Invitro Activity Research Articles

Efficacy and safety of ivermectin for the treatment of Plasmodium falciparum infections in asymptomatic male and female Gabonese adults – a pilot randomized, double-blind, placebo-controlled single-centre phase Ib/IIa clinical trial

Ivermectin's mosquitocidal effect and invitro activity against Plasmodium falciparum asexual stages are known. Its invivo blood-schizonticidal efficacy is unknown. Ivermectin's tolerability and efficacy against P.falciparum infections in Gabonese adults were assessed. The study consisted of a multiple dose stage and a randomized, double-blind, placebo-controlled stage. Adults with asymptomatic P.falciparum parasitaemia (200-5000 parasites/μl) were enrolled. First, three groups of five participants received 200μg/kg ivermectin once daily for one, two, and three days, respectively, and then 34 participants were randomized to 300μg/kg ivermectin or placebo once daily for 3 days. Primary efficacy outcome was time to 90% parasite reduction. Primary safety outcomes were drug-related serious and severe adverse events (Trial registration: PACTR201908520097051). Between June 2019 and October 2020, 49 participants were enrolled. Out of the 34 randomized participants, 29 (85%) completed the trial as per protocol. No severe or serious adverse events were observed. The median time to 90% parasite reduction was 24.1 vs. 32.0h in the ivermectin and placebo groups, respectively (HR 1.38 [95% CI 0.64 to 2.97]). Ivermectin was well tolerated in doses up to 300μg/kg once daily for three days and asymptomatic P.falciparum asexual parasitaemia was reduced similarly with this dose of ivermectin compared to placebo. Further studies are needed to evaluate plasmodicidal effect of ivermectin at higher doses and in larger samples. This study was funded by the Centre de Recherches Médicales de Lambaréné and the Centre for Tropical Medicine of the Bernhard Nocht Institute for Tropical Medicine.

Potentials of organic tellurium-containing compound AS101 to overcome carbapenemase-producing Escherichia coli.

The issue of carbapenem-resistant Escherichia coli was aggravated yearly. The previous studies reported the varied but critical epidemiology of carbapenem-resistant E. coli among which the carbapenemase-producing strains were regarded as one of the most notorious issues. AS101, an organic tellurium-containing compound undergoing clinical trials, was revealed with antibacterial activities. However, little is known about the antibacterial effect of AS101 against carbapenemase-producing E. coli (CPEC). The minimum inhibitory concentration (MIC) of AS101 against the 15 isolates was examined using a broth microdilution method. The scanning electron microscopy, pharmaceutical manipulations, reactive oxygen species level, and DNA fragmentation assay were carried out to investigate the antibacterial mechanism. The sepsis mouse model was employed to assess the invivo treatment effect. The blaNDM (33.3%) was revealed as the dominant carbapenemase gene among the 15 CPEC isolates, followed by the blaKPC gene (26.7%). The MICs of AS101 against the 15 isolates ranged from 0.5 to 32μg/ml, and 99.9% of bacterial eradication was observed at 8h, 4h, and 2h for 1×, 2×, and 4×MIC, respectively. The mechanistic investigations suggest that AS101 would enter the bacterial cell, and induce ROS generation, leading to DNA fragmentation. The invivo study exhibited that AS101 possessed a steady treatment effect in a sepsis mouse model, with an up to 83.3% of survival rate. The invitro activities, mechanisms, and invivo study of AS101 against CPEC were unveiled. Our finding provided further evidence for the antibiotic development of AS101.

Inhibition of a lower potency target drives the anticancer activity of a clinical p38 inhibitor

The small-molecule drug ralimetinib was developed as an inhibitor of the p38α mitogen-activated protein kinase, and it has advanced to phase 2 clinical trials in oncology. Here, we demonstrate that ralimetinib resembles EGFR-targeting drugs in pharmacogenomic profiling experiments and that ralimetinib inhibits EGFR kinase activity invitro and in cellulo. While ralimetinib sensitivity is unaffected by deletion of the genes encoding p38α and p38β, its effects are blocked by expression of the EGFR-T790M gatekeeper mutation. Finally, we solved the cocrystal structure of ralimetinib bound to EGFR, providing further evidence thatthis drug functions as an ATP-competitive EGFR inhibitor. We conclude that, though ralimetinib is>30-fold less potent against EGFR compared to p38α, its ability to inhibit EGFR drives its primary anticancer effects. Our results call into question the value of p38α as an anticancer target, and we describe a multi-modal approach that can be used to uncover a drug's mechanism-of-action.

Determination of Multidrug Resistance and Extended Drug Resistance Pattern of Pseudomonas aeruginosa in Clinical Isolates of Tertiary Care Hospital Lahore

Background: 
 Pseudomonas aeruginosa (PA) is a major public health community-acquired threat around the globe due to the growing rate of antimicrobial resistance. It is one of the most common trending causes of nosocomial infections. 
 Objective: 
 The current study aimed to check the rate of multidrug-resistant (MDR) and extended drug-resistant (XDR) PA and to analyze the invitro activity of different antimicrobial agents against clinically isolated bacterial samples. Molecular Detection and amplification of L lipoprotein (OprL gene) were also done to determine the frequency and species of different strains of Pseudomonas aeruginosa (PA2192, C3719, PA01, PA14 and PACS2).
 Method:
 This cross-sectional study was conducted at at the Department of Pathology, King Edward Medical University/ Mayo Hospital Lahore. Total 140 patients were included in the study. Biochemical characterization, molecular identification, antimicrobial susceptibility profiling and DNA sequencing of the desired gene were done to confirm different strains' identification. 
 Results:
 MDR and XDR Pseudomonas aeruginosa infection are more common among males 81(57.5%) and high among the 31-45 age group, i.e., 55 (39.3%). After antibiotic susceptibility testing, 60% of strains were found to be MDR PA, while 40% were categorized as XDR PA. Doripenem showed the highest sensitivity, 93 (66.4%) among all carbapenems. Polymyxin B showed the highest activity against Pseudomonas aeruginosa multi and extensively drug-resistant strains, i.e., 108 (77.1%). 
 Conclusion:
 The present study suggests that doripenem can be the only active agent for combating infections, and the Carbapenem drug appears effective against highly resistant strains of Pseudomonas aeruginosa.

In-Vitro Anti-Diabetic Activity and Phytochemical Screening of Ethanolic extract of Calotropis gigantea (Linn)

INTRODUCTION Diabetes Mellitus (DM) is metabolic disorder characterized by hyperglycaemia due to defect insulin release from pancreas and insulin resistance. The present study was aimed to screen the phytoconstituent present in leaf extract and evaluate α- amylase inhibitory activity of ethanolic extract of Calotropis gigantea leaf. Calotropis gigantea also known as crown flower is rich in phytochemicals like alkaloids, saponins, steroids, flavonoids and glycosides. It is used for asthma, bronchitis and dyspepsia, dried whole plant is a good tonic. MATERIAL AND METHODS About 58.45g coarse powder of Calotropis gigantea leaves was extracted with ethanol using Soxhlet apparatus. Then the phytochemical screening of ethanolic extract was done. Different concentration (0.1mg/ml to 1mg/ml) of ethanolic extracts of leaves, acarbose, sitagliptin and metformin was prepared, and all the concentration were evaluated for α- amylase inhibitory activity through spectrophotometric method. RESULTS Maximum inhibition of α- amylase was shown by acarbose at concentration of 1mg/ml and found to be 78.787 ± 0.00240 % whereas plant extract at concentration of 1mg/ml showed inhibition of α- amylase activity 54.6296 ± 0.00282 %. Percentage inhibition of α-amylase activity by plant extract was found to be dose dependent. CONCLUSION It was concluded that Calotropis gigantea leaves possess some bioactive compounds which were responsible for controlling blood glucose level by inhibiting α-amylase and its identification, isolation and characterization may lead to development of newer drugs with lesser side effects.

DOCKING STUDIES OF INDOLE ASSIMILATED PYRAZOLINE MOLECULAR HYBRIDS: DESIGN, SYNTHESIS AS ANTIINFLAMMATORY AGENTS AND ANTICANCER AGENTS

A series of novel compounds (4a-4l) have been synthesized by Claisen-Schmidt condensation, Schiff’s base and Cyclization mechanism. All the molecule structures were affirmation by IR, 1H NMR and Mass spectral data. The synthesized hybrids were screened for in vivo anti-inflammatory and invitro anticancer activities. Ant inflammatory activity was performed using carrageenan induced rat paw edema method using Diclofenac as standard drug. The anticancer activity has been assessing by using MTT assay against MCF7 and SKOV3 cell lines and Doxorubicin was used as reference standard. Among the compounds compound 4l exhibited the highest % inhibition of 98.4 when compared with the standard Diclofenac 94.2%.Compound 4f exhibited the lowest IC50 at concentration of 20.01µg against MCF7 cell lines and 32.87µg against SKOV3 cell lines. The molecular docking studies was performed using the Ligprep tool of Schrodinger suite. This study revealed that novel thiazolidne-4-one-pyrazole hybrids(4a-4j) had good interaction with the active site of EGFR receptor. Among the docked compounds, dock score of the compounds ranged from from -3.186 to -5.212. The highest score was exhibited by 4f with -5.212 with Glide binding energy of -34.697 Kcal/mol.

Superior antibody immunogenicity of a viral-vectored RH5 blood-stage malaria vaccine in Tanzanian infants as compared to adults

RH5 is a leading blood-stage candidate antigen for a Plasmodium falciparum vaccine; however, its safety and immunogenicity in malaria-endemic populations are unknown. A phase 1b, single-center, dose-escalation, age-de-escalation, double-blind, randomized, controlled trial was conducted in Bagamoyo, Tanzania (NCT03435874). Between 12th April and 25th October 2018, 63 healthy adults (18-35 years), young children (1-6 years), and infants (6-11months) received a priming dose of viral-vectored ChAd63 RH5 or rabies control vaccine. Sixty participants were boosted with modified vaccinia virus Ankara (MVA) RH5 or rabies control vaccine 8weeks later and completed 6months of follow-up post priming. Primary outcomes were the number of solicited and unsolicited adverse events post vaccination and the number of serious adverse events over the study period. Secondary outcomes included measures of the anti-RH5 immune response. Vaccinations were well tolerated, with profiles comparable across groups. No serious adverse events were reported. Vaccination induced RH5-specific cellular and humoral responses. Higher anti-RH5 serum immunoglobulin G (IgG) responses were observed post boost in young children and infants compared to adults. Vaccine-induced antibodies showed growth inhibition activity (GIA) invitro against P.falciparum blood-stage parasites; their highest levels were observed in infants. The ChAd63-MVA RH5 vaccine shows acceptable safety and reactogenicity and encouraging immunogenicity in children and infants residing in a malaria-endemic area. The levels of functional GIA observed in RH5-vaccinated infants are the highest reported to date following human vaccination. These data support onward clinical development of RH5-based blood-stage vaccines to protect against clinical malaria in young African infants. Medical Research Council, London, UK.

3D-printed wound dressings containing a fosmidomycin-derivative prevent Acinetobacter baumannii biofilm formation

Acinetobacter baumannii causes a wide range of infections, including wound infections. Multidrug-resistant A.baumannii is a major healthcare concern and the development of novel treatments against these infections is needed. Fosmidomycin is a repurposed antimalarial drug targeting the non-mevalonate pathway, and several derivatives show activity toward A.baumannii. We evaluated the antimicrobial activity of CC366, a fosmidomycin prodrug, against a collection of A.baumannii strains, using various invitro and invivo models; emphasis was placed on the evaluation of its anti-biofilm activity. We also developed a 3D-printed wound dressing containing CC366, using melt electrowriting technology. Minimal inhibitory concentrations of CC366 ranged from 1 to 64μg/mL, and CC366 showed good biofilm inhibitory and moderate biofilm eradicating activity invitro. CC366 successfully eluted from a 3D-printed dressing, the dressings prevented the formation of A.baumannnii wound biofilms invitro and reduced A.baumannii infection in an invivo mouse model.

Preliminary Phytochemical Screening and Study of In vitro Antibacterial Activity on H37RV Strain using roots of Ziziphus nummularia

Objective: To evaluate the invitro antimicrobial and anti-tuberculosis activity by screening its bacterial resistance using Ziziphus nummularia root extracts. Methods: Ziziphus nummularia root extracts such as aqueous and ethanol were prepared by using soxhalation process. The antimicrobial activity was screened by agar well diffusion method and antituberculosis activity were screened by MABA (Microplate Alamar Blue Assay). Results and conclusion: In preliminary phytochemical screening the extracts showed the presence of major phytoconstituents such as alkaloid, flavonoid, tannin, saponin, terpenoid, sterols, carbohydrate and protein. The Minimum inhibitory concentration (MIC) were noted in both invitro activity screening. In Antimicrobial screening, the ethanolic extract of Ziziphus nummularia root was more susceptible to Staphylococci with a maximum zone of inhibition 24mm, while aqueous extract showed zone of inhibition 14mm at 80 mg/ml. It shows that ethanolic extract of Ziziphus nummularia root has good potential antimicrobial activity against aqueous extract and standard drug. Similarly in antituberculosis activity, the aqueous extract of Ziziphus nummularia root showed minimum inhibitory at a concentration of 25 μg/ml, while ethanolic extract showed minimum inhibitory concentration at 100 μg/ml. The aqueous extract of Ziziphus nummularia has moderate antituberculosis activity when compared with ethanolic extract and standard drug we used.

The design of functional proteins using tensorized energy calculations

In protein design, the energy associated with a huge number of sequence-conformer perturbations has to be routinely estimated. Hence, enhancing the throughput and accuracy of these energy calculations can profoundly improve design success rates and enable tackling more complex design problems. In this work, we explore the possibility of tensorizing the energy calculations and apply them in a protein design framework. We use this framework to design enhanced proteins with anti-cancer and radio-tracing functions. Particularly, we designed multispecific binders against ligands of the epidermal growth factor receptor (EGFR), where the tested design could inhibit EGFR activity invitro and invivo. We also used this method to design high-affinity Cu2+ binders that were stable in serum and could be readily loaded with copper-64 radionuclide. The resulting molecules show superior functional properties for their respective applications and demonstrate the generalizable potential of the described protein design approach.

<i>Invitro</i> Antitrypanosomal activity of fractions of ethanol extract from <i>Terminalia cattapa</i> leaf against <i>Trypanosomal Brucei Brucei</i>

Trypanosomiasis is a tropical disease threatening human and animal health. Trypanosoma brucei brucei is unicellular parasites transmitted by the bite of tsetse fly and is the causative agent of sleeping sickness in humans and related diseases in animals. Over 25% of our common medicines contains some compounds obtained from plants. This research work is aimed at evaluating the invitro activity of fractionated ethanol extract of Terminalia cattapa leaf against Trypanosoma brucei brucei. Crude extract was obtained by cold maceration using absolute ethanol, followed by partial purification of the extract using column chromatography techniques. The test was performed in triplicates using a 96 well microtitre plate. Light microscope was used to view the parasite motility at magnification of × 400. Treatment with varying concentrations of pooled fractions F1, F2 and F3 (100, 50 and 25 mg/ml) resulted in reduction of number of motile parasites compared to the negative control loaded with parasites. In conclusion, fractions (F2 ans F3) from ethanol extracts of Terminalia cattapa leaf have anti-trypanosoma activities against Trypanosoma brucei brucei in a dose depended manner with F3 being the most potent..

Encapsulation of Diosgenin in chitosan nanoparticles with enhanced invitro and invivo anticancer activity in Female Sprague Dawley rats

The main purpose of this study was to optimize the conditions for synthesizing diosgenin-encapsulated chitosan nanoparticles (DIO@CS NPs) and anticancer activity. Nanoparticles encapsulating diosgenin were synthesized using ionic gelation utilizing three different chitosan weight percentages and polyanion STPP (Sodium tripolyphosphate) as the cross-linking agent. The synthesis depended on ionic interaction between positively charged chitosan and negatively charged STPP. The incorporation of diosgenin into the chitosan nanoparticles was verified by Fourier transform infrared spectroscopy (FTIR). Chitosan nanoparticle entrapment effectiveness (EE%) was between 76% to 94% and increased with diosgenin concentration. Invitro diosgenin drug release from nanoparticles was decelerated when employing greater molecular weight chitosan. Chitosan nanoparticles released diosgenin diffusion-controlled in drug release study. DIO@CS nanoparticles evaluated on A431 human skin cancer cells demonstrated significant anticancer activity. These results suggest that DIO@CS NPs could be a novel skin cancer therapy. Each rat received 25 mg/kg DMBA subcutaneously. Tumor-bearing animals were lighter. DMBA-induced mice gained less weight than DIO@CS NPs. Oral DIO@CS NPs (2.5 mg/kg b.wt) recovered cellular antioxidants and mitigated histopathological staining of hematoxylin and eosin on breast carcinoma. Based on the foregoing results, Diosgenin nanoformulations provide a novel breast cancer treatment.

Synthesis, glycosidase inhibitory activity and computational studies of dideoxymethylnojirimycin and its derivatives

We report here the synthesis and biological evaluation of dideoxynojirimycin and its analogs and their functional effect on glucosidase enzyme inhibition against α-glucosidase(yeast), α-galactosidase and β-galactosidase (kluyveromyces lactis). All the compounds significantly inhibited the α-glucosidase(yeast) activity when compared to DNJ and shown strong inhibition against β-galactosidase (kluyveromyces lactis) when compared to DNJ. The molecular docking studies also reveals that these compounds showing strong ligand binding energies against yeast-ɑ-glucosidase- I, yeast β-galactosidase and human lysosomal acid–ɑ-glucosidase. Interestingly the analogues having N-H, N-alkyl and N-benzyl group along with ethyl group significantly inhibited the β-galactosidase activity when compared to DNJ. The in-silico studies are in correlation with invitro activity data; therefore, this study will be useful to develop further glycosidase inhibitors.

Enhancing the effectiveness of γδ T cells by mRNA transfection of chimeric antigen receptors or bispecific T cell engagers

Adoptive cell therapy (ACT) utilizing γδ Tcells is becoming a promising option for the treatment of cancer, because it offers an off-the-shelf allogeneic product that is safe, potent, and clinically effective. Approaches to engineer or enhance immune-competent cells for ACT, like expression of chimeric antigen receptors (CARs) or combination treatments with bispecific Tcell engagers, have improved the specificity and cytotoxic potential of ACTs and have shown great promise in preclinical and clinical settings. Here, we test whether electroporation of γδ Tcells with CAR or secreted bispecific Tcell engager (sBite) mRNA is an effective approach to improve the cytotoxicity of γδ Tcells. Using a CD19-specific CAR, approximately 60% of γδ Tcells are modified after mRNA electroporation and these cells show potent anticancer activity invitro and invivo against two CD19-positive cancer cell lines. In addition, expression and secretion of a CD19 sBite enhances γδ Tcell cytotoxicity, both invitro and invivo, and promotes killing of target cells by modified and unmodified γδ Tcells. Taken together, we show that transient transfection of γδ Tcells with CAR or sBite mRNA by electroporation can be an effective treatment platform as a cancer therapeutic.

An optimized IL-12-Fc expands its therapeutic window, achieving strong activity against mouse tumors at tolerable drug doses

Interleukin-12 (IL-12) has emerged as one of the most potent cytokines for tumor immunotherapy due to its ability to induce interferon γ (IFNγ) and polarize Th1 responses. Clinical use of IL-12 has been limited by a short half-life and narrow therapeutic index. We generated a monovalent, half-life-extended IL-12-Fc fusion protein, mDF6006, engineered to retain the high potency of native IL-12 while significantly expanding its therapeutic window. Invitro and invivo activity of mDF6006 was tested against murine tumors. To translate our findings, we developed a fully human version of IL-12-Fc, designated DF6002, which we characterized invitro on human cells and invivo in cynomolgus monkeys in preparation for clinical trials. The extended half-life of mDF6006 modified the pharmacodynamic profile of IL-12 to one that was better tolerated systemically while vastly amplifying its efficacy. Mechanistically, mDF6006 led to greater and more sustained IFNγ production than recombinant IL-12 without inducing high, toxic peak serum concentrations of IFNγ. We showed that mDF6006's expanded therapeutic window allowed for potent anti-tumor activity as single agent against large immune checkpoint blockade-resistant tumors. Furthermore, the favorable benefit-risk profile of mDF6006 enabled effective combination with PD-1 blockade. Fully human DF6002, similarly, demonstrated an extended half-life and a protracted IFNγ profile in non-human primates. An optimized IL-12-Fc fusion protein increased the therapeutic window of IL-12, enhancing anti-tumor activity without concomitantly increasing toxicity. This research was funded by Dragonfly Therapeutics.

Correlation Betveen Erythromycin- Resistance Phenotypes ofStreptoco cc us Pne unrc nifi e ancl the Invitro Activitl' of Telith romycineand Azithrornycine

Tow principal mechanisms have so far been found to be responsible for acquired macrolide ,lincosamide and streptogramin B (MLSB) antibiotics resistance in Streptococcus pneumoniae : target site modification and active drug efflux .the target site modification is due to methylase prevents the binding of the antibiotic to its ribosomal target and can be expressed either in a constitutive (cMLS phenotype) or inducible (iMLS phenotype ) manner .the macrolide efflux system,M phenotype ,is mediated by a membrane protein responsible for the efflux resistance. Although the incidence of resistance to macrolides was low in the past today the incidence reported by several countries shows a sensible increase. Thus it is necessary to search and test novel antimicrobial agents characterized by a spectrum of activity against the most common respiratory pathogens. This study compared the invitro activity (MIC and MBC) of telithromycin with activity of azithromycin against Streptococcus pneumoniae recently isolated from San Giovanni Battista Hospital (Turin, Italy). Erythromycin — resistance phenotypes were determined through a triple — disk test to correlate a potential different bacterial pattern to antimicrobial s sceptibility. The incidence of erythromycin-resistance was 26.66% .In the group of Ery-R Streptococcus pneumoniae 58.33% strains belonged to ¢MLS phenotype, 33.33% to M phenotype and 8.33% to iMLS phenotype. Telithromycin presented MIC values lower than those detected with azithromycin against all isolated strains . Telithromycin appeared to be highly active against Streptococcus pneumoniae, in particular when resistance is mediated by the efflux system confirming its clinical efficacy among respiratory streptococcal infections.

Therapeutic targeting of PRAME with mTCRCAR T cells in acute myeloid leukemia.

Preferentially Expressed Antigen in Melanoma (PRAME), a cancer-testis antigen, provides an ideal target for immunotherapy in acute myeloid leukemia (AML). We have shown expression of PRAME in a significant subset of childhood and adult AML and lack of expression in normal hematopoiesis. Although an intracellular antigen, we developed a novel approach to target PRAME using a chimeric antigen receptor (CAR) construct encoding a targeting domain based on T-cell receptor (TCR) mimic antibodies that target the peptide-HLA complex. We used the antibody sequence from a previously designed TCR mimic (mTCR) antibody, Pr20, that recognizes the PRAME ALY peptide in complex with HLA-A∗02 and verified expression of PRAME in AML cell lines and primary AML blasts. Using the Pr20 antibody sequence, we developed CAR T cells (PRAME mTCRCAR T) to be tested against primary samples from patients with AML and AML cell lines that express the PRAME antigen in the context of HLA-A2 expression. In contrast to appropriate controls, PRAME mTCRCAR T cells demonstrate target-specific and HLA-mediated invitro activity in OCI-AML2 and THP-1 cell lines, HLA-A2 cell lines expressing the PRAME antigen, and against primary AML patient samples. Invivo cell-derived xenograft models treated with PRAME mTCRCAR T cells demonstrated potent leukemia clearance and improved survival compared with unmodified T-cell controls. Furthermore, the cytolytic activity of PRAME mTCRCAR T cells was enhanced by treating the target cells with interferon gamma, which increases PRAME antigen expression. These results demonstrate the feasibility and efficacy of targeting PRAME with novel PRAME mTCRCAR T cells.

In-Vitro Anti-inflammatory Activity of Traditionally reported Poly Herbal Combination

Inflammatory diseases are still one of the most important heath-problems in the world. Most of anti-inflammatory drugs such as non–steroidal anti-inflammatory drugs (NSAIDS) have number of adverse effects hence there are a need to develop safe and new anti-inflammatory formulation with minimum side effects. Present study focused on investigating and comparing anti-inflammatory potential of hydroalcoholic extracts of Tinospora cordifolia, Boerhavia diffusa, Tribulus terrestris and their combinations. Inhibition of heat induced HRBC membrane lysis was taken as a measure of the anti-inflammatory activity. The combination ratio of hydroalcoholic extracts of Tinospora cordifolia, Boerhavia diffusa, Tribulus terrestris (2:5:3) showed the most significant membrane stabilizing action on HRBC membrane as compare tohydroalcoholic extracts of individual drugs and theirother combinations. The present study revealed that the proper combination of Tinospora cordifolia, Boerhavia diffusa, Tribulus terrestris gives more effective anti-inflammatory activity than any of the individual drug.

Generation of a humanized afucosylated BAFF-R antibody withbroad activity against human B-cell malignancies.

B-cell activating factor receptor (BAFF-R) is a mature B-cell survival receptor, which is highly expressed in a wide variety of B-cell malignancies but with minimal expression in immature B cells. These properties make BAFF-R an attractive target for therapy of B-cell lymphomas. We generated a novel humanized anti BAFF-R monoclonal antibody (mAb) with high specificity and potent invitro and invivo activity against B-cell lymphomas and leukemias. The humanized variants of an original chimeric BAFF-R mAb retained BAFF-R binding affinity and antibody-dependent cellular cytotoxicity (ADCC) against a panel of human cell lines and primary lymphoma samples. Furthermore, 1 humanized BAFF-R mAb clone and its afucosylated version, glycoengineered to optimize the primary mechanism of action, prolonged survival of immunodeficient mice bearing human tumor cell lines or patient-derived lymphoma xenografts in 3 separate models, compared with controls. Finally, the tissue specificity of this humanized mAb was confirmed against a broad panel of normal human tissues. Taken together, we have identified a robust lead-candidate BAFF-R mAb for clinical development.

Synthesis, QSAR study and Pharmacological Evaluation of Novel Triazolidine-2-thione Analogues as Antimicrobial, Anti-inflammatory and Antioxidant agents.

The triazole analogues are molecules of immense attraction because of their wide pharmacological applications. Present research deals with the synthesis of triazole-2-thione analogues and their QSAR study. The synthesized analogs are also evaluated for their antimicrobial, anti-inflammatory, and antioxidant effect. It was revealed that the benzamide analogues (3a, 3d) and triazolidine analogue (4b) were found to be most active against P. aeruginosa and E. coli with pMIC values of 1.69, 1.69 and 1.72, respectively. The antioxidant study of the derivatives showed that 4b was the most active antioxidant with 79% protein denaturation inhibition. The highest anti-inflammatory activity was shown by 3f, 4a and 4f. This study provides certain potent leads for further development of more potential anti-inflammatory, antioxidant and antimicrobial agents.