A Study to Evaluate the Efficacy of Dexamethasone as an Adjuvant in Ultrasound-Guided Bilateral Superficial Cervical Plexus Block using 0.25% Bupivacaine in Patients Undergoing Thyroid Surgeries under Entropy-Guided General Anesthesia.

Context: Ultrasound-guided bilateral superficial cervical plexus block (BSCPB) is a technique described for thyroid surgeries for postoperative analgesia as the surgery can cause severe pain and discomfort. Perineural dexamethasone is known to prolong analgesic duration and reduce postoperative nausea/vomiting. Aims: To assess the efficacy of dexamethasone as an adjuvant to BSCPB with 0.25% bupivacaine on isoflurane consumption, intraoperative hemodynamic parameters, and postoperative analgesia in patients undergoing thyroid surgeries under general anesthesia. Settings and Design: This was a randomized control trial. Subjects and Methods: Eighty patients were randomized to two equal groups using random number table into Group A with BSCPB receiving 20 mL of 0.25% bupivacaine and Group B with BSCPB receiving 19 mL of 0.25% bupivacaine + injection dexamethasone 4 mg in the preinduction period. Hemodynamic parameters, isoflurane consumption, postoperative visual analog scale (VAS) score, and antiemetic effect over 24 h were compared between two groups. Statistical Analysis Used: Microsoft excel data sheet, Chi-square test, and independent t-test were used for statistical analysis. Results: The intraoperative hemodynamic parameters were comparable between the two groups. There was a significant difference in mean VAS score between two groups from 6 h to 20 h postoperatively. The time of rescue analgesic in Group A was 7.09 ± 1.04 min and Group was 13.19 ± 1.46 min with P < 0.0001. In Group A, 40% had nausea and 35% had vomiting, and in Group B, 7.5% had nausea and 5% had vomiting. Conclusions: Preinduction ultrasound-guided BSCPB with bupivacaine and dexamethasone provides longer duration of postoperative analgesia and lesser nausea and vomiting compared to bupivacaine alone.

Evaluation of perfusion index as an objective tool to assess analgesia during laparoscopic surgeries under general anaesthesia.

Background and Aims: Changes in the sympathetic nervous system by pain can impact smooth muscle tone and can alter perfusion. This can be monitored by perfusion index (PI). It is a non-invasive, indirect, and continuous measure of peripheral perfusion. This study investigates the changes in PI due to painful stimuli under general anaesthesia. Methods: Twenty patients between the ages of 20 and 45 years, with informed consent, who were undergoing elective laparoscopic procedure, and belonging to the American Society of Anesthesiologists (ASA) physical status class I were connected with standard monitors along with SEDLINE, pulse oximetry (Root, Masimo Corporation®, Irvine, CA, USA) to monitor PI and Pleth-Variability Index (PVi). General anaesthesia was administered. PI, PVi, heart rate (HR), and non-invasive blood pressure were recorded pre-induction, during induction, before and after intubation, at the time of pneumoperitoneum (P0), and first laparoscopic port insertion (P1). Later, intravenous injection of fentanyl 0.5 µg/kg was administered and values were recorded at the second (P2) and third (P3) port insertion. The aforementioned parameters were recorded for up to 30 minutes. Statistical confirmation was done through paired t tests. Results: PI values after fentanyl increased from 5.33 ± 2.67 (P1) to 5.99 ± 2.8 (P2) (P < 0.001), and to 6.3 ± 2.88 (P3) (P < 0.001). This increase correlated with a decrease in HR, from 101.42 ± 12.53 (P1) to 87.93 ± 10.98 (P2) (P < 0.001), and to 83 ± 10.82 (P3) (P < 0.001). Conclusion: PI can be a tool to monitor the nociception in anaesthetised patients when administering analgesia.

Diagnostic Values of Laboratory Biomarkers in Predicting a Severe Course of COVID-19 on Hospital Admission.

Objective: We intend to identify differences in the clinicodemographic and laboratory findings of COVID-19 patients to predict disease severity and outcome on admission. Methods: This single-centred retrospective study retrieved laboratory and clinical data from 350 COVID-19 patients on admission, represented as frequency tables. A multivariate regression model was used to assess the statistically significant association between the explanatory variables and COVID-19 infection outcomes, where adjusted odds ratio (AOR), p value, and 95% CI were used for testing significance. Results: Among the 350 COVID-19 patients studied, there was a significant increase in the WBC count, neutrophils, aggregate index of systemic inflammation (AISI), neutrophil-to-lymphocyte ratio (dNLR), neutrophil-to-lymphocyte and platelet ratio (NLPR), monocyte-to-lymphocyte ratio (MLR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), D-dimer, interleukin-6 (IL-6), ferritin, lactate dehydrogenase (LDH), prothrombin time (PT), glucose, urea, urea nitrogen, creatinine, alanine phosphatase (ALP), and aspartate aminotransferase (AST) and a significant decrease in lymphocytes, eosinophils, total protein, albumin, prealbumin serum, and albumin/globulin (A/G) ratio in the severe group when compared with the mild and moderate groups. However, after adjusting their age, gender, and comorbidities, WBC count (adjusted odds ratio (AOR) = 6.888, 95% CI = 1.590-29.839, p = 0.010), neutrophils (AOR = 5.912, 95% CI = 2.131-16.402, p = 0.001), and urea (AOR = 4.843, 95% CI = 1.988-11.755, p = 0.001) were strongly associated with disease severity. Interpretation and Conclusion. On admission, WBC count, neutrophils, and urea, with their cut of values, can identify at-risk COVID-19 patients who could develop severe COVID-19.

Oxaliplatin immunohybrid nanoparticles in vitro synergistic suppression evaluation in treatment of colorectal cancer.

In the present study, we have investigated the enhanced synergistic and apoptotic activity of immunohybrid nanoparticles encapsulating oxaliplatin and covalently conjugated with TRAIL (Apo-2L/CD-253). Time-dependent cytotoxicity activity of nanoparticles was determined by MTT assay in HT-29 cells. Nuclear morphological changes and assessment of apoptotic ratio was analyzed by DAPI (4'6-diamidino-2-phenylindole) staining and annexin-propidium iodide (PI) assay. Cell-cycle analysis of oxaliplatin in HT-29 cell was analyzed by flow cytometry at 72 h. Furthermore, molecular mechanisms related to oxaliplatin-induced anticancer activity was explored by western blot analysis. Our study revealed appreciable time-dependent cytotoxicity, apoptotic, and synergistic activity of oxaliplatin immunohybrid nanoparticles.

Oxaliplatin immuno hybrid nanoparticles for active targeting: an approach for enhanced apoptotic activity and drug delivery to colorectal tumors.

Tumor necrosis factor related apoptosis inducing ligand (TRAIL) proved to be a promising new target for colorectal cancer treatment. Elevated expression of TRAIL protein in tumor cells distinguishes it from healthy cells, thereby delivering the drug at the specific site. Here, we formulated oxaliplatin immunohybrid nanoparticles (OIHNPs) to deliver oxaliplatin and anti-TRAIL for colorectal cancer treatment in xenograft tumor models. The polymeric chitosan layer binds to the lipid film with the mixture of phospholipids by an ultra sound method followed by conjugating with thiolated antibody using DSPE-PEG-mal3400, resulting in the formation of OIHNPs. The polymer layer helps in more encapsulation of the drug (71 ± 0.09%) with appreciable particle size (95 ± 0.01 nm), and lipid layer prevents degradation of the drug in serum by preventing nanoparticle aggregation. OIHNPs have shown a 4-fold decrease in the IC50 value compared to oxaliplatin in HT-29 cells by the MTT assay. These immuno-nanoparticles represent the successful uptake and internalization of oxaliplatin in HT-29 cells rather than in MCF-7 cells determined by triple fluorescence method. Apoptotic activity in vitro of OIHNPs was determined by the change in the mitochondria membrane potential that further elevates its anti-tumor property. Furthermore, the conjugated nanoparticles can effectively deliver the drug to the tumor sites, which can be attributed to its ability in reducing tumor mass and tumor volume in xenograft tumor models in vivo along with sustaining its release in vitro. These findings indicated that the oxaliplatin immuno-hybrid nanoparticles would be a promising nano-sized active targeted formulation for colorectal-tumor targeted therapy.

5-Fluorouracil enteric-coated nanoparticles for improved apoptotic activity and therapeutic index in treating colorectal cancer.

5-Fluorouracil (5-FU) is one among the anti-cancer agents in FOLFORINOX treatment along with oxaliplatin and irinotecan for the treatment of colorectal cancer. Despite its potential activity on the tumor cells, it lacks site specificity partly attributed by its biodistribution to healthy cells resulting in toxic effects to healthy cells. Therefore, we have formulated 5-fluorouracil enteric-coated nanoparticles (5-FUEC) to localize the drug in the colon area that enables its prolonged presence in target area in a sustained manner. The current work emphasizes on enhanced anti-cancer activity of 5-FUEC sequencing its apoptotic activity on HCT 116 colorectal cancer cell lines in vitro. MTT assay exhibited 5.5-fold decrease in IC50 value of nanoparticles comparable to 5-FU. Nuclear fragmentation with irregular edges in nucleus of cells justified its improved activity. Furthermore, flow cytometric analysis confirms the majority of cells gated in early apoptotic (39.75%) and late apoptotic phase (36.25%). Acridine orange/ethidium bromide staining (AO/EB) exhibited cells with red fluorescence (indicating apoptosis) comparable to the control and 5-FU. γ-Scintigraphic studies determined the applicability and feasibility of the enteric coating with mean gastric emptying time, mean intestinal transit time and mean colon arrival time of 1.89 ± 0.03, 2.15 ± 0.05 and 4.03 ± 0.27 h, respectively. Moreover, nanoparticulate approach was found significant in reducing tumor size and volume in xenograft tumor models in vivo along with sustained release. These superior anti-cancer activities exhibited by 5-FUEC indicated that it could be a potential alternative to chemotherapy for colorectal cancer.

Formulation and optimization of oxaliplatin immuno-nanoparticles using Box-Behnken design and cytotoxicity assessment for synergistic and receptor-mediated targeting in the treatment of colorectal cancer.

Conventional chemotherapy majorly lacks clinical application attributed to its inspecificity, adverse effects and inability to penetrate into tumor cells. Hence, the aim of the study was to prepare oxaliplatin solid lipid nanoparticles (OP-SLN) by microemulsion method optimizing it by Box-Behnken design and then covalently conjugated to TRAIL (CD-253) monoclonal antibody (TR-OP-SLN) for targeting colorectal cancer cells. The optimized OP-SLN3 has shown an appreciable particle size (121 ± 1.22 nm), entrapment efficiency (78 ± 0.09%) and drug loading (32 ± 1.01%). Fluorescence study and the Bradford assay further confirmed the binding of the protein. A 1.5-fold increase in cytotoxicity of immuno-nanoparticles (4.9 µM) was observed.

Formulation and characterization of 5-Fluorouracil enteric coated nanoparticles for sustained and localized release in treating colorectal cancer.

5-Fluorouracil is used in the treatment of colorectal cancer along with oxaliplatin as first line treatment, but it is having lack of site specificity and poor therapeutic effect. Also toxic effects to healthy cells and unavailability of major proportion of drug at the colon region remain as limitations. Toxic effects prevention and drug localization at colon area was achieved by preparing enteric-coated chitosan polymeric nanoparticles as it can be delivered directly to large bowel. Enteric coating helps in preventing the drug degradation at gastric pH. So the main objective was to prepare chitosan polymeric nanoparticles by solvent evaporation emulsification method by using different ratios of polymer (1:1, 1:2, 1:3, 1:4). Optimized polymer ratio was characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), entrapment efficiency and particle size and further subjected to enteric coating. In vitro drug release studies were done using dialysis bag technique using simulated fluids at various pH (1.2, 4.5, 7.5, 7.0) to mimic the GIT tract. 5-FU nanoparticles with drug: polymer ratio of 1:2 and 1:3 has shown better particle size (149 ± 1.28 nm and 138 ± 1.01 nm respectively), entrapment efficiency (48.12 ± 0.08% and 69.18 ± 1.89 respectively). 5-FU E1 has shown better drug release after 4 h and has shown 82% drug release till 24 h in a sustained manner comparable to the non-enteric coated tablets, which released more than 50% of the drug before entering the colon region. So we can conclude that nanoparticles prepared by this method using the same polymer with the optimized ratio can represent as potential drug delivery approach for effective delivery of the active pharmaceutical ingredient to the colorectal tumors.

Effect of crude extract of Eugenia jambolana Lam. on human cytochrome P450 enzymes.

The fruit of Eugenia jambolana Lam. is very popular for its anti-diabetic property. Previous studies on the crude extract of E. jambolana (EJE) have successfully explored the scientific basis for some of its traditional medicinal uses. Considering its wide use and consumption as a seasonal fruit, the present study investigates the ability of E. jambolana to interact with cytochrome P450 enzymes. The standardized EJE was incubated with pooled human liver microsomes to assess the CYP2C9-, CYP2D6-, and CYP3A4-mediated metabolism of diclofenac, dextromethorphan, and testosterone, respectively. The metabolites formed after the enzymatic reactions were quantified by high performance liquid chromatography. EJE showed differential effect on cytochrome P450 activities with an order of inhibitory potential as CYP2C9 > CYP3A4 > CYP2D6 having IC50 of 76.69, 359.02, and 493.05 µg/mL, respectively. The selectivity of EJE for CYP2C9 rather than CYP3A4 and CYP2D6 led to perform the enzyme kinetics to explicate the mechanism underlying the inhibition of CYP2C9-mediated diclofenac 4'-hydroxylation. EJE was notably potent in inhibiting the reaction in a non-competitive manner with Ki of 84.85 ± 5.27 µg/mL. The results revealed the CYP2C9 inhibitory potential of EJE with lower Ki value suggesting that EJE should be examined for its potential pharmacokinetic and pharmacodynamic interactions when concomitantly administered with other drugs.

A molecular connection of Pterocarpus marsupium, Eugenia jambolana and Gymnema sylvestre with dipeptidyl peptidase-4 in the treatment of diabetes.

CONTEXT: Pterocarpus marsupium (PM) (Leguminosae), Eugenia jambolana (EJ) (Myrtaceae) and Gymnema sylvestre (GS) (Asclepiadaceae) are the most important medicinal plants in the Indian system of traditional medicine for the treatment of hyperglycemia. OBJECTIVES: Dipeptidyl peptidase-4 (DPP-4) inhibitors are the emerging class of anti-diabetic agents. However, only few compounds are commercially available. Therefore, in the present study we tried to explore the naturally occurring PM, EJ and GS semi-standardized extracts for their potential DPP-4 inhibition in vitro and in vivo. MATERIALS AND METHODS: DPP-4 inhibition was evaluated by in vitro inhibitory assay, and enzyme kinetics were calculated using one-phase exponential decay equation. Glucose load (2 g/kg) was administered to control and diabetic rats 30 min following extract administration (100, 200 and 400 mg/kg) orally once, and blood samples were withdrawn at 0, 0.5, 1, 1.5, 2 and 3 h to measure plasma active glucagon-like peptide-1 (GLP-1) levels. RESULTS: PM and EJ inhibit DPP-4 potently with IC50 values of 273.73 ± 2.96 and 278.94 ± 6.73 µg/mL, respectively, compared to GS (773.22 ± 9.21 µg/mL). PM, EJ and GS exhibit long duration of action with enzyme inhibitory half-lives of 462.3, 317.2 and 153.8 min, respectively. Extracts significantly increase GLP-1 levels compared to negative control groups and peak GLP-1 level was observed at 2 h for PM and EJ, whereas for GS it was at 1.5 h DISCUSSION AND CONCLUSION: Taken together, results suggest the extracts may have potent DPP-4 inhibitory action, and their hypoglycemic action attributed through an increase in plasma active GLP-1 levels.

Evaluation of anti-epileptic property of Marsilea quadrifolia Linn. in maximal electroshock and pentylenetetrazole-induced rat models of epilepsy.

OBJECTIVE: To study the anti-epileptic effects of methanolic extract of Marsilea quadrifolia Linn. (MQ) in maximal electroshock (MES) and pentylenetetrazole (PTZ) induced rat models of epilepsy. METHOD: A total of 84 adult male Wistar rats were used. An acute oral toxicity study was conducted on 36 rats and the remaining were used for other experiments. Each model had 24 rats which were allotted into four groups (n = 6). Group I (Control) received 1% carboxymethyl cellulose solution, Group II (Positive control) received phenytoin 300 mg kg(-1) b.w. in the MES model; sodium valproate 200 mg kg(-1) b.w. in the PTZ model, Group III (MQ) received 400 mg kg(-1) b.w. MQ extract and Group IV (MQ) received 600 mg kg(-1) b.w. MQ extract. Hind limb extension (HLE) time and recovery time were noted in the MES model. Latency for myoclonic jerk, seizures and EEG was recorded in the PTZ model. RESULTS: When compared to control, the phenytoin received group did not show HLE. In MQ pre-treated groups only 50% of rats showed HLE. Sodium valproate and various doses of MQ significantly increased the latency for onset of clonus and seizures. PTZ-induced EEG alterations were significantly attenuated by MQ administration and this was comparable to that of the sodium valproate effect. CONCLUSION: Marsilea quadrifolia Linn. showed significant anti-epileptic efficacy against various epilepsy models.

Hepatoprotective activity of the Indian medicinal plant Polygala arvensis on D-galactosamine-induced hepatic injury in rats.

The suspensions of chloroform extract of leaves in 0.3% carboxy methyl cellulose (CMC) was evaluated for hepatoprotective activity in Wistar albino rats by inducing hepatic injury with d-galactosamine (400 mg/kg). The chloroform extract of Polygala arvensis at an oral dose of 200 mg/kg and 400 mg/kg exhibited a significant (P<0.001, P<0.01 and P<0.05) protection effect by normalizing the levels of aspartate amino transferase (ASAT, GOT), alanine amino transferase (ALAT, GPT), alkaline phosphatase (ALP), total bilirubin (TB), lactate dehydrogenase (LDH), total cholesterol (TC), triglycerides (TGL), albumin, total protein (TP) which were significantly (P<0.001) increased in rats by treatment with 400 mg/kg i.p. of d-galactosamine. Silymarin (25 mg/kg), a known hepatoprotective drug used for comparison exhibited significant activity (P<0.001).

Improvement of physical stability and dissolution rate of celecoxib suspensions by complexation with beta-cyclodextrins.

Solid dispersions of celecoxib with beta-cyclodextrins were prepared by physical mixing, slugging and kneading methods at 1:1 and 1:2 molar ratios and characterized by differential scanning calorimetry. Celecoxib suspensions were formulated employing its solid dispersions with sodium carboxymethylcellulose as the suspending agent. Stability studies were conducted by subjecting all the suspensions to freeze-thaw cycling. The suspensions were evaluated for particle size, sedimentation volume, viscosity, redispersibility and dissolution rate initially and after stability testing. Celecoxib suspensions formulated employing its solid dispersions exhibited good physical stability and gave higher dissolution rates than those formulated with celecoxib alone. The suspension prepared from solid dispersions (1:2) by the kneading method gave the highest improvement in dissolution rate and efficiency. Celecoxib in the inclusion complex with beta-cyclodextrin produced suspensions of better physical stability and dissolution rate.

Enhanced degradation and decreased stability of eye lens alpha-crystallin upon methylglyoxal modification.

Methylglyoxal (MGO), a potent glycating agent, forms advanced glycation end products (AGEs) with proteins. Several diabetic complications including cataract are thought to be the result of accumulation of these protein-AGEs. alpha-Crystallin, molecular chaperone of the eye lens, plays an important role in maintaining the transparency of the lens by preventing the aggregation/inactivation of several proteins/enzymes in addition to its structural role. Binding of adenosine-5-triphosphate (ATP) to alpha-crystallin has been shown to enhance its chaperone-like function and protection against proteolytic degradation. In the earlier study, we have shown that modification of alpha-crystallin by MGO caused altered chaperone-like activity along with structural changes, cross-linking, coloration and subsequent insolubilization leading to scattering of light [Biochem. J. 379 (2004) 273]. In the present study, we have investigated ATP binding, stability and degradation of MGO-modified alpha-crystallin. Proteolytic digestion with trypsin and chymotrypsin showed that MGO-modified alpha-crystallin is more susceptible to degradation compared to native alpha-crystallin. Furthermore, ATP was able to protect native alpha-crystallin against proteolytic cleavage but not MGO-modified alpha-crystallin. Interestingly, binding studies indicate decreased ATP binding to MGO-modified alpha-crystallin and support the decreased protection by ATP against proteolysis. In addition, differential scanning calorimetric and denaturant-induced unfolding studies indicate that modification of alpha-crystallin by MGO leads to decreased stability. These results indicate that MGO-modification of alpha-crystallin causes partial unfolding and decreased stability leading to enhanced proteolysis. Cross-linking of these degraded products could result in aggregation and subsequent insolubilization as observed in senile and diabetic cataract lenses.

Novel delta2-isoxazolines as group II phospholipase A2 inhibitors.

The synthesized imidazolyl substituted delta2-isoxazolines were subjected to Phospholipase A(2) (PLA(2)) enzyme inhibitory activity against snake venom source and their structure-activity relationship with respect to different groups attached to this moiety is reported for the first time. The crystal structure of the compound 2-butyl-5-chloro-3H-imidazolyl-4-carbaldehyde oxime 2, an intermediate for the construction of isoxazolines is reported. These compounds exerted a significant PLA(2) enzyme inhibitory activity against group II PLA(2). The in vivo activity on mice of selected compounds 3bI and 3bIV shows the comparable anti-inflammatory activity with the known standard ursolic acid.

Ultrahigh-Temperature Metamorphism in Madurai Granulites, Southern India: Evidence from Carbon Isotope Thermometry.

Ultrahigh-temperature (UHT) metamorphism in the Madurai Block of the southern Indian granulite terrain has been verified using the calcite-graphite isotope exchange thermometer. Carbon isotope thermometry has been applied to marbles from a locality near the reported occurrence of sapphirine granulites that have yielded temperature estimates of around 1000 degrees C. The delta(13)C and delta(18)O values of calcite are homogenous, implying equilibration of the isotopes during metamorphism. However, the delta(13)C values of single graphite crystals show variations in the order of 1 per thousand within a hand specimen. Detailed isotopic zonation studies indicate that graphite preserves either the time-integrated crystal growth history or reequilibrium fractionation during its cooling history. The graphite cores preserve higher delta(13)C values than the rims. The fractionation between calcite and graphite cores gives the highest metamorphic temperature of about 1060 degrees C, which matches the petrologically inferred temperature estimates in the high-magnesian pelites. The fractionation between graphite rims and calcite suggests a temperature of around 750 degrees C, which is interpreted to reflect retrograde cooling. This event is also observed in the sapphirine granulites. Calcite-graphite thermometry thus provides a useful tool to define UHT metamorphism in granulite terrains.