Population Pharmacokinetic Analysis of Centrally Acting Drugs Metabolized by CYP2D6

A simple, sensitive, and reliable UPLC method has been developed and validated for simultaneous determination of risperidone, 9-hydroxyrisperidone and olanzapine in human plasma in vitro. • The developed method has been successfully adopted to evaluate the pharmacokinetic parameters of second generation antipsychotic drugs, risperidone and its major metabolite, 9-hydroxyrisperidone, in human plasma. • The distributions of normal, intermediate and poor metabolizers were found to be 70%, 25% and 5% respectively. The allelic frequencies of all SNP were in Hardy-Weinberg equilibrium (P ≥ 0.05). • The metabolic ratio was higher in intermediate metabolizers (2.04 ± 0.20) as compared to normal metabolizers (1.40 ± 0.22). • The pharmacokinetic parameters (Cmax, AUC0-t, T1/2 and CL) of active moiety were found to be significant in normal and intermediate metabolizers. • Poor metabolizers exhibited a higher prevalence of CNS (P = 0.001), CVS (P < 0.001), dizziness (P = 0.005), hypotension (P = 0.01) and GIT (P = 0.01) as compared to normal metabolizers. • Our data supports these above conclusions in our sample population, i.e., poor metabolizers require half the risperidone dose than that for normal metabolizers to reduce the incidence of adverse effects. CONCLUSION: In the current study, we have demonstrated significant association between the genotype status and pharmacokinetic parameter of normal subjects from our locale in South India with respect to the CYP2D6*10 genotype. Our data suggest that CYP2D6*10 polymorphism have significant association between risperidone and 9-hydroxyrisperidone pharmacokinetics. Active moiety is highly predictive of the clinical response to risperidone in healthy volunteers, which is dependent on the CYP2D6*10 genotype status. Additionally, we demonstrated that using NONMEM and multi-compartment mixed effect modelling of the population pharmacokinetics of risperidone and its metabolite, genotype has a major influence on determining the plasma concentrations of both risperidone and 9- hydroxyrisperidone. The pharmacogenetic variations in clearance of the risperidone and 9-hydroxyrisperidone may be due to differential expressions of CYP2D6 in intestinal epithelium in different genotypes of CYP2D6*10 allele. Further, this could be applied to clinical decision making such as determination of dosing intervals. We recommend that the dose of risperidone in slow metabolizers must be less that used in normal metabolizers, though it has to be confirmed in further studies in our population

Unusual Behavior in Children-Foreign Object in Tooth: A Report of Two Cases

Background: The chance of discovering foreign object in a root canal is more commonly seen in children. Foreign objects may act as a potential source of infection, which may hinder the complete debridement of root canal. Although the main etiology being an accidental insertion, there are other possibilities such as self-injurious habits which should be ruled out.Case Details: The present article describes two case of foreign object in root canal, their possible etiology and management modalities. The first case reports a usual case of staple pin in root canal of primary teeth. The second case was a broken pin inside anterior permanent teeth. The cases reported highlight the need for proper diagnosis and early management.Conclusion: This case report highlights the need for proper understanding of the etiology in management of foreign body in root canal system.Keywords: Foreign object, Self-Embedding habit, Stapler pi

Delay Comparison for 16x16 Vedic Multiplier Using RCA and CLA

In any integrated chip compulsory adders are required because first they are fast and second are the less power consumption and delay. And at the same time multiplication process is also used in various applications. So as the speed of multiplier increases then the speed of processor also increases. And hence we are proposing the Vedic multiplier using these adders. Vedic multiplier is an ancient mathematics which uses mainly 16 sutras for its operation. In this project we are using “urdhva triyagbhyam” sutra to do our process. This paper proposes the Vedic multiplier using the adders ripple carry adder(RCA) and carry look ahead adder(CLA) and puts forward that CLA is better than RCA.The major parameters we are simulating here are number of slices and delay. The code is written by using Verilog and is implemented using Xilinx ISE Design Suite

Multi-objective optimization in single-row layout design using a genetic algorithm

This paper presents the development of a genetic algorithm for determining a common linear machine sequence for multi-products with different operation sequences and facilities with a limited number of duplicate machine types available for a job. This work aims to minimize the total flow distance travelled by products, reduce the number of machines arranged in the final linear sequence, and decrease the total investment cost of the machines used in the final sequence. We assume that product flow runs only in the forward direction, either via in-sequence or bypass movement. We demonstrate the effectiveness of the proposed algorithm by solving a typical layout design problem taken from literature, and several randomly generated problems. Results indicate that the proposed algorithm serves as a practical decision support tool for resolving layout problems in manufacturing facilities

A Novel Three Phase Multilevel Inverter with Single Dc Link For Induction Motor Drive Applications

All industrial drives need a controlled output and it can be achieved by controlling the input supply. In this regard, the inverter circuit plays an important role in the applications of industrial drives. The industrial drives are operated at high rated power and the conventional inverters cannot be applicable for high power demands because of the large dV/dt (rate of change of voltage) and more switching losses. Therefore, multilevel inverters are introduced for high power-medium voltage applications. For all AC drives the MLIs are reliable in operation. This MLI topology also reduces the harmonics and bearings stress of a motor with low dV/dt. In most applications multilevel inverters are used because we can get more number of voltage levels. To increase the number of voltage levels, circuit needs to have more switches. But, we have to optimize the switch count and switching operations. The power level of the inverter is limited due to high currents and stress. In this paper, we proposed a new circuit topology which enables the switches to be active at different voltage levels, causes reduction of the switching losses and also increases the efficiency of the inverter. In this we have presented two configurations for an eleven level MLI for three phase induction motor drive application. In this an individual DC source is connected for each bridge circuit of each phase in one configuration and only one common DC link is used for three phases in another configuration. With this the size, cost and complexity could be decreased. In both the configurations the controlled output of the inverter is connected to the induction motor drive. The circuits are modeled using Matlab/simulink software and corresponding output waveforms are analyzed for both configurations

Rapid and Efficient Arsenic Removal by Iron Electrocoagulation Enabled with in Situ Generation of Hydrogen Peroxide.

Millions of people are exposed to toxic levels of dissolved arsenic in groundwater used for drinking. Iron electrocoagulation (FeEC) has been demonstrated as an effective technology to remove arsenic at an affordable price. However, FeEC requires long operating times (∼hours) to remove dissolved arsenic due to inherent kinetics limitations. Air cathode Assisted Iron Electrocoagulation (ACAIE) overcomes this limitation by cathodically generating H2O2 in situ. In ACAIE operation, rapid oxidation of Fe(II) and complete oxidation and removal of As(III) are achieved. We compare FeEC and ACAIE for removing As(III) from an initial concentration of 1464 μg/L, aiming for a final concentration of less than 4 μg/L. We demonstrate that at short electrolysis times (0.5 min), i.e., high charge dosage rates (1200 C/L/min), ACAIE consistently outperformed FeEC in bringing arsenic levels to less than WHO-MCL of 10 μg/L. Using XRD and XAS data, we conclusively show that poor arsenic removal in FeEC arises from incomplete As(III) oxidation, ineffective Fe(II) oxidation and the formation of Fe(II-III) (hydr)oxides at short electrolysis times (&lt;20 min). Finally, we report successful ACAIE performance (retention time 19 s) in removing dissolved arsenic from contaminated groundwater in rural California

Evaluation Changes of Lungs in Asthmatic Rats Treated with Aqueous and Non Aqueous Extract of Clerodendrum Serratum and Theophylline.

The present study Asthma is one of the common disorders encountered in clinical medicine in both adults and children are asthma and it is characterized by inflammation of the airways which causes airway dysfunction. Asthma is currently a worldwide problem with around 300 million people around the global suffering from it and world deaths of about 25000 annually. Inhaled bronchodilators and anti inflammatory drugs are available and effective and they require long term use and are associated with side effects. This is why alternative and complementary medicine is being sort after to prevent these side effects. Several medicinal plants have anti inflammatory effect and have proved effective in the treatment of asthma. Clerodendrum serratum Linn (Family-Verbenaceae) is very widely distributed in tropical and subtropical regions of the world. Citric acid, Acetylcholine, Histamine is mainly used for evaluating anti asthmatic activity of particular drug. This review contains list of medicinal plant which have been tested for anti asthmatic activity in the Citric acid, Acetylcholine induced asthmatic in Rat model Thus, the information provided in this research will help the researchers for the development of an alternative methods rather than inhalers and oral anti asthmatic drugs for the treatment of asthma and COPD which will minimize the complication. Many plants obtained from the natural source play a significant role in the health care system. Literature survey on herbal drugs has shown significant anti asthmatic activity which has not shown any remarkable side effect. The pharmacological mechanism which the phyto constituents producing the anti asthmatic activity are not clearly understood till date. The several herbal formulation have derived from the Ayurveda, traditional system of Indian medicine and its additional system of medicine, yet to be scientifically validated that they have exhibited pharmacological action against Asthmatic. Only less number of scientific data of traditional medicines is available for the treatment of Asthmatic. CONCLUSION: On the basis of the result in these experiments, this may be stated that the aqueous extract of Clerodendrum serratum 200mg/kg has a beneficial effect in asthmatic patients. It will reduce the alveolar thickness and Eosinophils counts in blood further studies are required to purify the active principle and to study the molecular mechanism of the exact pathway. Non aqueous extract of Clerodendrum serratum (400mg/kg) having fewer amounts of steroids and flavonoids because it will filter the all compounds and reduce the quantity of chemical moieties. But aqueous extract of Clerodendrum serratum (200mg/kg) having higher amount of chemicals when compare to Non aqueous extract of Clerodendrum serratum (400mg/kg) so it will produce anti asthmatic at equal to standard drug. In lungs alveolar thickness reduced by the AECS 200mg/kg as equal to standard drug and also it’s same as normal lungs. So aqueous extract of Clerodendrum serratum having good beneficial effect for the asthmatic patients. This information’s will be useful for the development of alternative method rather than anti asthmatic agents (Inhalers, Tablets, Injections, Nasal sprays, Respules) for the treatment of Asthmatic patients. This will minimize the wheezing and or asthmatic symptoms