Fundamental considerations in drug design

The drug discovery paradigm has been very time-consuming, challenging, and expensive;however, the disease conditions originating from bacteria, virus, protozoa, fungus and other microorganisms are steadily shooting up. For instance, COVID-19 is the latest viral infection that affects millions of people and the world’s economy very severely. Therefore, the quest for discovery of novel and potent drug compounds against deadly pathogens is crucial at the moment. Despite a lot of drawbacks in drug discovery and development and its pertaining technology, the advancement must be taken into account so the time duration and cost would be minimized. In this chapter, basic principles in drug design and discovery have been discussed together with advances in drug development. © 2022 Elsevier Inc. All rights reserved.

Immune Thrombocytopenia Post Covishield Vaccination

Introduction: Immune thrombocytopenia (ITP) after COVID-19vaccination is being increasingly reported worldwide.Aims &Objectives: We present five cases of ITP following theAstraZeneca Covishield vaccination.Materials &Methods: We retrospectively collected data on patientspresenting with immune thrombocytopenia post-Covishield vaccination at the Department of Hematology, AIIMS, New Delhi.Result: 5 patients diagnosed with ITP followingAstraZeneca Covishieldvaccination were included. Themedian age at diagnosis in our cohortwas44 years (21-67 years). Of the 5 patients, 2 are female and 3 aremale. Allof them received the Astrazeneca Covishield vaccine. Most of thepatients presented with petechiae and wet purpura with the onset ofsymptoms between 7-20 days (median 15 days) post-vaccination. All ofthese patients had severe thrombocytopenia at presentationwith amedianplatelet count of 7 × 109/l (range 1-14 × 109/l). Anti PF4 antibodytesting was done in two patients which were negative.Therapy details include IVIG (3), steroids (4), eltrombopag (2),azathioprine (1), and platelet transfusions (2). Of these, two patientshad no response to first-line therapies. One patient did not respond toIVIG, steroids, azathioprine, and subsequently developed anintracranial bleed. He was managed with platelet transfusions, IVIG,steroids, and eltrombopag. His platelet counts have stabilized at50 × 109/l and he did not have further bleeding manifestations. Atthe last follow-up, 80% (n = 4) of our patients have achieved aresponse.Conclusions: Immune thrombocytopenia is being increasingly recognized post-COVID vaccination. All our patients had severethrombocytopenia requiring therapy. The question of whether thesecases are actually primary ITP coinciding with the administration ofthe vaccine or ITP secondary to vaccination remains unanswered.Additional surveillance is needed to determine the true incidence ofCOVID-19 vaccine-induced ITP.

Infant COVID-19 Infection: An Experience from Pediatric Intensive Care Unit of a Tertiary Care Dedicated Pediatric COVID Hospital

This study aimed to assess different clinical, disease severity, laboratory, treatment, and outcome-related factors of COVID-19 positive infants admitted to a pediatric intensive care unit (PICU) and to compare these parameters with COVID-19 positive noninfants (1-12 years of age) who also required intensive care admission. This retrospective observational study was conducted in a PICU of a tertiary care, dedicated pediatric COVID facility. The clinical, epidemiological, laboratory parameters, and treatment outcomes of COVID-19 infected infants admitted to the PICU were recorded and analyzed. During comparison with the noninfant group, malignancy and coinfection with dengue and scrub typhus were excluded from both groups. A total 313 COVID-19 positive children aged from 1 month to 12 years old were admitted, of which 115 (36.7%) children required PICU admission. Infants constituted 37.4% of total PICU admissions. Most common symptoms were respiratory (83.7%) followed by fever (60.5%). Fifteen (34.9%) infants presented with shock. Ten infants (23.3%) had myocardial dysfunction. C-reactive protein (CRP) and ferritin were high in 60.5 and 16.7% infants, respectively. Fourteen infants needed invasive mechanical ventilation. Nine patients had acute respiratory distress syndrome (ARDS) and five had MIS-C. However, 53.5% infants had different comorbidities. Four infants died and all of them had severe comorbidities. Respiratory distress (p = 0.009), pediatric sequential organ failure assessment score (p = 0.032) and number of ARDS cases (p = 0.044) were significantly higher in infants than noninfants. Infants are one of the most vulnerable groups of children suffering from serious illness from COVID-19 infection requiring PICU admission due to predominantly respiratory involvement. Overall outcome was good among infants without significant comorbidity.

Addition of eltrombopag to immunosuppressive therapy (ATG, cyclosporine) in acquired aplastic anemia: A tertiary care center experience

Aims & Objectives: To assess the responses of Acquired Aplastic Anaemia patients who have received Eltrombopag in addition to Immunosuppressive therapy (ATG → Cyclosporine A) at our tertiary care center. Patients/Materials & Methods: We retrospectively analysed the responses of Acquired Aplastic Anaemia patients who have received Eltrombopag, Antithymocyte globulin, and Cyclosporine A from Jan 2019 to March 2020. Results: Thirty-eight patients were included in our study. The median age is 27.6 years (7-68). Male to Female ratio 1.2:1. 6 patients were less than 13 years of age and, 31 patients were between>13 years to<60 years and 1 patient was>60 years. PNH clone was positive in 6 patients(15%). Majority of our patients were Severe Aplastic Anemia (76.3%), and Non Severe Aplastic Anemia (10.5%), Very Severe Aplastic Anaemia(13.1%).All of our patients received Cyclosporine and Danazol before ATG. The median duration from diagnosis to treatment is 12.2 months(1-60 months). Except for one who received Rabbit ATG, everyone received Equine ATG. Eltrombopag was given at a dose of 75 mg in 13.15% (5) and 150 mg in 86.85% (33). Complete Response, Partial Response, No response were seen in 15.8%,57.8%,26.5% respectively. 3 patients expired within three months of treatment, 3 more patients expired by 6 months(1, COVID-19). Discussion & Conclusion: Overall Response rates of 75% in an Indian cohort of acquired aplastic anemia patients treated with ATG and Cyclosporine plus Eltrombopag is comparable to that reported in studies from US and Europe. Median duration of disease prior to ATG based IST was 1 year in our cohort of AA patients.Addition of eltrombopag to ATG and Cyclosporine was able to overcome the delayed initiation of IST in AA patients.Treatment was well tolerated in our patients.