhibition curves and genomic data of Escherichia coli populations. Our results show that resistance evolution, by coupling major metabolic pathways, is strongly intertwined with systems biology and ecology of microbial populations.

Computationally approached inhibition potential of Tinospora cordifolia towards COVID-19 targets.

Graphic abstractThe recent emergence of novel coronavirus (SARS-CoV-2) has been a major threat to human society, as the challenge of finding suitable drug or vaccine is not met till date. With increasing morbidity and mortality, the need for novel drug candidates is under great demand. The investigations are progressing towards COVID-19 therapeutics. Among the various strategies employed, the use of repurposed drugs is competing along with novel drug inventions. Based on the therapeutic significance, the chemical constituents from the extract of Tinospora cordifolia belonging to various classes like alkaloids, lignans, steroids and terpenoids are investigated as potential drug candidates for COVID-19. The inhibition potential of the proposed compounds against viral spike protein and human receptor ACE2 were evaluated by computational molecular modeling (Auto dock), along with their ADME/T properties. Prior to docking, the initial geometry of the compounds were optimized by Density functional theory (DFT) method employing B3LYP hybrid functional and 6–311 + + G (d,p) basis set. The results of molecular docking and ADME/T studies have revealed 6 constituents as potential drug candidates that can inhibit the binding of SARS-CoV-2 spike protein with the human receptor ACE2 protein. The narrowed down list of constituents from Tinospora cordifolia paved way for further tuning their ability to inhibit COVID-19 by modifying the chemical structures and by employing computational geometry optimization and docking methods. Supplementary InformationThe online version contains supplementary material available at 10.1007/s13337-021-00666-7.