Investigations of Limeum Indicum Plant for Diabetes Mellitus and Alzheimer's Disease Dual Therapy: Phytochemical, GC-MS Chemical Profiling, Enzyme Inhibition, Molecular Docking and In-Vivo Studies.

Limeum indicum has been widely utilized in traditional medicine but no experimental work has been done on this herb. The primary objective of this study was to conduct a phytochemical analysis and assess the multifunctional capabilities of aforementioned plant in dual therapy for Alzheimer's disease (AD) and Type 2 diabetes (T2D). The phytochemical screening of ethanol, methanol extract, and their derived fractions of Limeum indicum was conducted using GC-MS, HPLC, UV-analysis and FTIR. The antioxidant capacity was evaluated by DPPH method. The inhibitory potential of the extracts/fractions against α-, ß-glucosidase acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and monoaminine oxidases (MAO-A & B) was evaluated. Results revealed that acetonitrile fraction has highest inhibitory potential against α-glucosidase (IC50=68.47±0.05 µg/mL), methanol extract against ß-glucosidase (IC50=91.12±0.07 µg/mL), ethyl acetate fraction against AChE (IC50=59.0±0.02 µg/mL), ethanol extract against BChE (28.41±0.01 µg/mL), n-hexane fraction against MAO-A (IC50=150.5±0.31 µg/mL) and methanol extract for MAO-B (IC50=75.95±0.13 µg/mL). The docking analysis of extracts\fractions suggested the best binding scores within the active pocket of the respective enzymes. During the in-vivo investigation, ethanol extract produced hypoglycemic effect (134.52±2.79 and 119.38±1.40 mg/dl) after 21 days treatment at dose level of 250 and 500 mg/Kg. Histopathological findings further supported the in-vivo studies.

Phytochemical analysis, in vitro and in silico effects from Alstonia boonei De Wild stem bark on selected digestive enzymes and adipogenesis in 3T3-L1 preadipocytes.

BACKGROUND: Obesity is a global health issue arising from the unhealthy accumulation of fat. Medicinal plants such as Alstonia boonei stem bark has been reported to possess body weight reducing effect in obese rats. Thus, this study sought to investigate the in vitro and in silico effects of fractions from Alstonia boonei stem bark on selected obesity-related digestive enzymes and adipogenesis in 3T3-L1 preadipocytes. METHOD: Two fractions were prepared from A. boonei: crude alkaloid fraction (CAF) and crude saponin fraction (CSF), and their phytochemical compounds were profiled using Liquid chromatography with tandem mass spectrometry (LCMS/MS). The fractions were assayed for inhibitory activity against lipase, α-amylase and α-glucosidase, likewise their antiadipogenic effect in 3T3-L1 adipocytes. The binding properties with the 3 enzymes were also assessed using in silico tools. RESULTS: Eleven alkaloids and six saponin phytochemical compounds were identified in the CAF and CSF using LCMS/MS. The CAF and CSF revealed good inhibitory activity against pancreatic lipase enzyme, but weak and good activity against amylase respectively while only CSF had inhibitory activity against α-glucosidase. Both fractions showed antiadipogenic effect in the clearance of adipocytes and reduction of lipid content in 3T3-L1 adipocytes. The LCMS/MS identified compounds (41) from both fractions demonstrated good binding properties with the 3 enzymes, with at least the top ten compounds having higher binding energies than the reference inhibitors (acarbose and orlistat). The best two docked compounds to the three enzymes were firmly anchored in the substrate binding pockets of the enzymes. In a similar binding pattern as the reference acarbose, Estradiol-17-phenylpropionate (-11.0 kcal/mol) and 3α-O-trans-Feruloyl-2 α -hydroxy-12-ursen-28-oic acid (-10.0 kcal/mol) interacted with Asp197 a catalytic nucleophile of pancreatic amylase. Estradiol-17-phenylpropionate (-10.8 kcal/mol) and 10-Hydroxyyohimbine (-10.4 kcal/mol) interacted with the catalytic triad (Ser152-Asp176-His263) of pancreatic lipase while Estradiol-17-phenylpropionate (-10.1 kcal/mol) and 10-Hydroxyyohimbine (-9.9 kcal/mol) interacted with Asp616 and Asp518 the acid/base and nucleophilic residues of modelled α-glucosidase. CONCLUSION: The antiobesity effect of A. boonei was displayed by both the alkaloid and saponin fractions of the plant via inhibition of pancreatic lipase and adipogenesis.

Anticandidal activity of green synthesised silver nanoparticles and extract loaded chitosan nanoparticles of Euphorbia prostata.

This study aimed to synthesize the silver nanoparticles (SNPs) and loaded chitosan nanoparticles (LCNPs) using Euphorbia prostata based on their anticandidal activity. Antioxidant capacity and the total phenolic and total flavonoid content of plant samples and synthesized nanoparticles (NPs) were also evaluated. SNPs and LCNPs were prepared, respectively using chemical reduction of silver salt solution and ionotropic gelation method. The anticandidal activity was assessed by broth micro-dilution method and the antioxidant activity was determined using free-radical scavenging assays. The synthesized NPs after the optimization process were found to be spherical with sizes ranging from 12 to 100 nm. Spectroscopic analysis of NPs showed the appearance of peaks in prescribed wavelength ranging between 402 and 493 nm. The synthesized NPs showed potent anticandidal activity compared to the free extract. The SNPs formulations NpEPM 7.5 and NpEPMR 7.5, showed significantly low MIC values ranging between 2 and 128 µg/mL. In the case of LCNPs, NpEPM (4:1) and NpEPME (4:1) also showed lower MIC values ranging from 32 to 256 µg/mL. The plant samples as well as NPs showed antioxidant potential. In addition, plant extracts and NPs possess the potent biological potential and can be further investigated through in vivo experiments.

Antimicrobial and α-glucosidase inhibitory activities of chemical constituents from Gardenia aqualla (Rubiaceae).

An aliphatic alkene namely pentapentacontene (4) was isolated for the first time from a natural source, Gardenia aqualla, along with fourteen other compounds including nonacosanol (1), tetratriacontanol (2), octatriacontanol (3), ß-sitosterol (5) and stigmasterol (6), daucosanol (7), ursolic acid (8), uvaol (9), 3ß,19α,23ß,24α-tetrahydroxyurs-12-en-28-oic acid (10), lupenone (11), oleanolic acid (12), vanillin (13), vanillic acid (14) and D-mannitol (15). α-glucosidase inhibitory assay revealed that MeOH and EtOAc extracts of leaves had the best activity with IC50 of 9.65 and 20.03 µg/ml respectively. All the tested compounds showed dose dependent inhibition of α-glucosidase and some of them were found to be comparable to acarbose. Compound 10 was the most potent with IC50 = 1.72 µM. It also showed the most interesting antibacterial activity, against the isolate strain of S. typhi and P. aeruginosa and also exhibited the most significant antifungal activities against all the tested yeasts.

Poncirin, an orally active flavonoid exerts antidiabetic complications and improves glucose uptake activating PI3K/Akt signaling pathway in insulin resistant C2C12 cells with anti-glycation capacities.

Poncirin, a natural flavanone glycoside present abundantly in many citrus fruits, contains an extensive range of biological activities. However, the antidiabetic mechanism of poncirin is unexplored yet. In this study, we examined the anti-diabetic prospective of poncirin by evaluating its ability to inhibit protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, human recombinant AR (HRAR), rat lens aldose reductase (RLAR), and advanced glycation end-product (AGE) formation (IC50 = 7.76 ± 0.21, 21.31 ± 1.26, 3.56 ± 0.33, 11.91 ± 0.21, and 3.23 ± 0.09 µM, respectively). Kinetics data and docking studies showed the lowest binding energy and highestaffinityforthemixed and competitivetypeof inhibitorsof poncirin. Moreover, the molecular mechanisms underlying the antidiabetic outcomes of poncirin in insulin resistant C2C12 skeletal muscle cells were explored, which significantly increased glucose uptake and decreased the expression of PTP1B in C2C12 cells. Consequently, poncirin increased GLUT-4 expression level by activating the IRS-1/PI3K/Akt/GSK-3 signaling pathway. Moreover, poncirin (0.5-50 µM) remarkably inhibited the formation of fluorescent AGE, nonfluorescent CML, fructosamine, and ß-cross amyloid structures in glucose-fructose-induced BSA glycation during 4 weeks of study. Poncirin also notably prevented protein oxidation demonstrated with decreasing the protein carbonyl and the consumption of protein thiol in the dose-dependent manner. The results clearly expressed the promising activity of poncirin for the therapy of diabetes and its related complications.

Hypnosis regulation in propofol anaesthesia employing super-twisting sliding mode control to compensate variability dynamics.

Regulation of hypnosis level on bi-spectral index monitor (BIS) during a surgical procedure in propofol anaesthesia administration is a challenging task for an anaesthesiologist in multi-tasking environment of the operation theater. Automation in anaesthesia has the potential to solve issues arising from manual administration. Automation in anaesthesia is based on developing the three-compartmental model including pharmacokinetics and pharmacodynamic of the silico patients. This study focuses on regulation of the hypnosis level in the presence of surgical stimulus including skin incision, surgical diathermy and laryngoscopy as well as inter-patient variability by designing super-twisting sliding mode control (STSMC). The depth of the hypnosis level is maintained to 50 on the BIS level in the maintenance phase after improving the induction phase to 60 s using the conventional sliding mode control and 30 s with STSMC. The proposed scheme also compensates the inter-patient variability dynamics including height, age and weight of the different silico patients. Moreover, the surgical stimuli direct the hypnosis level towards the state of consciousness and stimulate the controller to provide continuous drug infusion during the interval 80-90 s. Simulation results witness that the oscillatory behaviour is observed in drug infusion to ensure the moderate level of hypnosis (40-60) for general surgery.

Datura suaveolens and Verbena tenuisecta mediated silver nanoparticles, their photodynamic cytotoxic and antimicrobial evaluation.

Biogenic production of nanoparticles is eco-friendly, less expensive method with various medical and biological applications. Nanotechnology along with photodynamic therapy is gaining tremendous importance with enhanced efficacy. The present work was aimed to evaluate methanolic extracts and nanoparticles of two selected plants (Datura suavolens and Verbina tenuisecta) for cytotoxic photodynamic, antioxidant and antimicrobial study. Both extract and silver (5 mM) nanoparticles of Datura plant showed significant activities against bacterial strains. Maximum ZOI of 27.3 ± 1.6 mm was observed with nanoparticles of Datura branches with minimum inhibitory (MIC) value of 32 µg/ml. In case of antifungal and antioxidant assay samples were moderately active. Silver nanoparticles and extracts were effective against rhabdomyosarcoma cell line with lowest IC50 value of 42.5 ± 0.6 µg/ml and percent viability of 25.6 ± 1.3 of Verbena tenuisecta. However, nanoparticles of Datura leaves and branches were more potent with IC50 value of 2.4 ± 0.9 µg/ml and 7.8 ± 1.1 µg/ml respectively. The result of photodynamic study showed that efficacy of photosensitizer was enhanced and percent viability reduced when nanoparticles used as an adjunct. The color change and UV spectra (415‒425 nm) indicated the production of nanoparticles. Fourier transform infrared spectroscopy (FTIR) spectra showed presence of different functional groups e.g., hydroxyl, carbonyl and amino. Nanoparticles are sphenoid in morphology and size ranges between 20-150 nm. Current study showed these silver nanoparticles can be used as cytotoxic agent in photodynamic therapy and can play a critical role to establish medicinal potential of selected plants.

Eco-friendly green synthesis of silver nanoparticles and their potential applications as antioxidant and anticancer agents.

Eco-friendly green synthesis of nanoparticles using medicinal plants gained immense importance due to its potential therapeutic uses. In the current study, silver nanoparticles (AgNPs) were synthesized using water extract of Jurinea dolomiaea leaf and root at room temperature. MTT assay was used to study anticancer potential of AgNPs against cervical cancer cell line (HeLa), breast cancer cell lines (MCF-7), and mouse embryonic fibroblast (NIH-3 T3) cell line for toxicity evaluation. The antioxidant potential was evaluated using stable DPPH radicals. In addition, the apoptotic nuclear changes prompted by AgNPs in more susceptible HeLa cells were observed using fluorescence microscope through DAPI and PI staining. Physiochemical properties of biosynthesized AgNPs were characterized using various techniques. AgNPs were formed in very short time and UV-vis spectra showed characteristic absorption peak of AgNPs. SEM and TEM showed spherical shape of AgNPs and XRD revealed their crystalline nature. EDX analysis revealed high percentage of silver in green synthesized AgNPs. FTIR analysis indicated involvement of secondary metabolites in fabrication of AgNPs. In vitro cytotoxic and antioxidant study revealed that herb and biosynthesized AgNPs exhibited significant dose-dependent and time-dependent anticancer and antioxidant potential. Furthermore, study on normal cell line and microscopic analysis of apoptosis revealed that AgNPs exhibited good safety profile as compared to cisplatin and induces significant apoptosis effect. Based on the current findings, it is strongly believe that use of J. dolomiaea offers large scale production of biocompatible AgNPs that can be used as alternative anticancer agents against cancer cell lines tested.

Benzoxazinone-thiosemicarbazones as antidiabetic leads via aldose reductase inhibition: Synthesis, biological screening and molecular docking study.

Aldose reductase is an important enzyme in the polyol pathway, where glucose is converted to fructose, and sorbitol is released. Aldose reductase activity increases in diabetes as the glucose levels increase, resulting in increased sorbitol production. Sorbitol, being less cell permeable tends to accumulate in tissues such as eye lenses, peripheral nerves and glomerulus that are not insulin sensitive. This excessive build-up of sorbitol is responsible for diabetes associated complications such as retinopathy and neuropathy. In continuation of our interest to design and discover potent inhibitors of aldo-keto reductases (AKRs; aldehyde reductase ALR1 or AKR1A, and aldose reductase ALR2 or AKR1B), herein we designed and investigated a series of new benzoxazinone-thiosemicarbazones (3a-r) as ALR2 and ALR1 inhibitors. Most compounds exhibited excellent inhibitory activities with IC50 values in lower micro-molar range. Compounds 3b and 3l were found to be most active ALR2 inhibitors with IC50 values of 0.52 ±â€¯0.04 and 0.19 ±â€¯0.03 µM, respectively, both compounds were more effective inhibitors as compared to the standard ALR2 inhibitor (sorbinil, with IC50 value of 3.14 ±â€¯0.02 µM).

Antidiabetic activities of chloroform fraction of Anthocleista vogelii Planch root bark in rats with diet- and alloxan-induced obesity-diabetes.

ETHNOPHARMACOLOGICAL RELEVANCE: Anthocleista vogelii Planch is a medicinal plant traditionally used in West Africa for the management and treatment of diabetes mellitus. AIM OF THE STUDY: To determine the antidiabetic activities of chloroform fraction (CF) of Anthocleista vogelii Planch root bark in rats with diet- and alloxan-induced obesity-diabetes. MATERIALS AND METHODS: Inhibitory activities of CF against α-amylase and α-glucosidase activities were determined in vitro. Three weeks old rats were fed with high-fat diet for 9 weeks to induce obesity prior to further induction of diabetes using alloxan (150 mg/kg body weight, i.p.). Blood glucose levels and body weight were measured every 7 days throughout the experiment. Glucose tolerance was assessed in normal and CF-treated rats on day 21. Terminal blood samples were collected from sacrificed animals for the measurement of serum insulin levels. Pancreases were excised from treated and untreated animals for histopathological examination. RESULTS: LCMS/MS chromatographic profile of CF via positive and negative modes revealed 13 and 23 compounds respectively. Further analysis revealed quebrachitol (QCT), loganin, sweroside, oleoside 11-methyl ester and ferulic acid, which have been previously reported for their antidiabetic activities, as constituents of CF. CF inhibited activities of α-amylase (IC50 = 51.60 ±â€¯0.92 µg/ml) and α-glucosidase (IC50 = 5.86 ±â€¯0.97 µg/ml) in a dose-dependent manner. Treatment of animals with obesity-diabetes with 100 and 200 mg/kg CF significantly improved glucose tolerance (P < 0.001) and enhanced serum insulin levels (P < 0.05) compared to diabetic control rats. CONCLUSIONS: Antidiabetic activities of CF might be mediated via inhibition of α-amylase and α-glucosidase activities, elevation of serum insulin concentration, and enhancement of insulin and leptin sensitivity in obesity-diabetes rats. This study further substantiates the traditional use of A. vogelii in the management and treatment of diabetes in Africa and encourages further studies to investigate its mechanism of action.

Pluronic-Based Mixed Polymeric Micelles Enhance the Therapeutic Potential of Curcumin.

Curcumin is a naturally occurring constituent of turmeric that is a good substitute for synthetic medicines for the treatment of different diseases, due to its comparatively safer profile. However, there are certain shortcomings that limit its use as an ideal therapeutic agent. In order to overcome these drawbacks, we prepared novel curcumin-loaded mixed polymeric micelles using different biocompatible polymers by the thin-film hydration method. We investigated the critical micelle concentration and temperature, drug loading and encapsulation efficiency, and minimum inhibitory concentration by spectrophotometry. Surface morphology, stability, particle size, drug-polymer interaction, and physical state of the prepared formulations were investigated using scanning electron microscopy, zeta potential, particle size analyzer, Fourier-transform infrared spectroscopy, and X-ray diffraction, respectively. The drug loading and entrapment efficiency were significantly increased (P < 0.01) when curcumin was encapsulated with pluronic-based mixed polymeric micelles as compared to that of pluronic-based micelles alone. In vitro studies exhibited that pluronic-based mixed polymeric micelles significantly increased anticancer (P < 0.01), antimicrobial (P < 0.001), antioxidant (P < 0.001), and α-amylase inhibitory (P < 0.001) activities when compared to pure curcumin and/or pluronic-based micelles alone. These findings suggest that the formation of mixed polymeric micelles increases the stability and solubility of curcumin.

Identification of new potent inhibitor of aldose reductase from Ocimum basilicum.

Recent efforts to develop cure for chronic diabetic complications have led to the discovery of potent inhibitors against aldose reductase (AKR1B1, EC 1.1.1.21) whose role in diabetes is well-evident. In the present work, two new natural products were isolated from the ariel part of Ocimum basilicum; 7-(3-hydroxypropyl)-3-methyl-8-ß-O-d-glucoside-2H-chromen-2-one (1) and E-4-(6'-hydroxyhex-3'-en-1-yl)phenyl propionate (2) and confirmed their structures with different spectroscopic techniques including NMR spectroscopy etc. The isolated compounds (1, 2) were evaluated for in vitro inhibitory activity against aldose reductase (AKR1B1) and aldehyde reductase (AKR1A1). The natural product (1) showed better inhibitory activity for AKR1B1 with IC50 value of 2.095±0.77µM compare to standard sorbinil (IC50=3.14±0.02µM). Moreover, the compound (1) also showed multifolds higher activity (IC50=0.783±0.07µM) against AKR1A1 as compared to standard valproic acid (IC50=57.4±0.89µM). However, the natural product (2) showed slightly lower activity for AKR1B1 (IC50=4.324±1.25µM). Moreover, the molecular docking studies of the potent inhibitors were also performed to identify the putative binding modes within the active site of aldose/aldehyde reductases.

A multi-target therapeutic potential of Prunus domestica gum stabilized nanoparticles exhibited prospective anticancer, antibacterial, urease-inhibition, anti-inflammatory and analgesic properties.

BACKGROUND: Phytotherapeutics exhibit diverse pharmacological effects that are based on the combined action of a mixture of phytoconstituents. In this study, Prunus domestica gum-loaded, stabilized gold and silver nanoparticles (Au/Ag-NPs) were evaluated for their prospective anticancer, antibacterial, urease-inhibition, anti-inflammatory, and analgesic properties. METHODS: Au/Ag-NPs were biosynthesized and characterized with UV-Vis, FTIR, SEM, EDX, and XRD techniques. The effect of gum and metal ion concentration, reaction temperature, and time on the synthetic stability of nanoparticles was studied along with their post-synthetic stability against varying pH and salt concentrations, long-term storage and extremes of temperature. Nanoparticles were tested for anticancer (HeLa cervical cancer cells), antibacterial (Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa), urease inhibition (jack-bean urease), anti-inflammatory (carrageenan-induced paw edema), and antinociceptive (abdominal constriction response) activities. RESULTS: The nanoparticles were mostly spherical with an average particle size between 7 and 30 nm (Au-NPs) and 5-30 nm (Ag-NPs). Au/Ag-NPs maintained their colloidal stability and nanoscale characteristics against variations in physicochemical factors. Au/Ag-NPs have potent anticancer potential (IC50 = 2.14 ± 0.15 µg/mL and 3.45 ± 0.23 µg/mL). Au/Ag-NPs selectively suppressed the growth of S. aureus (10.5 ± 0.6 mm, 19.7 ± 0.4 mm), E. coli (10 ± 0.4 mm, 14.4 ± 0.7 mm), and P. aeruginosa (8.2 ± 0.3 mm, 13.1 ± 0.2 mm), as well as showed preferential inhibition against jack-bean urease (19.2 ± 0.86%, 21.5 ± 1.17%). At doses of 40 and 80 mg/kg, Au-NPs significantly ameliorated the increase in paw edema during the 1st h (P < 0.05, P < 0.01) and 2-5 h (P < 0.001) of carrageenan-induced inflammation compared to the 200 and 400 mg/kg doses of P. domestica gum (P < 0.05, P < 0.001). At similar doses, Au-NPs also significantly abolished (P < 0.01) the tonic visceral, chemically-induced nociception, which was comparable to that of P. domestica gum (200 mg/kg; P < 0.05, 400 mg/kg; P < 0.01).

Regulation of hypnosis in Propofol anesthesia administration based on non-linear control strategy / Controle da hipnose na administração de propofol com base na estratégia de controle não linear

Abstract Continuous adjustment of Propofol in manual delivery of anesthesia for conducting a surgical procedure overburdens the workload of an anesthetist who is working in a multi-tasking scenario. Going beyond manual administration and Target Controlled Infusion, closed-loop control of Propofol infusion has the potential to offer several benefits in terms of handling perturbations and reducing the effect of inter-patient variability. This paper proposes a closed-loop automated drug administration approach to control Depth Of Hypnosis in anesthesia. In contrast with most of the existing research on anesthesia control which makes use of linear control strategies or their improved variants, the novelty of the present research lies in applying robust control strategy i.e. Sliding Mode Control to accurately control drug infusion. Based on the derived patient's model, the designed controller uses measurements from EEG to regulate DOH on Bispectral Index by controlling infusion rate of Propofol. The performance of the controller is investigated and characterized with real dataset of 8 patients undergoing surgery. Results of this in silico study indicate that for all the patients, with 0% overshoot observed, the steady state error lies in between ±5. Clinically, this implies that in all the cases, without any overdose, the controller maintains the desired DOH level for smooth conduction of surgical procedures.

Resumo O ajuste contínuo de propofol na administração manual de anestesia para um procedimento cirúrgico onera a carga de trabalho de anestesistas que trabalham em ambiente multitarefa. Indo além da administração manual e da infusão alvo-controlada (IAC), o controle de circuito fechado da infusão de propofol tem o potencial de oferecer vários benefícios em termos de manejo das perturbações e reduzir o efeito da variabilidade interpaciente. Este artigo propõe uma abordagem para a administração automatizada de drogas em circuito fechado para controlar a profundidade da hipnose (PDH) em anestesia. Em contraste com a maioria das pesquisas existentes sobre o controle da anestesia que usam estratégias de controle linear ou de suas variantes melhoradas, a novidade da presente pesquisa reside na aplicação de uma estratégia de controle consistente; isto é, o Controle por Modos Deslizantes (CMD) para controlar com precisão a infusão da droga. Com base no modelo derivado do paciente, o controlador projetado usa as medições do EEG para regular a PDH no Bispectral Index (BIS), controla a taxa de infusão de propofol. O desempenho do controlador é investigado e caracterizado com um conjunto de dados reais de oito pacientes submetidos à cirurgia. Os resultados deste estudo in silico indicam que, para todos os pacientes, com 0% de excesso observado, o erro de estado estacionário fica entre ± 5. Clinicamente, isso implica que em todos os casos, sem qualquer sobredosagem, o controlador mantém o nível desejado de PDH para a condução tranquila dos procedimentos cirúrgicos.

Regulation of hypnosis in Propofol anesthesia administration based on non-linear control strategy.

Continuous adjustment of Propofol in manual delivery of anesthesia for conducting a surgical procedure overburdens the workload of an anesthetist who is working in a multi-tasking scenario. Going beyond manual administration and Target Controlled Infusion, closed-loop control of Propofol infusion has the potential to offer several benefits in terms of handling perturbations and reducing the effect of inter-patient variability. This paper proposes a closed-loop automated drug administration approach to control Depth Of Hypnosis in anesthesia. In contrast with most of the existing research on anesthesia control which makes use of linear control strategies or their improved variants, the novelty of the present research lies in applying robust control strategy i.e. Sliding Mode Control to accurately control drug infusion. Based on the derived patient's model, the designed controller uses measurements from EEG to regulate DOH on Bispectral Index by controlling infusion rate of Propofol. The performance of the controller is investigated and characterized with real dataset of 8 patients undergoing surgery. Results of this in silico study indicate that for all the patients, with 0% overshoot observed, the steady state error lies in between ±5. Clinically, this implies that in all the cases, without any overdose, the controller maintains the desired DOH level for smooth conduction of surgical procedures.

[Regulation of hypnosis in Propofol anesthesia administration based on non-linear control strategy]. / Controle da hipnose na administração de propofol com base na estratégia de controle não linear.

Continuous adjustment of Propofol in manual delivery of anesthesia for conducting a surgical procedure overburdens the workload of an anesthetist who is working in a multi-tasking scenario. Going beyond manual administration and Target Controlled Infusion, closed-loop control of Propofol infusion has the potential to offer several benefits in terms of handling perturbations and reducing the effect of inter-patient variability. This paper proposes a closed-loop automated drug administration approach to control Depth Of Hypnosis in anesthesia. In contrast with most of the existing research on anesthesia control which makes use of linear control strategies or their improved variants, the novelty of the present research lies in applying robust control strategy i.e. Sliding Mode Control to accurately control drug infusion. Based on the derived patient's model, the designed controller uses measurements from EEG to regulate DOH on Bispectral Index by controlling infusion rate of Propofol. The performance of the controller is investigated and characterized with real dataset of 8 patients undergoing surgery. Results of this in silico study indicate that for all the patients, with 0% overshoot observed, the steady state error lies in between ±5. Clinically, this implies that in all the cases, without any overdose, the controller maintains the desired DOH level for smooth conduction of surgical procedures.

Isonicotinohydrazones as inhibitors of alkaline phosphatase and ecto-5'-nucleotidase.

A series of isonicotinohydrazide derivatives was synthesized and tested against recombinant human and rat ecto-5'-nucleotidases (h-e5'NT and r-e5'NT) and alkaline phosphatase isozymes including both bovine tissue-non-specific alkaline phosphatase (b-TNAP) and tissue-specific calf intestinal alkaline phosphatase (c-IAP). These enzymes are implicated in vascular calcifications, hypophosphatasia, solid tumors, and cancers, such as colon, lung, breast, pancreas, and ovary. All tested compounds were active against both enzymes. The most potent inhibitor of h-e5'NT was derivative (E)-N'-(1-(3-(4-fluorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)ethylidene)isonicotinohydrazide (3j), whereas derivative (E)-N'-(4-hydroxy-3-methoxybenzylidene)isonicotinohydrazide (3g) exhibited significant inhibitory activity against r-e5'NT. In addition, the derivative (E)-N'-(4'-chlorobenzylidene)isonicotinohydrazide (3a) was most potent inhibitor against calf intestinal alkaline phosphatase and the derivative (E)-N'-(4-hydroxy-3-methoxybenzylidene)isonicotinohydrazide (3g) was found to be most potent inhibitor of bovine tissue-non-specific alkaline phosphatase. Furthermore, putative binding modes of potent compounds against e5'NT (human and rat e5'NT) and AP (including b-TNAP and c-IAP) were determined computationally.

Synthesis, crystal structure and biological evaluation of some novel 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines.

Nitrogen-containing heterocycles are of particular interest and significant importance for the discovery of potent bioactive agents in pharmaceutical industry. The present study reports the synthesis of a library of new conjugated heterocycles including 3,6-disubstituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazoles (4a-g and 5a-e) and 3,6-disubstituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazines (6a-h), by cyclocondensation reaction of 4-amino-5-(pyridin-4-yl)-4H-1,2,4-triazole-3-thiol 3 with various substituted aromatic acids and phenacyl bromides, respectively. The structures of newly synthesized compounds were characterized by elemental analysis, IR, (1)H and (13)C NMR spectroscopy and in case of 4c by X-ray crystallographic analysis. Newly synthesized triazolothiadiazoles and thiadiazines were screened for acetyl- and butyryl-cholinesterases and alkaline phosphatase inhibition. Almost all of the compounds showed good to excellent activities against acetylcholinesterase more than the reference drugs. Compound 5d exhibited IC50 value 0.77 ± 0.08 µM against acetylcholinesterase and 4a showed IC50 9.57 ± 1.42 µM against butyrylcholinesterase. Among all the tested compounds, 4a also proved as excellent inhibitor of alkaline phosphatase with IC50 0.92 ± 0.03 µM. These heteroaromatic hybrid structures were also tested for their anticancer activity against lung carcinoma (H157) and kidney fibroblast (BHK-21) cell lines and leishmanias. Variable cell growth inhibitory activities were obtained and many compounds exhibit potent %inhibition.

Design, synthesis, molecular docking studies and in vitro screening of ethyl 4-(3-benzoylthioureido) benzoates as urease inhibitors.

Thioureas are exceptionally versatile building blocks towards the synthesis of wide variety of heterocyclic systems, which also possess extensive range of pharmacological activities. The substituted benzoic acids were converted into corresponding acid chlorides, these acid chlorides were then treated with potassium thiocyanate in acetone and then the reaction mixture was refluxed for 1-2h afford ethyl 4-(3-benzoylthioureido)benzoates thioureas in good yields. All the newly synthesized compounds were evaluated for their urease inhibitory activities and were found to be potent inhibitors of urease enzyme. Compounds 1f and 1g were identified as the most potent urease inhibitors (IC50 0.21 and 0.13 µM, respectively), and was 100-fold more potent than the standard inhibitors. Further molecular docking studies were carried out using the crystal structure of urease to find out the binding mode of the inhibitors with the enzyme.

A portable rehabilitation device for the Hand.

This paper presents the design of a direct driven under-actuated portable hand exoskeleton for rehabilitation. The design of the proposed Hand EXOskeleton SYStem (HEXOSYS) was driven by multi-objective optimisation strategy and inspiration from the human hand. The optimisation algorithm resulted in the choice of optimum link lengths of the device. The optimisation criteria are based on dexterity, isotropy and exertion of perpendicular forces on the finger digits. Furthermore, a series of experiments on the human hand using appropriate sensory instrumentation guided the selection of actuators thereby resulting in a rehabilitation device which is compatible with the human hand force capabilities. The provision of force as well as position feedback gives quantitative feedback to the therapist and would imply a more efficient rehabilitation process. The first prototype of the device has been designed and realized.