Addressing The Threat Of Multidrug Resistant Infectious Diseases By Synthesis Of Novel Aminoglycoside Antibiotics

The ever-growing increase in multidrug resistant infectious diseases is one of the major cause of human mortality, and there is an inherent need for the development of new antibiotics. Since the discovery of streptomycin, AGAs have been playing a very important role in human therapy as highly potent broad-spectrum antibiotics and are listed as one of the critically important antimicrobials by WHO. AGAs act by inhibiting the bacterial protein synthesis and by targeting the A-site present in the small subunit of bacterial ribosome. The clinical use of AGAs is somewhat restricted due to their toxic effects (ototoxicity and nephrotoxicity) and emergence of resistant bacterial strains. However, with the increase in resistance to current antibiotics and significant hurdles in discovering a new class of antibiotics, researchers started to revisit the AGAs, leading to much interest in development of novel AGAs. The goal of this thesis is to utilize the well understood mechanism of action and mechanisms of resistance for the development of novel AGAs. This research work is mainly focused on the modification of neomycin B and paromomycin. Chapter one introduces the problem of infectious diseases caused by bacteria, history of antibiotics and need for the development of new antibiotics. Then it discusses history of AGAs, their classification, mechanism of action, and toxic effects. It also discusses the common mechanisms of resistance adopted by bacteria and the recent strategies used to evade those resistance mechanisms. Chapter two discusses a series of modifications made to neomycin B and the influence of each modification on antibacterial activity and ribosomal selectivity. Fourteen different neomycin B derivatives were synthesized and their antiribosomal and antibacterial activities were determined. These derivatives include modifications at 2’-, 4’-, 6’-, and 6’’’ positions. Newly synthesized compounds were also screened against ESKAPE pathogens and engineered strains of E. Coli carrying specific resistance determinants in order to determine their susceptibility to modifications by common AMEs. Chapter three describes the modifications at 2’- and 5’’- positions in paromomycin and their influence on antiribosomal activity and selectivity. The 2’-position is susceptible to modification by AAC-(2’) and was mainly modified by alkylating the 2’-amino substituent. APH-(3’, 5’’) is one of the most important AME and has been known to modify most of the AGAs. There has been a lot of effort in the past to circumvent the action of this AME and it still remains a great challenge. This chapter also discusses the successful 5’’-formamido and 5’’-ureido modifications to paromomycin. These 5’’-modifications provide an effective alternative for 5’’-hydroxy substituent and are not susceptible to modification at this position by APH-(3’, 5’’). In Chapter four, an efficient and facile method for the synthesis of highly substituted pyrimidine-2,4-dione derivatives was described. Pyrimidine-2,4-diones are important nitrogen-based heterocycles and present in biologically active natural products and pharmaceuticals. This chapter discuss their synthesis form easily accessible and inexpensive maleic anhydrides and primary amines

Nutritional Status and its Determinants in Toddlers: A case study of Hilly region of Uttarakhand

Background: Nutrition in early childhood is of utmost importance specifically for first 1000 days. (1) If in this phase nutrition is neglected, it drags the child into the trap of malnutrition. Aims & Objectives: The objectives were:  assess the nutritional status of children and identify the risk factors related to malnutrition in children (1-3) years. Methods & Material: Descriptive exploratory design- conducted in rural villages of Haldwani block, Uttarakhand. Multi stage random sampling technique was used to select 703 children of (1-3) years and their mothers. The children were screened for malnutrition and mothers were interviewed via semi – structured interview schedule. Results: It was found that, 74(11%) children were undernourished, 28 (3.9%) were wasted in mild category and 11 (1.5%) in moderate category. About 87 (12%) were found to be stunted in mild to moderate category. Children below 2.5kg at birth [(1.106, 3.817), p= 0.023], non-initiation of breast feed in one hour [(0.979, 3.344), p=0.055], delayed initiation of weaning [(1.162,4.026), p=0.013] and recurrent illness [(1.187,3.447), p=0.009] were factors associated with malnutrition in children at 95% CI. Conclusion: It is very important to follow up the identified malnourished children so that in the preschool age the nutritional status can be improved

Stress Indices for Non-Radial Branch Connections for Piping

AbstractProcedure for determining the stress indices for non radial branch connections is discussed. A typical non radial branch connection, commonly used in the piping system of FRFCF is modeled and analyzed using CAST-3M for calculation various stress indices for the connection. B2 Stress indices for the branch connection for in plane bending and out of plane bending is arrived at based on nonlinear finite element analysis and limit load approach. K2 factor is determined using Peterson's curve, based on the curvature at the junction of run pipe and branch connection. Stress index C2 and the stress intensification factor i are determined by employing the relations of these factors with other stress indices

Phytochemical and Pharmacological Potential of Aristolochia indica: A review

ABSTRACT Aristilochia indica is credited with innumerable medicinal activities. The therapeutic value of A. indica has been recognized in different system of traditional medicine for the treatment of different ailments of human beings. Several phytoconstituents like aristolochic acid, ceryl alcohol, β-sitosterol, stigmast-4-en-3-one, friedelin, cycloeucalenol and rutin have been isolated from different parts of the plant. It has been r ecommended for the treatment of dry cough, joints pain, inflammation, biliousness, dysphoea of children, snake bite and also used as abortifacient. Most importantly, the studies have shown that the plant exhibited significant antimicrobial activity. This probably explains the use of this plant by the indigenous people against a number of infections. It has significantly decreased the fertilizing capacity in experimental animals

An invasive plant Sonchus asper (L.) Hill: A review of its ethnopharmacology, phytochemistry, and pharmacological properties

India is well known for medicinal plants because of rich plant biodiversity. Kumaun Himalayan region of Uttarakhand state occupies a great place in having good number of medicinal plants. The uses of plants in the indigenous cultures of developing countries are numerous and diverse. In a developing country, 65% population is dependent upon traditional medicinal system. The plant based traditional medicinal system play an important role in curing the health from various diseases all over the world. The present review reveals the updated information regarding the ethnopharmacology, phytochemistry, and pharmacological properties of an invasive plant Sonchus asper (L.) Hill. For this study, an extensive and intensive field survey by visiting the nearby villages of Nainital district was carried out along with detailed literature survey. Multitudinous ethnic properties and pharmacological study may help in development of new drug for the treatment of cancer and infectious diseases from this plant. The documentation of isolated compounds may afford new drug entity for pharmacy sector with lesser cost and more efficacy

Comparative evaluation of polyphenol contents and antioxidant activities between ethanol extracts of Vitex negundo and Vitex trifolia L. leaves by different methods

The in vitro antioxidant potential assay between ethanolic extracts of two species from the genus Vitex (Vitex negundo L. and Vitex trifolia L.) belonging to the Lamiaceae family were evaluated. The antioxidant properties of different extracts prepared from both plant species were evaluated by different methods. DPPH scavenging, nitric oxide scavenging, and β-carotene-linoleic acid and ferrous ion chelation methods were applied. The antioxidant activities of these two species were compared to standard antioxidants such as butylated hydroxytoluene (BHT), ascorbic acid, and Ethylene diamine tetra acetic acid (EDTA). Both species of Vitex showed significant antioxidant activity in all of the tested methods. As compared to V. trifolia L. (60.87–89.99%; 40.0–226.7 μg/mL), V. negundo has been found to hold higher antioxidant activity (62.6–94.22%; IC50 = 23.5–208.3 μg/mL) in all assays. In accordance with antioxidant activity, total polyphenol contents in V. negundo possessed greater phenolic (89.71 mg GAE/g dry weight of extract) and flavonoid content (63.11 mg QE/g dry weight of extract) as compared to that of V. trifolia (77.20 mg GAE/g and 57.41 mg QE/g dry weight of extract respectively). Our study revealed the significant correlation between the antioxidant activity and total phenolic and flavonoid contents of both plant species

Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations

Purpose To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. Patients and Methods One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). Results There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Conclusion Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit