A journey of celecoxib from pain to cancer.

The most enthralling and versatile class of drugs called the Non-steroidal anti-inflammatory (NSAIDs) showed its therapeutic utility in inflammation, beginning from the era of classic drug 'Aspirin'. NSAIDs and their well-established action based on inhibiting the COX-1 and COX-2 enzyme leads to blockage of prostaglandin pathway. They further categorized into first generation (non-selective inhibitor) and second generation (selective COX-2 inhibitors). Selective COX-2 inhibitors has advantage over non-selective in terms of their improved safety profile of gastro-intestinal tract. Rejuvenating and recent avenues for COXIBS (selective COX-2 inhibitors) explains its integrated role in identification of biochemical pain signaling as well as its pivotal key role in cancer chemotherapy. A key role player in this class is the Celecoxib (only FDA approved COXIB) a member of Biopharmaceutical classification system (BCS) II. Low solubility and bioavailability issues related with celecoxib lead to the development and advancement in the discovery and research of some possible formulation administered either orally, topically or via transdermal route. This review article intent to draw the bead on Celecoxib and it clearly explain extensive knowledge of its disposition profile, its dynamic role in cancer at cellular level and cardiovascular risk assessment. Some of the possible formulations approaches with celecoxib and its improvement aspects are also briefly discussed.

Synthesis and anti-inflammatory activity evaluation of novel triazolyl-isatin hybrids.

New isatin-triazole based hybrids have been synthesized and evaluated for their inhibitory activity of TNF-α induced expression of Intercellular Adhesion Molecule-1 (ICAM-1) on the surface of human endothelial cells. Structure-activity relationship (SAR) studies revealed that the presence of the electron-attracting bromo substituent at position-5 of the isatin moiety played an important role in enhancing the anti-inflammatory potential of the synthesized compounds. Z-1-[3-(1H-1,2,4-Triazol-1-yl)propyl]-5-bromo-3-[2-(4-methoxyphenyl)hydrazono]indolin-2-one (19) with an IC50 = 20 µM and 89% ICAM-1 inhibition with MTD at 200 µM was found to be the most potent of all the synthesized derivatives. Introduction of 1,2,4-triazole ring and electron-donating methoxy group on the phenylhydrazone moiety resulted in four-fold increase of the anti-inflammatory activity.

Transrectal ultrasonography (TRUS)-guided pelvic plexus block to reduce pain during prostate biopsy: a randomised controlled trial.

OBJECTIVE: To assess the role of pelvic plexus block (PPB) in reducing pain during transrectal ultrasonography(TRUS)-guided prostate biopsy, compared with the conventional periprostatic nerve block (PNB). PATIENTS AND METHODS: A prospective, double-blind observational study was conducted with patients being randomised into three groups. Group-1 (47 patients) received intrarectal local anaesthesia (IRLA) with 10 mL 2% lignocaine jelly along with pelvic plexus block (PPB) with 2.5 mL 2% lignocaine injection bilaterally. Group-2 (46 patients) received IRLA with periprostatic nerve block (PNB). Group-3 (46 patients) received only IRLA without any type of nerve block. The patients were requested to rate the level of pain from 0 to 10 on a visual analogue scale (VAS) at two time points: VAS-1: during biopsy procedure and VAS-2: 30 min after the procedure. RESULTS: The mean age of the patients, mean volume of the prostates and mean serum PSA values were comparable among the three groups. The mean pain score during biopsy was significantly less in the PPB group [mean (range) sore of 2.91 (2-4)] compared with the PNB group [mean (range) score of 4 (3-5)], and both these groups were superior to the no nerve block group [mean score of 5.4 (3-7)]. There was no significant difference between the mean pain scores, 30 min after the procedure among the three groups with the mean (range) scores being 2.75 (2-4), 2.83 (2-4) and 2.85 (2-4), respectively. CONCLUSION: PPB is superior to conventional periprostatic nerve block (PNB) for pain control during TRUS-guided biopsy and both are in turn superior to no nerve block.

LONG-TERM EFFICACY OF SYSTEMIC INFLIXIMAB IN RECALCITRANT RETINAL VASCULITIS.

PURPOSE: To evaluate the efficacy of systemic infliximab for the induction of remission in patients with retinal vasculitis, inadequately responsive to other immunomodulatory therapy, based on fluorescein angiography grading for retinal vasculitis evaluation. METHODS: We analyzed 60 patients with retinal vasculitis, from the Massachusetts Eye Research and Surgery Institution in Cambridge, MA. Response to therapy was based on analysis of serial fluorescein angiography and fundus photography, including a baseline angiogram before initiation of infliximab. RESULTS: Sixty patients received infliximab therapy between July 2007 and July 2012 at Massachusetts Eye Research and Surgery Institution for a diagnosis of retinal vasculitis. All had previously showed a poor clinical response to other immunomodulatory regimens, or ceased therapy due to intolerable side effects. The initial dose of infliximab was 5 mg/kg in all patients and remained at this dose for the extent of treatment in 57 (95%) patients. At 6 months, 45 of 51 (88.23%) patients were maintaining remission with therapy, 5 (9.8%) were in partial remission, and 1 patient had failed. At 12 months, 39 of 39 (100%) patients were maintaining remission with therapy. CONCLUSION: Infliximab is effective for the treatment of recalcitrant noninfectious retinal vasculitis, refractory to conventional immunomodulatory therapy.

Extraction and characterization of Aegle marmelos derived polymer as a pharmaceutical excipient.

BACKGROUND: Natural polymers have been used as pharmaceutical excipients. They are easily available, cheap, less toxic andbiodegradable. Many of them have been identified and research is ongoing regarding their characterization. OBJECTIVE: The present study depicts the extraction and characterization of Aegle marmelos derived polymer which can be used as a pharmaceutical excipient. MATERIAL AND METHODS: A water based extraction method was used to extract Aegle marmelos derived polymer. Its yield was found to be 15.07%. Characterization was based on various parameters such as a test for carbohydrates, test for purity, organoleptic properties, ash value, solubility behavior, pH, swelling index, surface tension, viscosity, particle size, loss on drying, bulk density, bulkiness, powder flow behavior, etc. RESULT: The polymer was yellowish-brown and showed poor flow (angle of repose 19.28 degrees ± 0.883) with neutral pH, i.e. 7, and bulkiness depicting the heaviness of polymer. The extracted polymer showed solubility in warm water and insolubility in organic solvents. CONCLUSIONS: The results easily predict the fact that the yield of the polymer was quite good, so it can be used as a commercial source of mucilage. The isolated polymer can be used as a pharmaceutical excipient in different dosage forms. 2 /

Confidence Interval: Advantages, Disadvantages and the Dilemma of Interpretation.

Confidence interval (CI) is one of the important reporting tools for research data as it not only provides valuable information about the effect size along with its width but also possible clinical significance. Unfortunately, this approach is not being utilized to its fullest extent. Determining point estimate always includes an element of uncertainty due to associated sampling error. A confidence interval may be an appropriate tool to measure this uncertainty. Further, the P value does not convey information about the magnitude of an effect and the error associated with it. Thus, in an ideal situation effect size should preferably be associated with a confidence interval to assess precision. Not only does CI let us assess likely effects but also decides whether the intervention applied could have clinical utility. In contrast, the p-value limits our option to either reject any differences that are not significant or accept those that are. However, confidence intervals are commonly misinterpreted. It is imperative to understand that the CI is not the range of effects that 95% of patients in the population exhibit. Moreover, it would also be erroneous to say that there is a 95% probability that the CI includes the true population effect. Interpretation is usually based on the context in which the confidence interval is being looked at. From a utility point of view and like other statistical tools confidence interval approach does have several advantages as well as disadvantages and is far beyond being a perfect statistical tool.

The analgesic efficacy of ultrasound-guided erector spinae plane block versus ultrasound-guided caudal epidural block for abdominal surgery in pediatric patients - A patient and assessor-blind, randomized controlled study.

Background: Literature on the efficacy and safety of erector spinae plane block (ESPB) in pediatric patients is limited. Hence, we aimed to compare ESPB versus caudal epidural block (CEB) in children undergoing abdominal surgery. Methods: In this patient and assessor-blind study, fifty-two ASA I-II patients, between 1 to 9 years of age, were randomized into groups of 26 each. ESPB group received unilateral or bilateral ultrasound (USG)-guided ESPB with 0.5 ml/kg of 0.25% bupivacaine per side. CEB group received USG-guided CEB with 1 ml/kg of 0.25% bupivacaine. The primary objective was to estimate the proportion of patients requiring postoperative rescue analgesia. The secondary objectives were to assess postoperative Face, Legs, Activity, Cry and Consolability (FLACC) scale scores, duration of analgesia, and consumption of rescue analgesic drugs. Results: More patients in the ESPB group (88.4%), compared to the CEB group (42.3%), required rescue analgesics (P value <0.001). FLACC scores in the ESPB group, though satisfactory, were inferior, to the CEB group. The duration of postoperative analgesia was shorter in the ESPB group by 9.54 h (95% CI: 4.51 to 14.57 h, P value <0.001). The median (IQR) consumption of rescue paracetamol was significantly higher in the ESPB group (20 mg/kg (10,20) compared to the CEB group (0.0 mg/kg (0.0,10) P value <0.001)). No adverse effects were reported. Conclusion: In children undergoing abdominal surgery, both ESPB and CEB were safe and efficacious. CEB provided a longer duration and better quality of analgesia. ESPB may be considered when CEB is contraindicated or difficult.

Ultrasound-guided procedures for postoperative pain management in pediatric patients undergoing abdominal surgeries: A systematic review.

Many ultrasound-guided procedures are available for administering analgesia via peripheral nerve blockade. This systematic review aims to compare different ultrasound-guided procedures to determine which procedure is better suited for pediatric abdominal surgeries. The objective is to understand the efficacy of ultrasound-guided procedures for postoperative pain management in children undergoing abdominal surgeries and to identify which procedure takes less time and is better suited for a particular surgery. A systematic literature search was performed in PubMed, SCOPUS, Central Cochrane Registry of Controlled Trials (The Cochrane Library), and ScienceDirect databases for pediatric abdominal surgeries conducted with ultrasound-guided procedures for administering analgesia. We included studies involving randomized controlled trials (RCTs). Quasi-randomized controlled studies, prospective, retrospective observational studies, case series, case reports, letters, editorials, comments, animal studies, and studies from non-English literature were excluded. We reviewed 13 articles with 910 patients included. Age groups varied from 6 months to 21 years. The most common block used was the transversus abdominis block (47.76%), and the most common surgery performed was hernia and hydrocele (52.10%). Quadratus lumborum block was used in 26.92%, erector spinae block in 8.97%, modified transversus abdominus block and rectus sheath block in 9.62%, and ilioinguinal block in 6.73% of the patients. No complications were reported in any of the studies. Transversus abdominus block is less effective in two of the studies. Each procedure for pediatric postoperative analgesia has specific advantages and limitations, highlighting the complexity of tailoring interventions. Our review focuses on the advancements in ultrasound-guided analgesia for lower abdominal surgeries in pediatric patients while also emphasizing the need for future randomized controlled trials (RCTs) to compare efficacy, standardize practices, and improve patient outcomes.

A QSAR study on a series of N-methyl pyrimidones acting as HIV integrase inhibitors.

A quantitative structure-activity relationship (QSAR) study has been performed on integrase (IN) inhibition activity of a large series of N-methyl pyrimidones [Gardelli et al. (2007) J Med Chem 50, 4953-4975)] having varying heterocyclic ring substitution at 2-position of pyrimidone ring. The activity is found to be significantly correlated with surface tension and molar volume of the molecules. The whole series of compounds is divided into two subsets: a training set and a test set. A significant correlation is obtained for the training set, which is then used to predict the activity of compounds in the test set. The predicted activities of compounds in the test set are found to be very close to their observed activities. The predicting ability of the correlation obtained is judged by leave-one-out jackknife procedure. The correlation shows the effective role of the surface tension and molar volume of the molecules. From the correlation obtained, the integrase inhibition activities are predicted for some new prospective compounds.

Pharmacophore modeling, docking and the integrated use of a ligand- and structure-based virtual screening approach for novel DNA gyrase inhibitors: synthetic and biological evaluation studies.

Fluoroquinolones, a class of compound, act via inhibiting DNA gyrase and topoisomerase IV enzymes. This is an important class of drugs with high success rates for the treatment of tuberculosis and other bacterial infections. An indirect drug design approach was used to develop a meaningful pharmacophore model using the HypoGen module of Discovery Studio 2.0 on a set of 27 structurally diverse compounds with a wide range of biological activity (5 log units). The best hypothesis had three hydrogen bond acceptors (HBA) and one hydrophobic (Hy) moiety, showing r = 0.95, and it predicts the test set of 44 compounds well, with r 2 = 0.823. The same features (acceptor and hydrophobic functionality) were validated at the binding site of the DNA gyrase active site using GOLD version 3.0.1 and Molegro Virtual Docker, which showed corresponding hydrogen bond interactions and also π-π stacking interactions that correlated well with the PIC50 values (r 2 = 0.6142). The thoroughly validated model was used to screen an extensive database of 0.25 million compounds to identify potential leads. The validated model was implemented for the identification, design, synthesis, and biological evaluation of leads. Ten new chemical entities were synthesized based on our scaffold hopping techniques from the identified virtual screening and tested against the tuberculosis bacterium to obtain preliminary MIC values. The results showed that 3 out of 10 synthesized compounds exhibited good MICs, from 1.25 to 50 µM. This proves the robustness and applicability of the developed model, which is a promising tool for identifying new topoisomerase II inhibitors for the treatment of tuberculosis.

Risk Recognition and Multidisciplinary Approach for Non-Cardiac Surgeries in Paediatric Cardiac Patients: A Retrospective Observational Study.

Background Congenital heart disease (CHD), a structural and functional heart disease, is the commonest birth defect with an incidence of one in 125 live births worldwide with ventricular septal defect (VSD), atrial septal defect (ASD) and tetralogy of Fallot (TOF) constituting the majority. Surgery for associated extra-cardiac anomalies (airway, skeletal, genitourinary, and gastrointestinal) may be required in 30% of these patients. Delivery of uneventful anaesthesia in these children requires an understanding of not only paediatric anaesthesia but also of the pathophysiology of the cardiac lesion and its associated risks. Aims The purpose of this retrospective review was to highlight the approach to the anaesthetic management and outcomes of patients with significant cardiac lesions presenting for non-cardiac surgeries. Material and methods A retrospective chart review of all children with congenital heart disease (CHD) (repaired or unrepaired) who were posted for a non-cardiac surgery in this tertiary care Paediatric super-specialty hospital from January 1, 2018 to December 31, 2019 was carried out. Data on demographics, peri-operative management, and clinical course was retrieved. Inclusion criteria were paediatric patients (0-18 years) of either gender with a diagnosis of a CHD (repaired or unrepaired) undergoing any non-cardiac surgeries (NCS) under anaesthesia/Monitored Anaesthesia Care (MAC). Exclusion criteria were procedures only under local anaesthesia (LA) or a minor procedure done solely under sedation not involving an anaesthesiologist. Results During the study period, we found five eligible cases who underwent a total of six procedures. Five procedures were elective and one was an emergency. Preoperative optimization was conducted by a multidisciplinary team including paediatric surgeons, anaesthesiologists, physicians, and cardio-thoracic surgeons. Anaesthesia was conducted by at least a consultant paediatric anaesthesiologist. Overall all patients tolerated anaesthesia well without any adverse events or complications. All six anaesthetic encounters were safe and uneventful.

Synthesis of functionalized amino acid derivatives as new pharmacophores for designing anticancer agents.

A new series of functionalized amino acid derivatives N-substituted 1-N-(tert-butoxycarbonyl)-2,2-dimethyl-4-phenyl-5-oxazolidine carboxamide (1-17) and 1-N-substituted-3-amino-2-hydroxy-3-phenylpropane-1-carboxamide (18-34) were synthesized and evaluated for their in vitro cytotoxicity against human cancer cell lines. Compound 6 has shown interesting cytotoxicity (IC(50) = 5.67 microm) in ovarian cancer, while compound 10 exhibited promising cytotoxicity in ovarian (IC(50) = 6.1 microm) and oral (IC(50) = 4.17 microm) cancers. These compounds could be of use in designing new anti-cancer agents.

Anticancer and immunomodulatory activities of novel 1,8-naphthyridine derivatives.

A number of 1,8-naphthyridine derivatives (22-62) have been synthesized and screened for their in vitro cytotoxicity against eight tumors and two non-tumor cell lines. Halogen substituted 1,8-naphthyridine-3-caboxamide derivatives showed potent activity with compound 47 having IC(50) of 0.41 and 0.77 microM on MIAPaCa and K-562 cancer cell lines, respectively while, compound 36 had IC(50) of 1.19 microM on PA-1 cancer cell line. However, one of the unsubstituted 1,8-naphthyridine-C-3'-heteroaryl derivative 29 showed potent cytotoxicity with IC(50) of 0.41 and 1.4 microM on PA-1 and SW620 cancer cell lines, respectively. These compounds were also evaluated for anti-inflammatory activity as suggested by downregulation of proinflammaotory cytokines.

An open-label, randomized, 10 weeks prospective study on the efficacy of vitamin D (daily low dose and weekly high dose) in vitamin D deficient patients.

BACKGROUND: Vitamin D is an important vitamin required to maintain normal skeletal as well as nonskeletal functions. The daily supplementation of vitamin D not only have poor adherence to the regimen but also of doubtful efficacy in deficient patients. OBJECTIVES: The aim of this study was to compare the effect of oral high-dose vitamin D regimens (60,000 IU weekly) and daily low-dose vitamin D regimen of 1000 IU in mitigating symptoms and increase in serum levels of vitamin D in patients with hypovitaminosis D. MATERIALS AND METHODS: A total of 90 patients aged 18-60 years with vitamin D deficiency (serum levels < 30 ng/mL) were enrolled. A total of 38 subjects received 60,000 IU of vitamin D weekly with 500 mg/day calcium and 40 subjects received a dose of 1000 IU of vitamin D daily with 500 mg/day calcium for 10 weeks. Baseline and follow-up total serum vitamin D levels and improvement in symptoms were measured within and between groups. RESULTS: For high-dose vitamin D (60,000 IU weekly), the increase in mean serum vitamin D levels from baseline was 28.33 ng/mL over 10 weeks' treatment period; whereas for the low-dose group (1000 IU daily) the mean increment in serum vitamin D was 6.79 ng/mL for the same period. The mean difference in increase in serum vitamin D between two groups was highly significant (P < 0.001). In both the groups, decrease in myalgia as evaluated on visual analog scale was observed after 10 weeks. CONCLUSIONS: High-dose vitamin D (60,000 IU weekly) regimen rapidly normalized 25(OH) D levels and ensure symptomatic relief earlier than daily dosing of 1000 IU vitamin D for same duration.

Synthesis and cytotoxic activity of heterocyclic ring-substituted betulinic acid derivatives.

A new series of betulinic acid derivatives have been synthesized by introducing heterocyclic ring between C-2 and C-3 positions of betulinic acid. Further modifications were also carried out by reduction of C-20(29) unsaturated bond and substitution of C-28 carboxyl group by ester and amide linkage to enhance the selectivity. Compound 11 resulted in IC(50) of 2.44, 2.5, and 2.7 microg/ml on MIAPaCa, PA-1, and SW620 cancer cell lines, respectively. Compound 38 resulted in IC(50) of 0.67 microg/ml on MIAPaCa cell line.

Treatment planning comparison of electron arc therapy and photon intensity modulated radiotherapy for Askin's tumor of chest wall.

BACKGROUND AND PURPOSE: A dosimetric study to quantitatively compare radiotherapy treatment plans for Askin's tumor using Electron Arc (EA) vs. photon Intensity Modulated Radiotherapy (IMRT). MATERIALS AND METHODS: Five patients treated with EA were included in this study. Treatment plans were generated for each patient using EA and IMRT. Plans were compared using dose volume histograms (DVH) of the Planning Target Volume (PTV) and Organs at Risk (OAR). RESULTS: IMRT resulted in superior PTV coverage, and homogeneous dose distribution compared to EA. For EA, 92% of the PTV was covered to 85% of the dose compared to IMRT in which 96% was covered to 95% of the dose. V(107) that represents the hot spot within the PTV was more in IMRT compared to EA: 7.4(+/-2)% vs. 3(+/-0.5)%, respectively. With PTVs located close to the spinal cord (SC), the dose to SC was more with EA, whereas for PTVs located away from the SC, the dose to SC was more with IMRT. The cardiac dose profile was similar to that of SC. Ipsilateral lung received lower doses with IMRT while contralateral lung received higher dose with IMRT compared to EA. For non-OAR normal tissues, IMRT resulted in large volumes of low dose regions. CONCLUSIONS: IMRT resulted in superior PTV coverage and sparing of OAR compared to EA plans. Although IMRT seems to be superior to EA, one needs to keep in mind the volume of low dose regions associated with IMRT, especially while treating young children.