The dose regimen of a drug gives important information about the dose sizes, dose frequency and the duration of treatment. Optimisation of dose regimens is critical to ensure therapeutic success of the drug and to minimise its possible adverse effects. The central theme of this thesis is the Efficient Dosing (ED) algorithm - a computation algorithm developed by us for optimisation of dose regimens. In this thesis, we have attempted to develop a quantitative framework for measuring the efficiency of a dose regimen for specified criteria and computing the most efficient dose regimen using the ED algorithm. The criteria considered by us seek to prevent over- and under-exposure to the drug. For example, one of the criteria is to maintain the drug's concentration around a desired target level. Another criterion is to maintain the concentration within a therapeutic range or window. The ED algorithm and its various extensions are programmed in MATLAB R . Some distinguishing features of our methods are: mathematical explicitness in the optimisation process for a general objective function, creation of a theoretical base to draw comparisons among competing dose regimens, adaptability to any drug for which the PK model is known, and other computational features. We develop the algorithm further to compute the optimal ratio of two partner drugs in a fixed dose combination unit and the efficient dose regimens. In clinical trials, the parameters of the PK model followed by the drug are often unknown. We develop a methodology to apply our algorithm in an adaptive setting which enables estimation of the parameters while optimising the dose regimens for the typical subject in each cohort. A potential application of the ED algorithm for individualisation of dose regimens is discussed. We also discuss an application for computation of efficient dose regimens for obliteration of a pre-specified viral load.

Earthworking activities have the potential to accelerate soil erosion through vegetation clearance and soil compaction processes. The eroded sediment can have many detrimental effects on receiving aquatic environments, and thus its discharge is controlled under the Resource Management Act, 1991. Two chemically dosed sediment retentions ponds at the SH20 extension project in Mount Roskill, Auckland were investigated, and the impact of the discharge of one of these ponds on a receiving waterbody was assessed using the Stream Ecological Valuation (SEV) method. Rainfall and suspended solid data was collected for a nine month period between November 2006 and August 2007, although sampling did not commence at one of the ponds until March 2007. Two SEV samples were undertaken within the receiving waterbody; one in November 2006 and the other in November 2007 to assess environmental changes resulting from the sediment retention pond discharge. The suspended solids results measured within the sediment retention ponds during this study were much lower than those reported by other studies on earthwork sites. This is believed to be due to the effective implementation of sediment and erosion control measures onsite. The Somerset Road pond was very effective at removing suspended solids throughout the sampling period, with the majority of suspended solid removal occurring in the forebay as it typically did not become full enough to overflow into the main pond. When the forebay was full of water, the PAC dosing system resulted in large reductions in suspended solid levels over a short horizontal distance within the forebay. A smaller amount of suspended solid reduction was achieved in the main pond, predominately through dilution, with the major function of the main pond being additional storage capacity for runoff. Discharge from the Somerset Road Pond was not continuous due to low water levels in the main pond. However, when discharge did occur, the suspended solids levels were very low compared with other studies investigating sediment retention pond discharge. The Richardson Road pond was less effective at removing suspended solids due to the flow regime within the forebay. There were two runoff channels entering the forebay, as well as a continual flow of groundwater. Only one of the runoff channels was directly dosed with PAC, and as the water level in the forebay was typically at, or just below, the level spreader at all times, there was a decreased potential for the PAC to become evenly distributed through the forebay and achieve dosing of all runoff. Furthermore, the main pond discharged continuously during the study period, resulting in reduced residence times of runoff within the pond system. Nonetheless, the discharge from the main pond was much lower than other studies, implying suspended solid reduction was being achieved. The SEV method indicated that the receiving environment was already degraded due to modifications to the riparian vegetation, increased dissolved oxygen demand, and moderate bank erosion. This was reflected in the macroinvertebrate population, with only pollution tolerant taxa being collected, thus limiting the use of macroinvertebrates as an assessment tool in this study. However, the SEV method, which assesses a wide range of ecological functions, implied that very little environmental change occurred as a result of the sediment retention pond discharge. A small increase in deposited sediment was observed on the stream bed, however indications are that deposited sediment is rapidly washed away once earthworks are completed. Thus this deposited sediment may not have a permanent impact within the receiving environment.

Warfarin is one of the most widely used anticoagulants in the world. Treatment is complicated by a large inter-individual variation in the dose needed to reach adequate levels of anticoagulation i.e. INR 2.0 – 3.0. The objective of this thesis was to evaluate which factors, mainly genetic but also non-genetic, that affect the response to warfarin in terms of required maintenance dose, efficacy and safety with special focus on warfarin dose prediction. Through candidate gene and genome-wide studies, we have shown that the genes CYP2C9 and VKORC1 are the major determinants of warfarin maintenance dose. By combining the SNPs CYP2C9 *2, CYP2C9 *3 and VKORC1 rs9923231 with the clinical factors age, height, weight, ethnicity, amiodarone and use of inducers (carbamazepine, phenytoin or rifampicin) into a prediction model (the IWPC model) we can explain 43 % to 51 % of the variation in warfarin maintenance dose. Patients requiring doses < 29 mg/week and doses ≥ 49 mg/week benefitted the most from pharmacogenetic dosing. Further, we have shown that the difference across ethnicities in percent variance explained by VKORC1 was largely accounted for by the allele frequency of rs9923231. Other novel genes affecting maintenance dose (NEDD4 and DDHD1), as well as the replicated CYP4F2 gene, have small effects on dose predictions and are not likely to be cost-effective, unless inexpensive genotyping is available. Three types of prediction models for warfarin dosing exist: maintenance dose models, loading dose models and dose revision models. The combination of these three models is currently being used in the warfarin treatment arm of the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) study. Other clinical trials aiming to prove the clinical validity and utility of pharmacogenetic dosing are also underway. The future of pharmacogenetic warfarin dosing relies on results from these ongoing studies, the availability of inexpensive genotyping and the cost-effectiveness of pharmacogenetic driven warfarin dosing compared with new oral anticoagulant drugs.

No description available.

Fine-powdered bulk materials exhibit high compressibility even under low pressure. The dosing error in volumetric dosing devices increases fundamentally with increasing product compressibility. In order to increase the dosing accuracy of a volumetric dosing of powdered bulk solids, the dosing process must be adapted to the product parameters. The most important parameter is the time-variable product density. With a pure volumetric dosage, it has a direct influence on the actually filled product quantity. Attempts are often made to obtain feedback by means of a scale in order to continuously adjust the volume. However, this is often associated with a delay. In this article, the approach is to measure the product mass flow directly by means of a microwave sensor and to regulate it to a predetermined mass flow. The experimental investigations were carried out with a screw dosing device FVS 3111. Two scenarios were tested: on the one hand, the integration of the sensor directly at the product delivery point, whereby the difference of the average value of the dosed quantity to the target weight could be improved with the sample product coffee; on the other, the sensor was integrated directly at the beginning of the screw and the remaining product flow was simulated. A reduction of the standard deviation compared with the conventional control could also be achieved, but here, the difference between the average of the dosed quantity and the nominal quantity is greater. The cause is presumed to be the too generalized assumption of product behaviour in the case of vertical conveying by means of a screw. In summary, the dosing accuracy of a screw dosing device could be increased by measuring and regulating the mass flow and thus the costs of a manufactured packaging could be reduced.

Electromagnetically driven dosing pumps are suitable for metering any kind of liquid in motor vehicles in a precise manner. Due to the working principle and the pump design, an undesired noise occurs when the armature reaches the mechanical end stops. The noise can be reduced by an adequate self-learning control of the supply energy using a position estimation and velocity control. Based on preliminary investigations /1/, a method for noise reduction is realised by using a user-friendly, tiny and cost-efficient hardware, which enables a use in series manufacturing. The method requires only a voltage and current measurement as input signals. The core of the hardware is an 8-bit microcontroller with 8 kilobytes flash memory including necessary peripherals. A smart software development enables an implementation of the entire noise reduction method onto the tiny flash memory.

Background: The effectiveness of inhaled salbutamol in routine care depends particularly on prescribed dosage and applied inhalation technique. To achieve maximum effectiveness and to prevent drug-related problems, prescription and administration need to work in concert. Methods: We performed a controlled intervention pilot study with 4 consecutive groups in a general paediatric unit and assessed problems in salbutamol prescribing and administration. Control group [i]: Routine care without additional support. First intervention group [ii]: We carried out a teaching session for nurses aimed at preventing problems in inhalation technique. Independently from this, a pharmacist counselled physicians on problems in salbutamol prescribing. Second intervention group [iii]: Additionally to the first intervention, physicians received standardised feedback on the inhalation technique. Follow-up group [iv]: Subsequently, without any delay after the second intervention group had been completed, sustainability of the measures was assessed. We performed the chi-square test to calculate the level of significance with p ≤ 0.05 to indicate a statistically significant difference for the primary outcome. As we performed multiple testing, an adjusted p ≤ 0.01 according to Bonferroni correction was considered as significant. Results: We included a total of 225 patients. By counselling the physicians, we reduced the number of patients with problems from 55% to 43% (control [i] vs. first intervention [ii], n.s.). With additional feedback to physicians, this number was further reduced to 25% ([i] vs. [iii], p < 0.001). In the follow-up [iv], the number rose again to 48% (p < 0.01 compared to feedback group). Conclusions: Teaching nurses, counselling physicians, and providing feedback on the quality of inhalation technique effectively reduced problems in salbutamol treatment. However, for success to be sustained, continuous support needs to be provided. Trial registration: German Clinical Trials register: DRKS00006792.

AR-67 is a lipophilic third generation camptothecin analogue, currently under early stage clinical trials. It acts by targeting Topoisomerase 1 (Top1), a nuclear enzyme essential for DNA replication and transcription and is present in two forms, the pharmacologically active lipophilic lactone and the charged carboxylate. In oncology patients participating in a phase I clinical trial, AR-67 lactone was the predominant species in plasma. Similarly to other camptothecins, the identified dose-limiting toxicities for AR-67 were neutropenia, thrombocytopenia and fatigue. In addition, in vitro metabolism studies indicated AR-67 lactone as a substrate for CYP3A4/5 as well as the UGT1A7 and UGT1A8 enzymes localizing in the liver and the gut. Numerous studies have demonstrated the over-expression of transporters in certain tumor types. Here, the effect of interactions between AR-67 and efflux or uptake transporters on the antitumor efficacy of AR-67 in vitro was studied. We showed that BCRP and MDR1 overexpression confers resistance to AR-67. Moreover, we demonstrated the therapeutic superiority of protracted dosing over more intense dosing regimens of AR-67 using xenografts models. Our studies indicated the schedule-dependent expression of Top1 and the preferential partitioning of AR-67 in the tumor tissue. We reason that these are factors that need to be taken into consideration when designing dosing schedules aiming to maximize efficacy. As most cytotoxic drugs, AR-67 has a narrow therapeutic window. Thus, it is essential to identify the variables influencing exposure to this camptothecin analogue. A thorough compartmental pharmacokinetic analysis was performed on the patient data obtained in a phase 1 clinical trial on AR-67. Moreover, sources of intersubject variability associated with obtaining pharmacokinetic parameter estimates were identified and a population covariate pharmacokinetic model was developed. In conclusion, the drug development of AR-67 is a work in process. Findings presented above provide an insight on the factors contributing to its efficacy and toxicity when given to cancer patients.

BACKGROUND: Parent medication errors are exceedingly common, with one child experiencing an outpatient medication error every 8 minutes. In a previous randomized controlled trial where the intervention was carried out under ideal conditions, we examined the efficacy of a pictographic, health literacy-informed medication instruction sheet-based intervention (HELPix) in reducing parent dosing errors. While our intervention was efficacious in reducing errors, reproducing these results in a real world setting, is necessary to examine the true effectiveness of HELPix. OBJECTIVES: 1) To examine the impact of HELPix implementation on parent medication dosing errors. 2) To assess the effect of HELPix implementation on provider use of medication counseling strategies. DESIGN/METHODS: A pre-implementation/post-implementation study design was used in 2 pediatric Emergency Departments (EDs) in New York City, one with planned implementation of the HELPix intervention (HELPix site) and the other a control site within the same hospital network. Subject inclusion criteria included: 1) English or Spanish-speaking parent, 2) child <9 years old, child prescribed a short course (≤14 days) daily liquid medicine, and 3) parent present with the child in the emergency department and received medication counseling. Parents were recruited over the phone; those who enrolled completed a phone interview along with a follow-up in-person assessment (median time to follow-up=15 days). ED providers (residents, fellows, attendings) were also recruited. The HELPix intervention consists of: 1) provider provision of patient- and medicine-specific pictographic instruction sheets, 2) provider use of pictures/drawings as part of counseling to reinforce dosing information, 3) provider demonstration of the dose using an oral syringe, 3) teachback of dose information, 4) parent showback of the dose they plan to give, and 5) provider provision of an oral syringe. At the HELPix site, ED providers were trained in the use of HELPix counseling strategies as well as how to use the electronic medical record (EMR) system to generate the instruction sheets while ordering a prescription. Outcomes assessed were: 1) provider provision of HELPix instruction sheets via web tracking, 2) dosing errors ≥ 20% deviation from prescribed dose, assessed from observation at follow-up visit, 3) provider counseling practices (i.e. use of pictures/drawings, demonstration, teachback, showback, provision of dosing tool) obtained by parent report. RESULTS: A total of 1493 parents were assessed by telephone for eligibility in the pre-/post-implementation phases. 561 parent-child dyads were recruited by phone (284 at HELPix site; 277 at control site). A total of 92% were mothers, 52% were Spanish speakers, 78% were Latino, 16% were Black, and 85% were of low socioeconomic status. Web tracking at the HELPix intervention site indicated that for 58% of the enrolled families in the post-implementation period, providers generated HELPix medication instruction sheets. Compared to the pre-implementation period at the intervention site, parent dosing errors rates were significantly reduced during the post-implementation period (37% versus 16%; AOR=0.3, p<0.001); with an overall Relative Risk Reduction (RRR)=57%, with greatest reductions in errors among those that received HELPix sheets (12% error rate, RRR=68%). Providers at the HELPix implementation site were significantly more likely to use recommended provider counseling strategies post-implementation compared to pre-implementation (pictures/drawings: 37% versus 1%; dosing demonstration: 59% versus 33%; teachback: 24% versus 8%; showback: 33% vs. 13%, and provision of oral syringe 79% versus 25%; p<0.0001 for all strategies). In the non-intervention site, there were no differences in parent dosing error rates, or in provider use of counseling strategies between the pre- and post-implementation periods. CONCLUSION: Implementation of the HELPix intervention resulted in increased provider use of recommended counseling strategies as well as decreased parent medication dosing errors in an urban public hospital setting serving low socioeconomic status families. Use of HELPix supports high quality provider medication counseling and appears to be feasible to incorporate as part of routine Emergency Department discharge practices.

An ideal drinking water distribution system (DWDS) must supply safe drinking water with free chlorine residual (FCR) in the form of HOCI and OCIֿ at a required concentration level. Meanwhile the FCR is consumed in the bulk liquid phase and at the DWDS pipes wall as the result of chemical reactions. Because of these, an optimized chlorine dosing for the DWDS using model-based predictive control (MBPC) is developed through the steps of modelling the FCR transport along the main pipes of the DWDS, designing chlorine dosing and implementing a multiple-input multiple-output system control scheme in Matlab 7.0.1 software. Discrete time-space models (DTSM) that can be used to predict free chlorine residual (FCR) concentration along the pipes of the DWDS over time is developed using explicit finite difference method (EFDM). Simulations of the DTSM using step and rectangular pulse input show that the effect of water flow rate velocity is much stronger than the effect of chlorine effective diffusivity coefficient on the FCR distribution and decay process in the DWDS main pipes. Therefore, the FCR axial diffusion in single pipes of the DWDS can be neglected. Investigating the effect of injection time, initial chlorine distribution, and overall chlorine decay rate constant involved in the process have provided a thorough understanding of chlorination and the effectiveness of all the parameters. This study proposed a model-based chlorine dosing design (MBCDD) based on a conventional-optimum design process (CODP) (Aurora, 2004), which is created for uncertain water demand based on the DTSM simulation. / In the MBCDD, the constraints must be met by designing distances between chlorine boosters and optimal value of the initial chlorine distribution in order to maintain the controlled variable (CV), i.e. FCR concentration with a certain degree of robustness to the variations of water flow rate. The MBCDD can cope with the simulated DWDS (SDWDS) with the conditions; the main pipe is 12 inch diameter size with the pipe length of 8.5 km, the first consumers taking the water from the point of 0.83 km, the assumed pipe wall chlorine decay rate constant of 0.45 m/day, and the value of chlorine overall decay rate constants follow Rosman's model (1994), by proposing a set of rules for selecting the locations for additional chlorine dosing boosters, and setting the optimal chlorine dosing concentrations for each booster in order to maintain a relatively even FCR distribution along the DWDS, which is robust against volumetric water supply velocity (VWS) variations. An example shows that by implementing this strategy, MBCDD can control the FCR along the 8.5 km main pipe of 12 inch diameter size with the VWS velocity from 0.2457 to 2.457 km/hr and with the assumed wall and bulk decay constants of 0.45 and 0.55 m/day, respectively. An adaptive chlorine dosing design (ACDD) as another CODP of chlorine dosing which has the same concept with the MBCDD without the rule of critical velocity is also proposed in this study. The ACDD objective is to obtain the optimum value of initial chlorine distribution for every single change in the VWS. Simulation of the ACDD on the SDWDS shows that the ACDD can maintain the FCR concentration within the required limit of 0.2-0.6 mg/1. / To enable water quality modelling for studying the effectiveness of chlorine dosing and injection in the form of mass flow rate of pure gaseous chlorine as manipulated variable (MV), a multiple-input multiple-output (MIMO) system is developed in Simulink for Matlab 7.0.1 software by considering the disturbances of temperature and circuiting flow. The MIMO system can be used to design booster locations and distribution along a main pipe of the DWDS, to monitor the FCR concentration at the point just before injection (mixing) and between two boosters, and to implement feedback and open-loop control. This study also proposed a decentralized model-based control (DMBC) based on the MBCDD-ACDD and centralized model predictive control (CMPC) in order to optimize MV to control the CV along the main pipe of the DWDS in the MIMO system from the FCR concentration at just after the chlorine injection (CVin) to the FCR concentration (CVo) before the next chlorine injection with the constraints of 0.2-0.6 ppm for both the CVin and CVo. A comparison of the performances of decentralized PI (DPI) control, DMBC and CMPC, shows that the performances of the DMBC and CMPC in controlling the MIMO system are almost the same, and they both are significantly better than the DPI control performance. In brief, model-based predictive control (MBPC), in this case a decentralized model-based control (DMBC) and a centralized predictive control (CMPC), enable optimization of chlorine dosing for the DWDS.