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Evaluation of drug-drug interaction (DDI) involving circulating inhibitory metabolites of perpetrator drugs has recently drawn more attention from regulatory agencies and pharmaceutical companies. Here, using amiodarone (AMIO) as an example, we demonstrate the use of physiologically based pharmacokinetic (PBPK) modeling to assess how a potential inhibitory metabolite can contribute to clinically significant DDIs. Amiodarone was reported to increase the exposure of simvastatin, dextromethorphan, and warfarin by 1.2- to 2-fold, which was not expected based on its weak inhibition observed in vitro. The major circulating metabolite, mono-desethyl-amiodarone (MDEA), was later identified to have a more potent inhibitory effect. Using a combined "bottom-up" and "top-down" approach, a PBPK model was built to successfully simulate the pharmacokinetic profile of AMIO and MDEA, particularly their accumulation in plasma and liver after a long-term treatment. The clinical AMIO DDIs were predicted using the verified PBPK model with incorporation of cytochrome P450 inhibition from both AMIO and MDEA. The closest prediction was obtained for CYP3A (simvastatin) DDI when the competitive inhibition from both AMIO and MDEA was considered, for CYP2D6 (dextromethorphan) DDI when the competitive inhibition from AMIO and the competitive plus time-dependent inhibition from MDEA were incorporated, and for CYP2C9 (warfarin) DDI when the competitive plus time-dependent inhibition from AMIO and the competitive inhibition from MDEA were considered. The PBPK model with the ability to simulate DDI by considering dynamic change and accumulation of inhibitor (parent and metabolite) concentration in plasma and liver provides advantages in understanding the possible mechanism of clinical DDIs involving inhibitory metabolites.
Recently, more attention has been drawn to the perpetrator drug's metabolites that may also contribute to cytochrome P450 (P450) inhibition (Isoherranen et al., 2009; Yeung et al., 2011; Callegari et al., 2013). In light of the Food and Drug Administration 2012 drug-drug interaction (DDI) draft guidance (http://wwwfdagov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm292362pdf), evaluation of the enzyme inhibition of metabolites which are present at 25% or more of the parent drug area under the curve (AUC) is recommended. Similarly, the European Medicines Agency 2010 DDI guidance (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf) recommends a 20% cutoff.
Scientists from 18 IQ (International Consortium Innovation & Quality in Pharmaceutical Development) member companies have formed a working group with one of the goals being to understand the contribution of inhibitory metabolites to P450-mediated DDIs by investigating 140 of the most frequently prescribed drugs. Detailed information for each drug and its reported metabolites, such as the exposure ([I]) and in vitro inhibition potency [Ki (inhibition constant) for reversible inhibitors or kinact/KI (maximum inactivation rate constant/inactivation rate constant) for time-dependent inhibitor] for both the parent drug and metabolite(s), and the magnitude of clinical DDIs, was collected through literature searches. Although the majority of DDIs can be traced back to the perpetrator drug itself, eight of 137 drugs were identified as having unexpected clinical DDIs based on the parent drug inhibition potency. Five of these eight drugs—namely, amiodarone, atorvastatin, bupropion, gemfibrozil, and sertraline—show evidence that the underpredicted DDI (based on [I]Ki) could be due to the omission of the contribution from the inhibitory metabolite(s).
Amiodarone (AMIO) is an effective class III antiarrhythmic agent. AMIO has documented clinical DDIs with comedications, including cyclosporine A, simvastatin, dextromethorphan, metoprolol, and warfarin. It was reported that multiple doses of AMIO (200–400 mg) increased the exposure of simvastatin by 1.7-fold, dextromethorphan by 1.3- to 2-fold, and warfarin by 1.2- to 2-fold (Heimark et al., 1992; Werner et al., 2004; Becquemont et al., 2007). These clinically observed DDIs were not expected based on in vitro competitive inhibition data from AMIO itself (Ki > 45 μM for all P450s, using the [I]Ki method) (Ohyama et al., 2000b). Several in vitro studies, however, indicated the possible inhibitory effect of an AMIO metabolite, mono-desethyl-amiodarone (MDEA) (Ohyama et al., 2000b; McDonald et al., 2012). Considering that MDEA is the major metabolite with plasma exposure in humans comparable to the parent (∼1–5 μM at steady state) after long-term treatment (Latini et al., 1984), it was hypothesized that inhibition of MDEA may play an important role in amiodarone DDIs with the comedications mentioned earlier.
To gain a mechanistic understanding of how inhibitory metabolites could contribute to the clinically observed AMIO DDIs, a physiologically based pharmacokinetic (PBPK) modeling approach was taken in the present study. The mechanistic PBPK models allow "what-if" scenario analysis that is particularly useful when the in vitro and in vivo experimental data for complex DDIs involving inhibitory metabolite are limited (Sager et al., 2014). Although many clinical pharmacokinetic (PK) studies for AMIO were reported during the 1980s (Kannan et al., 1982; Bonati et al., 1983; Holt et al., 1983), the conventional PK model has not been successful in describing the disposition kinetics of AMIO and its metabolite (Weiss, 1999). Highly variable PK parameters, such as the large volume of distribution (10–65 l/kg) (Latini et al., 1984) and long terminal half-life (16 hours to 58 days after single dose, >50 days following cessation of long-term treatment) (Latini et al., 1984; Marchiset et al., 1985), have been reported. Therefore, one of the main challenges in assessing the DDI caused by AMIO is to be able to model the PK profile of both AMIO and its metabolite, MDEA, with particular emphasis on the accumulation of AMIO and MDEA in plasma and the liver. It has been reported that both AMIO and MDEA have extensive tissue accumulation, especially after long-term therapy, and that the accumulated plasma concentration is several times higher than that predicted from single-dose PK data (Latini et al., 1984). By considering the dynamic change of inhibitor concentration and the accumulation of both parent and metabolite, PBPK modeling may help with understanding the disconnection between in vitro inhibition potency and in vivo clinical DDIs.
The objectives of the present work are 1) to build a PBPK model that can describe the PK profile of AMIO and MDEA, especially their accumulation in plasma and tissue; 2) to simulate the clinically observed DDIs of AMIO with CYP2C9, 2D6, and 3A substrates by considering the inhibition of AMIO alone or including the contribution from the inhibitory metabolite MDEA; and ultimately, 3) to contribute to the understanding of the involvement and impact of inhibitory metabolites for DDIs observed in the clinic.
Materials and Methods
Data Collection for AMIO and MDEA
The in silico and in vitro data used for AMIO and MDEA PBPK model development are shown in Table 1. The reported free fraction of AMIO in plasma is highly variable, ranging from 0.04 to 0.0002 (Lalloz et al., 1984; Veronese et al., 1988). The data generated in house using the RED device (Waters et al., 2008) at 5 μM show that both AMIO and MDEA are highly bound to plasma protein with fu,p < 0.001. The free fraction in liver microsome (fu,mic) measured in house was 0.04 and 0.188, as compared with calculations of 0.4 and 0.58 using the in silico method for AMIO and MDEA, respectively. The model-based sensitivity analysis was conducted to evaluate the effect of variable fu values on hepatic clearance prediction (see PBPK Model Development section). In vitro metabolic intrinsic clearance (CLint) of AMIO and MDEA was determined in human liver microsome incubations using an in-house assay (Halladay et al., 2007). The CLint was 28 µl/min per mg for AMIO and 4 µl/min per mg for MDEA incubated at 1 μM of substrate concentration. The enzyme kinetics of AMIO to form MDEA via CYP1A2, 2C8, 2C19, 2D6, and 3A4 were also reported (Ohyama et al., 2000a). Based on reported Km and Vmax and using scaling factor and P450 abundance data in the model, the contribution of each P450 to the formation of metabolite MDEA was estimated (Rowland Yeo et al., 2010). The data indicated that CYP3A4 and CYP2C8 are the major enzymes responsible for more than 80% (∼50% by CYP3A4 and ∼30% by 2C8) of the MDEA formation.
In vitro P450 inhibition data reported by Ohyama et al. (2000b) and generated in house are summarized in Table 2. In general, AMIO is a weak reversible inhibitor of CYP2C9, 2D6, and 3A with Ki values of 94.6, 45.1, and 271.6 μM, respectively. However, the metabolite MDEA is a more potent reversible inhibitor with Ki values of 2.3, 4.5, and 12.1 μM, respectively. In addition, MDEA was also reported as a time-dependent inhibitor (TDI) for CYP2D6, and AMIO was reported as a TDI for CYP2C9 and CYP3A4 with KI and kinact values listed in Table 2.
PBPK Model Development
A PBPK model was constructed for AMIO and its metabolite MDEA using a population-based absorption, distribution, metabolism, and excretion simulator (V12; Simcyp, Sheffield, UK). To better describe disposition kinetics of AMIO and MDEA, the model was first developed to be able to simulate the PK of AMIO and MDEA formation after intravenous administration of AMIO, from which best estimates of clearance (CL) and volume of distribution at steady state (Vss) were obtained. Then the model was expanded to include absorption to simulate the oral PK of AMIO and formation of MDEA after single and multiple doses. The verified PK model was then used for DDI prediction by considering the inhibitory effect of both AMIO and its metabolite MDEA.
Even though many clinical PK studies for AMIO were reported in the 1980s, very limited full concentration-time profile data, especially for metabolite MDEA, were available. Clinical PK data from various studies, even with very small sample sizes, were used in the model development (Canada and Lesko, 1980; Holt et al., 1983; Latini et al., 1984; Plomp et al., 1984) and verification (Andreasen et al., 1981; Staubli et al., 1985; McDonald et al., 2012). Detailed model input parameters with source information for clinical study are also listed in Table 1.
Model for AMIO and MDEA PK after Intravenous Administration.
A full PBPK distribution model was built for AMIO to best describe the multiexponential PK profile with long terminal half-life. The Vss of AMIO was predicted using a mechanistic tissue composition equation (Rodgers and Rowland, 2006) built in Simcyp, with input tissue:plasma partition coefficient (kp) estimated based on tissue distribution of AMIO in adipose, liver, lung, heart, and kidney observed in human subjects (Plomp et al., 1984). Kp values of all other organs for which no clinical accumulation data were reported are set as 1.
AMIO is cleared primarily through hepatic metabolism, less via biliary excretion, and negligibly in urine (Holt et al., 1983; Latini et al., 1984). The reported in vivo CL is variable, mostly ranging from 8 to 46 l/h, depending on the length of plasma sampling in the clinical study and PK model used (Riva et al., 1982; Latini et al., 1984). A higher value of CL was reported mostly from studies with a short sampling period and/or insufficient terminal data points used in PK modeling. The metabolic CL predicted from in vitro data using in vitro–in vivo extrapolation (IVIVE) with the well stirred model ranges 2.6∼9.3 l/h, depending on the plasma protein and microsomal binding data used, 0.0009–0.04 for free fraction (fu,p) and 0.04–0.4 for fu,mic, respectively. These values are on the lower end of the observed range. The CL of 9.3 l/h obtained from IVIVE, which is close to the lower end of reported values, was used in the initial model development. The final estimate of CL was determined to be the value that allows the model to best recover the observed PK profile in the simulations using predicted Vss. Since AMIO is primarily eliminated through metabolic pathways, and MDEA is the predominant metabolite, the model assumed ∼90% of AMIO metabolic CL going to the formation of metabolite MDEA, mainly by CYP3A4 (∼50%), followed by CYP2C8 (∼30%), and CYP1A2 and CYP2C19 (∼10%). The remaining ∼10% of AMIO metabolic CL was assigned to additional metabolism. The model inputs for each P450 as CLint back calculated using a Simcyp retrograde calculator are listed in Table 1.
The metabolite MDEA was modeled using a minimal-PBPK distribution model (Cao and Jusko, 2012). To more accurately describe the shape of the concentration-time profile of MDEA, the minimal-PBPK distribution model with the addition of a single adjusting compartment set in Simcyp was adapted. The Vss was predicted by inputting the Kp of MDEA in adipose, kidney, liver, lung, and heart estimated from clinical data (Plomp et al., 1984) into the mechanistic tissue composition equation (Rodgers and Rowland, 2006) built in Simcyp. The volume of distribution of compartment (Vsac) was estimated and optimized based on best fitting of the observed time-concentration profile of MDEA.
The formation of MDEA was driven by the metabolic clearance of AMIO described earlier. The CL of MDEA determined using IVIVE from in vitro human liver microsome data is ∼1 l/h, much lower than the rate of formation clearance from AMIO (≥8 l/h reported). Considering that the observed half-life for MDEA is similar to or slightly longer than that for AMIO (Holt et al., 1983; Latini et al., 1984), it can be assumed that the kinetics of MDEA are more formation rate–limited. Therefore, the value of CL at ∼8 l/h (close to the formation CL from AMIO) was used as the initial input in the MDEA model development. The final value for this unknown parameter was determined based on the simulation that can best recover the observed PK profile of MDEA (Table 1).
Model for AMIO and MDEA PK after Single and Multiple Oral Doses.
The AMIO-MDEA–linked PBPK model that can well capture the intravenous dose PK of AMIO and MDEA formation was then used to simulate PK of AMIO and MDEA after single and multiple oral doses (Jamei et al., 2009). The reported fraction and rate of absorption (fa and ka; Table 1) were used because the permeability data are not available for prediction due to low recovery in the Madin-Darby canine kidney assay conducted in house. The CL and Vss remained the same as determined based on the intravenous PK simulation. The ability of the model to recover the PK of AMIO and MDEA after oral dosing was verified by comparing the simulated data with the observed data.
Simulation of PK and DDI
The simulation was conducted using the developed model implemented in Simcyp (V12). The Sim-Healthy volunteer population with randomly selected individuals aged 20–50 years with a gender ratio of 1:1 was used for the PK and DDI simulation. The trial size used in the simulation was according to each clinical study detailed in the following sections.
Simulation of PK.
For the initial PK model development, a total of 10 trials of 6 subjects receiving a single intravenous infusion (10 minutes) of 400 mg of AMIO were simulated. The simulated PK profiles for AMIO and MDEA were compared with observed data from Holt et al. (1983). The model was then applied to simulate the PK of AMIO and MDEA formation following a single oral dose of 400 mg of AMIO with a trial size of 10 (trial) × 7 (subject) and 14 weeks' oral dosing of 350 mg of AMIO with a trial size of 10 × 3, respectively. Ten separate trials were generated in simulation to evaluate variability across different trial groups. The predictability of the model for oral dosing PK was verified by comparing the predicted PK profile with the observed data from Andreasen et al. (1981) and McDonald et al. (2012).
Simulation of DDI.
The DDIs between AMIO and substrates warfarin (CYP2C9), metoprolol (CYP2D6), and simvastatin (CYP3A4) were simulated using the established PK model with incorporation of in vitro inhibition IC50 of CYP1A2, 2D6, and 3A4 by AMIO and its metabolite MDEA (Table 2). The inhibition parameters, Ki and KI, were corrected for fu,mic. Models for warfarin, metoprolol, and simvastatin are available in Simcyp, and the default profiles for these substrates were used, except that the gut availability for simvastatin was changed from ∼0.12 to ∼0.4 by modifying input parameters fa and fraction of drug unbound in the gut (fu,gut) from 1 to 0.26 and 1 to 0.16, based on a recent update on simvastatin incorporated in the new version of software (V13).
The DDI simulations were conducted using the dose regimen described in the clinical DDI study reports (O'Reilly et al., 1987; Heimark et al., 1992; Werner et al., 2004; Becquemont et al., 2007). In brief, the interactions between AMIO [300 mg, every day (QD) for 13 days or 200 mg twice a day (BID) for 14 days] and warfarin (0.75 mg/kg, day 4), AMIO (1200 mg, QD for 6 days) and metoprolol (119 mg, QD, day 6), and AMIO (400 mg, QD for 4 days) and simvastatin (40 mg, day 4) were simulated with 10 trials each containing 5, 10, and 12 subjects, respectively. The following scenarios were simulated as listed in Table 3: 1) competitive inhibition by AMIO only, 2) competitive inhibition by AMIO and MDEA, 3) both competitive and time-dependent inhibition by AMIO only (for CYP2C9 and CYP3A), and 4) competitive and time-dependent inhibition from both AMIO and MDEA (CYP2C9 and CYP2D6). The simulated AUC and Cmax ratio were compared with the observed data.
Simulation of AMIO and MDEA PK after Single Intravenous Dose
The PBPK model built for AMIO was able to simulate the PK profile observed from clinical study following a 400-mg i.v. infusion of AMIO (Fig. 1A). The very large volume of distribution predicted (Vss = 64 l/kg) using the full PBPK distribution model by considering extensive tissue:plasma partitioning in major organs reasonably captured the distribution phase that drives the PK profile, with a multiexponential decline and long terminal half-life (t1/2). The predicted Vss (64 l/kg) is on the high end of reported values mostly ranging from 12 to 65 l/kg (Riva et al., 1982; Holt et al., 1983). The CL for AMIO is ∼9.4 l/h, estimated from simulation that best recovers the observed PK data, and is close to the lower end of the range of reported values (8–46 l/h). This rate of AMIO elimination determines the rate of MDEA formation.
The PBPK model for the metabolite MDEA was developed using in silico, in vitro, and in vivo data (Table 1). MDEA was predicted to also have a large volume of distribution (Vss ∼47 l/kg) based on its extensive tissue distribution data that were reported. The estimate of MDEA CL from the simulation with best fit was ∼8.3 l/h. This value is close to that for AMIO (9.4 l/h), which is consistent with the assumption that the kinetic for MDEA PK is mostly formation rate–limited based on the observed similar t1/2 for AMIO and MDEA. The optimized minimal-distribution model with the addition of a single adjusting compartment (volume of distribution of compartment [Vsac] ∼31 l/kg) captured the shape of the MDEA concentration-time curve that exhibited a multiexponential decline with a long terminal half-life (Fig. 1A). At a 400-mg intravenous infusion of AMIO, the formation of MDEA, expressed as Cmax and AUC, was simulated to be 0.08 μg/ml (0.13 μM) and 37.6 hours*μg/ml (60.9 μM*h), compared with the observed values of 0.09 μg/ml (0.16 μM) and 39.8 hours*μg/ml (64.5 μM*h), respectively (Holt et al., 1983). The time for MDEA to reach its maximum concentration as determined by the rate of AMIO elimination and MDEA clearance is about 42 hours (mean), which is in the range of observed values (24–72 hours) (Holt et al., 1983).
Simulation of AMIO and MDEA PK after Single and Multiple Oral Doses
The AMIO-MDEA–linked PBPK model with CL and Vss for both AMIO and MDEA characterized based on the intravenous PK profile was then used to simulate the PK profile of AMIO and MDEA after oral administration of AMIO. The parameters of fa (0.6), ka (0.3 hour−1), and time lag (1 hour) reported from clinic studies were incorporated into the model (Canada and Lesko, 1980; Plomp et al., 1984). The simulated AMIO PK profile and parameters of Tmax (7.25 hours), Cmax (0.43 μg/ml) (0.66 μM), and AUC (6.6 hours*μg/ml) (10.2 μM*h) are in good agreement with the mean observed data [7.3, 0.46 (0.71 μM), and 7.9 (12.2 μM*h), respectively] from a single 400-mg oral dose of AMIO (Andreasen et al., 1981; Latini et al., 1984) (Fig. 2A). The predicted formation of MDEA does not completely reach maximum concentration for over 24 hours (Fig. 2B), similar to the clinical observation (Staubli et al., 1985; McDonald et al., 2012). However, no concentration-time profile data for MDEA from this same study are available for direct comparison.
The PK profile of AMIO and MDEA after long-term treatment was also simulated and compared with reported data (McDonald et al., 2012). The accumulation of AMIO and, in particular, the constantly increasing MDEA level over long-term treatment were captured by the PBPK model simulation. The simulated mean plasma concentration of AMIO and MDEA following a dose of 350 mg/day AMIO for 14 weeks was comparable to the observed mean plasma concentration (n = 3) in samples collected once every 3 weeks during 14 weeks of treatment (Fig. 3, A and B). The AMIO dose in the clinical study varied between 230 and 500 mg/day over the treatment period. An overall mean value of 350 mg/day was used in the simulation.
Simulation of DDI
The PBPK model with incorporation of in vitro inhibition potency data (Table 2) from AMIO and MDEA on CYP2C9, 2D6, and 3A was used to simulate the effect of AMIO on substrate warfarin (CYP2C9), metoprolol (CYP2D6), and simvastatin (CYP3A4). Different doses were used for each simulation to match the reported clinical DDI studies. The simulated effect, expressed as a ratio of AUC and Cmax in the presence and absence of AMIO, was compared with observed data and presented in Table 3. In addition, the simulation of DDIs by considering all plausible mechanisms of P450 inhibition by AMIO and MDEA can be found in the Supplemental Material.
Effect of AMIO on Warfarin PK.
The effect of AMIO on the PK of warfarin after a 300-mg QD dose for 13 days or 200-mg BID dose for 14 days was simulated. As expected, AMIO was predicted to have no effect on warfarin PK if only competitive inhibition by AMIO (Ki 96 μM) was considered. With incorporation of competitive inhibition from both AMIO and MDEA (Ki 2.3 μM), and the time-dependent CYP2C9 inhibition by AMIO (kinact 0.005 minute−1, KI 7.89 μM), the model predicted a mean of 14 and 18% increase in the AUC of warfarin compared to the observed 27 and 100% increase after 300-mg QD and 200-mg BID doses, respectively. Even though the predictions were improved after including the inhibitory metabolite, and the AUC ratio predicted is within 2-fold of the observed value, a trend of underprediction for 200 mg BID was observed (Table 3).
Effect of AMIO on Metoprolol PK.
The effect of AMIO on the PK of metoprolol after a 1200-mg QD dose for 6 days was simulated. When CYP2D6 inhibition from metabolite MDEA was not counted, AMIO alone (Ki 45.1 μM) was predicted to have no effect on the metoprolol PK. Even with incorporation of competitive inhibition for both AMIO and MDEA, a minimal effect of AMIO on metoprolol was predicted (1.03 and 1.02 in AUC and Cmax ratios, respectively), whereas when both competitive and time-dependent inhibition (kinact 0.12 minute−1, KI 1.3 μM) from MDEA were incorporated, significant DDI was predicted with the Cmax ratio (1.53) and AUC ratio (2.45), slightly higher than the clinical observed data (Table 3).
Effect of AMIO on Simvastatin PK.
The interaction between AMIO and simvastatin following a 400-mg QD dose of AMIO for 4 days was simulated using the model with the updated value of gut availability (0.4) for simvastatin. The model predicted no effect of AMIO on simvastatin PK when only the competitive inhibition of AMIO was incorporated. The model predicted a 1.93-fold increase in both simvastatin Cmax and AUC when competitive inhibition from both AMIO and MDEA is considered. These values are similar to the observed data: 2.0- and 1.73-fold increase in Cmax and AUC, respectively (Table 3). Interestingly, if both CYP3A4 competitive and time-dependent inhibition from AMIO and reversible inhibition from MDEA were incorporated, the model predicted a more than 2-fold inhibition for both Cmax (3.0-fold) and AUC (3.5-fold) of simvastatin.
Even though the underestimation of clinical DDI solely due to the overlooking of contributions from inhibitory metabolites is uncommon, when unexpected DDI is observed in clinical studies, the potential contribution of metabolites to the observed DDI should be evaluated. Obtaining a mechanistic understanding of inhibitory metabolite contributions to the observed DDI is important, and the use of PBPK modeling could be advantageous, especially considering that complex drug interactions involving inhibitory metabolite as the model will allow the considerations of nonlinear PK, accumulation of inhibitor concentration (parent and metabolites) over the treatment period, and extensive tissue distribution. However, the use of the PBPK model for a true prospective prediction of DDI caused by inhibitory metabolite is still very challenging, as the in vitro inhibition and human PK data for the metabolite are not routinely generated. The AMIO case study presented here demonstrates the utility of PBPK modeling in a retrospective way to gain a mechanistic understanding of the unexpected clinical DDI potentially caused by an inhibitory metabolite. The development of the PBPK model from additional case studies will prove useful for the prediction of DDI involving inhibitory metabolite in the future.
The disposition kinetics of AMIO were poorly understood until sensitive bioanalytical methods were developed, long after the drug was approved. AMIO and its metabolite, MDEA, have unique pharmacokinetic properties characterized by extensive tissue distribution, very long half-life (up to 100 days), and accumulation during chronic oral therapy. In addition, nearly 100-fold variation in the reported PK parameters, such as terminal half-life and steady-state volume of distribution, may also be due to inappropriate PK modeling (McDonald et al., 2012). Therefore, characterizing the concentration-time profile of inhibitors, AMIO and its metabolite MDEA, in plasma and liver after single and multiple doses is the first and critical step toward understanding the underestimated clinical DDI using a PBPK modeling approach.
The PBPK model developed using a mixed "bottom-up" and "top-down" approach leverages the use of all existing AMIO and MDEA in vitro absorption, distribution, metabolism, and excretion data and clinical PK data. Large Vss values were predicted for both AMIO and MDEA by incorporating tissue distribution into mechanistic tissue composition equations (Rodgers and Rowland, 2006). The use of a full PBPK distribution model for AMIO and minimal PBPK + single adjusting compartment distribution model for MDEA enabled a good description of the multiphasic decline of the concentration-time profile and long terminal t1/2 for both AMIO and MDEA following an intravenous infusion of AMIO. The AMIO-MDEA–linked PBPK model predicted both the formation and elimination of metabolite MDEA successfully, as the observed and simulated MDEA PK profiles match reasonably well. More importantly, the accumulation of AMIO and MDEA in plasma and liver after chronic oral dosing was captured in the simulations as well. The simulated mean plasma concentration increased ∼3-fold for AMIO and ∼20-fold for MDEA after 8 weeks of a QD dose of AMIO (Fig. 3). At steady state, the simulated plasma concentration of metabolite MDEA reached a similar level as the parent AMIO (∼1 μg/ml), which is very similar to the clinical observations (Holt et al., 1983; McDonald et al., 2012). Moreover, the simulated total liver concentrations for both AMIO and MDEA are several hundred–fold higher than that in plasma due to extensive tissue distribution considered in the model (Fig. 4, A and B). The accumulation of MDEA in the liver is more than that of AMIO due to higher liver:plasma partitioning of MDEA incorporated in the model based on reported data (Holt et al., 1983). Overall, the dynamic change of inhibitor (AMIO and MDEA) concentration over time and its accumulation in plasma and liver, especially for inhibitory metabolite MDEA, were characterized in the PBPK model. The successful simulations of clinically observed PK profile build confidence in the prediction and mechanistic understanding of the DDI caused by AMIO, particularly the DDI potential in chronic therapy.
In general, the addition of the inhibitory metabolite, MDEA, into the PBPK model resulted in more accurate prediction of all AMIO DDIs (AUC and Cmax ratio) than that only considering parent drug (AMIO) P450 inhibition. However, considering that the magnitude of DDIs observed in clinic is rather small (mostly 1.2- to ∼2.0-fold) and the PK parameters reported for AMIO are largely variable, more clinical study data would be useful to build up confidence in the model prediction. Nevertheless, for the AMIO-metoprolol DDI, when the competitive inhibition of AMIO and competitive and time-dependent inhibition of MDEA were considered, the model provided the best prediction. Nearly no effect of AMIO on metoprolol PK would be predicted if TDI of MDEA was not incorporated, which suggests that the underlying mechanism for the AMIO-metoprolol interaction may be more attributable to the TDI by MDEA on CYP2D6.
In terms of the AMIO-simvastatin interaction, the best prediction was achieved when the competitive inhibition from both AMIO and MDEA was considered. Addition of TDI from AMIO would overpredict the observed DDI (close to 2-fold), although intuitively, one may expect that the best prediction should come from the scenario in which all mechanisms of inhibition are incorporated. It is known that drugs may be mischaracterized as mechanism-based inhibitors, although they behave as time-dependent inhibitors due to the formation of a metabolite which can be a more potent reversible inhibitor (Parkinson et al., 2011). Different from a true mechanism-based inhibitor, the phenotype of such time-dependent inhibitors demonstrated the increased inhibition through the time required to form the inhibitory metabolite during the preincubation. Considering the MDEA is a more potent competitive CYP3A inhibitor than AMIO, and has a lower intrinsic clearance than AMIO (4 vs. 28 μl/min per mg) in human liver microsomes, it is possible that the formation (and less turnover) of MDEA may be the reason why AMIO has been reported as a CYP3A time-dependent inhibitor. Consequently, considering only competitive inhibition from AMIO and MDEA provided the best DDI prediction for simvastatin.
Interestingly, for the warfarin-AMIO interaction, although incorporation of all of the inhibition from both AMIO and MDEA into the model resulted in a better prediction, it still underestimated the DDI reported in some clinic studies (O'Reilly et al., 1987). The fact that both CYP2D6 and CYP3A DDIs were well predicted suggests that underprediction of CYP2C9 DDI is more likely due to other unknown mechanisms or the variability of clinical DDI data from a small trial (n = 5). Recently, several other metabolites have been identified in plasma samples of subjects receiving AMIO, including 3′-hydroxy-N-monodesethylamiodarone, N,N-didesethylamiodarone, and deaminated amiodarone, O-desalkylamiodarone. These metabolites have equal (deaminated amiodarone, 3′-hydroxy-N-monodesethylamiodarone) or much more potent (N,N-didesethylamiodarone, O-desalkylamiodarone) CYP2C9 inhibition than MDEA (McDonald et al., 2012). The contribution of these metabolites to the observed in vivo AMIO-warfarin interaction is yet to be assessed.
The current study investigated the impact of adding inhibitory metabolite on the magnitude of the predicted DDIs while all rest parameters were kept consistent as either defined in the verified PK model or default Simcyp model. Although this retrospective PBPK modeling helped to understand the possible inhibition mechanism of clinically observed AMIO DDI, the prospective prediction of DDI involving inhibitory metabolite would require further development of the PBPK model. Although it is reasonable to assume that the free liver concentration could be similar to the free plasma concentration when a perfusion-limited model is used, the use of this assumption to determine the metabolite concentration at interacting sites is still uncertain, especially for a highly lipophilic metabolite such as MDEA. Other parameters, such as free inhibitory metabolite concentration in the gut (Yang et al., 2007; Karlsson et al., 2013) and in vivo inhibition potency of the inhibitory metabolite, can also affect the prediction. A good understanding of the source of uncertainty for these parameters and its impact on the prediction is important. In addition, understanding and incorporating the metabolic clearance pathways of the inhibitory metabolite could be critical if the autoinhibition by the inhibitory metabolite exists.
This work demonstrates the utility of PBPK modeling in developing mechanistic understanding of the clinical DDI attribute to the contribution of inhibitory metabolite. Accurate simulation of PK profiles of both parent and metabolite is required to maximize confidence in the DDI prediction. Refinement of the PK model, especially for the metabolite, should be conducted whenever more in vitro enzyme kinetic and inhibition data and clinical PK data become available. In discovery and early development stages, prospective prediction of DDI involving an inhibitory metabolite is challenging and has inherent uncertainty due to limited information available for the metabolite, and therefore, hypothesis-driven sensitivity analysis is highly recommended to understand the extent of DDI risk. It also emphasizes the need for users to be fully aware of the model assumptions and limitations as well as underlines the importance of comparing PBPK model predictions with those from simpler models to understand the differences in outcome. In a late stage of development, with full validation of the PK model, PBPK modeling can provide greater value to address clinical questions, such as why more significant DDI was observed than was expected, through simulating the proposed mechanism of inhibition from both parent and metabolites to understand the disconnect.
The authors thank Dr. Malcolm Rowland for his critical input to this work, Dr. Matthew Wright for his thorough review of this manuscript, and the Drug Metabolism and Pharmacokinetics Absorption, Distribution, Metabolism, and Excretion group for generating the in vitro data.
Authorship Contributions
Participated in research design: Chen, Mao.
Performed data analysis: Chen, Mao.
Wrote or contributed to the writing of the manuscript: Chen, Mao, Hop.
- Received June 4, 2014.
- Accepted October 15, 2014.
This study was funded by Genentech (a member of the Roche group). All authors were employees of Genentech when this work was carried out. They have no other conflicts of interest to declare.
↵This article has supplemental material available at dmd.aspetjournals.org.
- amiodarone
- area under the curve
- drug-drug interaction
- in vitro–in vivo extrapolation
- mono-desethyl-amiodarone
- cytochrome P450
- PBPK modeling
- physiologically based pharmacokinetic modeling
- pharmacokinetic
- t1/2
- half-life
- time-dependent inhibitor
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics


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|A file photo of Rihanna/Reuters
AFP Relaxnews
Rihanna may have just hinted at a new Fenty Beauty collection.
The singer and makeup entrepreneur sparked the rumors when she rocked up to the premiere of her new film "Ocean's 8" this week, sporting a striking aubergine-hued red carpet beauty look.
Her makeup, which was provided entirely by her own Fenty Beauty by Rihanna brand, featured some of the label's most recognizable products, such as its Pro Filtr primer and foundation, its Matchstix concealer and its Killawatt blush. It also included a mystery deep purple metallic lip color and dusky purple eyeshadow that fans are speculating could be part of the star's next release.
So will Riri be championing purple for her fall collection? Neither Fenty or Rihanna has confirmed the news yet, but the star does have a penchant for teasing her upcoming makeup launches at red carpet events.
Rihanna has been steadily growing her beauty business since she launched it last September, with the latest installment of her "Beach, Please" summer collection dropping on May 21. She also unveiled her debut "Savage X Fenty" 90-piece lingerie line last month.

subset: commoncrawl


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On 11 December 2015, a man bought a return train ticket to Manchester from Euston station, London. From Manchester he travelled on to Greenfield, Saddleworth and stopped at the Clarence pub, where he asked about how to get to the top of the hill. Despite warnings from the landlord about the late hour and poor weather conditions, the man set off anyway. He was spotted twice making his way up the hill.
The following morning the man was found dead on Saddleworth moor, near Dovestone reservoir. He was found by a passing cyclist lying on his back with his arms by his side. His pockets held £130 in cash and three train tickets. There were no items on the body, such as credit cards or driving licence, that could be used to name him. Despite the best efforts of the police, his identity remains a mystery. The circumstances of his death are also mysterious, but some light has recently been shed on this aspect of a puzzling case.
Preliminary toxicology results have identified traces of strychnine in the dead man's body. Strychnine is a notorious poison, but outside of Agatha Christie novels it rarely makes an appearance in the modern world. In Christie's day strychnine was frighteningly easy to get hold of: you could buy it over the counter in any local chemist's shop. Strychnine was available as a rat poison or as a medicine. Little old ladies, like Mrs Inglethorp in Christie's 1920 novel The Mysterious Affair at Styles, were prescribed strychnine tonics to increase their appetite and invigorate their nerves.
Strychnine certainly invigorates nerves, but not in a medically beneficial way and has therefore been removed from the British Pharmacopoeia. Strychnine interacts with chemical receptors on motor neurones, those that control movement. Electrical signals are sent along nerves but at the junctions between nerve cells, chemicals (neurotransmitters) are released to pass on the message. Two neurotransmitters are important in the case of strychnine: acetylcholine, which is the "go" message telling the adjoining nerve or muscle cell to fire, and glycine, the "stop" message, which tells the nerve not to fire. The balance of these two chemicals prevents false signals triggering nerves to fire and muscles to spasm. Strychnine attaches to glycine receptors and blocks the stop signals. The result is that the slightest stimulus can cause the nerve to signal or a muscle to contract.
An overdose of strychnine usually starts with twitching but progresses to horrific whole body convulsions as the nervous system careers out of control. The muscles on the back of the body are usually stronger than those on the front, so victims arch upwards with their arms clenched at their sides and only the heels and back of the head resting on the ground. There will be a period of convulsion followed by a period of calm before another bout of spasms begins. Most victims survive between two and five of these bouts before the muscles controlling their breathing become paralysed and they suffocate. During the whole process the victim is horribly and painfully aware of what is going on, as the nerves of the brain are also stimulated to give heightened perception. It is an agonising way to die.
Thankfully, strychnine rarely causes death. Since Christie wrote her poisoning plots the rules around its purchase have been tightened considerably. A paper published in 1979 explains that in the preceding 30 years there was on average one death per year in the UK due to strychnine poisoning; all but one were suicides. Most of the individuals who took strychnine had obtained it in the form of pesticide. Until recently strychnine was still used by licenced pest controllers to exterminate moles, but in 2006 it was banned from this final use because it causes the animals unnecessary suffering. It is now illegal to purchase strychnine in the UK.
Where does this leave the case of the mysterious man on Saddleworth moor? Whoever he was, his body appears to have contained an illegal lethal substance. A second postmortem being conducted this week will hopefully reveal more details. As well as establishing the cause of death police are still working to identify the man. Hopefully someone will recognise the images of him captured on CCTV at Euston station, or know him from the police description - white, aged between 65 and 75, of slim build, with a receding hairline with grey hair to the side and back. He had a large nose that may have been previously broken, and was clean shaven. He wore a brown heavy jacket, blue jumper, white long-sleeve shirt, blue corduroy trousers and black slip-on shoes.
What is really tragic about this case is in the three months since this man's death no one appears to have missed him. Anyone with information should phone police on 0161 856 8972 or the independent charity Crimestoppers, anonymously, on 0800 555 111.
Dr Kathryn Harkup is a chemist and science communicator. Her book, A Is for Arsenic: The Poisons of Agatha Christie, is published by Bloomsbury.
• This article was amended on 17 March 2016. An earlier version contained a line in the final paragraph implying that the death in the Saddleworth moor case was suicide. The police investigation is ongoing and no conclusions have yet been reached.


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You can now go on a brunch date with a royal couple at Disney World
Disney is getting into the dating business. This spring, the park is offering double dates with the princesses and their princes. Since couples goes on dates, and even get married, at Disney all the time anyway, makes sense that the park would find a way to further expand the experience. And a fun date with a royal couple sounds perfectly magical!
Now you can dine with Ariel and Prince Eric, and Rapunzel and Flynn Rider.
The park yet to announce additional possible royal couples, like Cinderella and Prince Charming, or Sleeping Beauty and Prince Philip. They must be booked elsewhere, famous as they are.
(Hopefully they're sending post-spell Ariel, because otherwise, what a drag those two would be.)
The date is part of Walt Disney World's "Bon Voyage Breakfast."
Each couple will meet the enchanted folk at Trattoria al Forno at Disney's Boardwalk hotel. Prices are $34 per adult and $20 for kids, if you've got your family in tow. The food includes a "Shipwreck al Forno" and "Tangled Eggs" with fresh mozzarella and Sunday gravy. Knowing the quality of food at Disney, we're certain it'll be magically delish.
Oh, and mimosas and Bellinis are also on the menu, so you can put yourselves under a spell.
Reservations are now open to book for dates beginning April 2, 2017.


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* a science that dealing with the structure, composition and properties of items and with the transformations that they undergo * the composition and chemical properties of a substance * chemical processes and phenomena (as of an organism) Examples:
- Digestion; enzymes promoting chemical reactions that power our bodies. Lifting your arm requires your body to make and burn ATP using oxygen with carbon dioxide as one of the waste gases produced. - The internal combustion engine takes liquid gasoline, converts it to a gas, burns it takes the waste to make mechanical energy and then expels some noxious gases. The rare metals in the catalytic converter scrub out the sulfuric acid, but we still get the ingredients for smog out of them. - Cooking is the heating and combination of compounds to make something new. In some cases, like rising bread we have an actual chemical reaction where the yeast changes the food. - When concrete dries and hardens the water actually causes a chemical reaction with the cement making a binding action drying concrete isn't just losing water it is undergoing a chemical change and one that creates heat as well (an exothermic reaction). - When you write with ink on paper, the ink and paper unite in a chemical reaction so that you can't erase it. Specialized inks allow a short period where you can erase some inks, but most inks dry and can't be erased; they have bound with the paper. This includes your pen and your ink jet printer.
Analytical Chemistry
* Analytical chemistry is the chemistry discipline concerned with the chemical composition of materials. * Analytical chemistry also is concerned with developing the tools used to examine chemical compositions. Examples:
- The Culligan Man comes to your house and tests your water hardness.
- You have your blood sugars tested.
- You check the pH in your fish tank.
- The quantity of metal in an ore is tested to determine if it is feasable to mine. - you have 3000 grams of sulfur and burn it in an excess of air. if you end up with 4000 grams of sulfur dioxide, then what was the efficiency of the reaction?
Organic Chemistry
* The chemistry of carbon compounds (other than simple salts such as carbonates, oxides, and carbides). Examples:
* photosynthesis of a plant leaf is organic chemistry.
* behavior of cancer cells is organic chemistry.
* determine the structure of this newly discovered molecule and then modify it to enhance the desired activity and specificity of action, while decreasing undesired side effects. * Glucose
* Fructose
Inorganic Chemistry
* The chemistry of compounds that do not contain hydrocarbon radicals.
* Sodium Chloride (table salt)
* Carbon Tetrachloride (no C-H bond!)
* Sulfuric Acid
* Ammonia
* Calcioum Carbonate (chalk)
* The branch of science concerned with the chemical and physicochemical processes that occur within living organisms. Examples:
* Monosaccharide-1 glucose, fructose, galactose
* Lipids- contain carbon, hydrogen, and oxygen.
* Polysaccharides-starch, glycogen, cellulose.
* Nucleic Acids- chain of nucleotides, carbon, hydrogen, oxygen, nitrogen, and phosphate, contains hereditary info, DNA, RNA, produce protons * Peptide bonds- joining of 2 amino acids
Physical Chemistry
* The branch of chemistry concerned with the application of the techniques and theories of physics to the study of chemical systems. Examples:
* Macroscopic:
Macroscopic properties of substances describe how relatively large quantities of the substance behave as a group, e.g. melting points and boiling points, latent heats of fusion and vapourization, thermal conductivity, specific heat capacity, coefficient of linear thermal expansion, and many other "physical properties". * Microscopic:
Microscopic properties of substances concern details of their physical properties observable...
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What: Florida 1/2 Mile Shootout
When: October 20-21, 2018
Where: Jumbolair Airport, 1201 NE 77th St, Ocala, FL 34479
Contact: (850) 797-8579
All of our participants will be given a chance to take their vehicle's Top Speed down Jumbolair's private 7550 ft runway and race door-to-door against the competitor of their choice. See what it's finally like to race without the restrictions of speed limits, on what is basically your own private proving grounds in Ocala, FL! This event is limited to only 150 cars per day and is sure to sell out quick so register today and we promise to make your automotive dreams come true.
Award Classes: (based off vehicle trap speeds)


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Thanks to Freya for choosing another one of my haiku for her 'disintegrate' themed session. It's an honor. Please visit Pure Haiku to read it as well as many other wonderful choices.
Tag: Pure Haiku
Thanks Pure Haiku!
Once again, Freya at Pure Haiku has chosen one of my pieces for her "emergence" themed series. Thanks!!! You can read my piece (and many other great haiku) at Pure Haiku.
Thanks once again to Freya for including this in her Emergence series. I love this piece!
dawn, adorned in red
penetrates night's solitude
to dance a new day
dawn, adorned in red
penetrates night's solitude
to dance a new day
© Tina Stewart Brakebill 2019
Tina's blog continues to grow and change but happily her haiku addiction continues unabated. Find out more at Tina Stewart Brakebill!
This haiku is part of our Emergence theme.
Proud to have one of my haiku chosen for the theme of Emergence. Thanks Freya! You can find some hope for spring (and other great haiku) at Pure Haiku shoots of deep green rise daffodils wake from slumber and hope springs alive Plus (spoiler alert) there's more coming down the road!
Pure Haiku Pride
Yesterday, Pure Haiku posted another one of my pieces. It may be (a bit?) dark, but I'm (a bit!) happy and proud. It's a great site if you dig haiku as much as I do! So check them (and my little piece) out by clicking here: Pure Haiku


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Sally King, ISA AM, Fine Art
Sally King
ISA member since Apr 29, 2002
(214) 695-3094 (Mobile)
(469) 206-7149 (Office)
5706 E. Mockingbird
Suite 115-04
Dallas, TX 75206 map
Specialist in American and Contemporary art especially Taos Society of Artists, early and contemporarySanta Fe and Western art, Early Texas Art, Mid-Century Texas Art, Contemporary Texas Art, East and West Coast contemporary art: paintings, watercolors, drawings, prints, photographs and sculpture. Fourteen years as corporate curator for large collections of museum quality art, contemporary, 100 year old Western landscapes and figurative works for two Fortune 100 companies. Acquired 200 contemporary western landscapes; planned and supervised installations in architecturally significant buildings across corporate campuses. Handled, framing, restoration, and cataloging as well as appraisals, research, writing, education, exhibitions and presentations about individual artists, artworks and the overall collections.
Appraisals, collection management and acquisitons for private clients since 2003; MA art history studies completed at SMU and UTD
- Art
- Paintings
- Prints
- Sculpture
- Watercolors


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Arizona REALTORS® has entered into forms licensing agreements with TransactionDesk®, zipForm®, dotLoop, DocuSign®, SkySlope and Brokermint.
These companies can provide state association, local association forms and multiple listing service forms to all Arizona REALTORS® via their respective platforms.
The state association provides TransactionDesk® to its members free of charge and the National Association of REALTORS® provides zipForm® Plus (Online edition) to all REALTORS® as part of member benefits through 2020.
Please note that the zipForm® Plus member benefit does not include zipForm® Mobile or zipFormMLS-Connect®.
Both TransactionDesk® and zipForm® Plus can be accessed via www.aaronline.com and all Arizona REALTORS® members can quickly access forms providers via the state association's Single Sign-On dashboard.
If you have questions about zipForm®, eSign or Single Sign-On, contact Arizona REALTORS® Business Services Support. If you need TransactionDesk® support, call 800.668.8768 or email firstname.lastname@example.com 24/7.
If you encounter a problem using state association forms in TransactionDesk®, report it to email@example.com. To see a list of ongoing issues already being addressed by Arizona REALTORS®, click here.


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The least dramatic classification in the state provide the most drama in the postseason this season and we have the Bainbridge Bearcats to thank for it.
Expansion to seven classifications hurt Class AAAAA more than any other and created a strata of elite teams. Those big boys – Rome, Buford, Warner Robins, Stockbridge and Carrollton – seemed almost a certainty to win the state championship.
Problem was, no one told Bainbridge.
The Bearcats provided one of the most compelling storylines in many years. Think of any of your favorite sports movies – the ones with the unbelievable ending – and Bainbridge topped them all on the way to its state championship. They were real-life Rockys and Rudys. And they proved that there may be some validity to many of those sports clichés that coaches spout so often.
Consider this: Bainbridge won the Class AAAAA championship in a three-overtime classic against Warner Robins. Bainbridge blew a 28-point lead and still won. They did it despite starting the playoffs with a 5-5 record.
They won it despite facing five ranked teams in the playoffs and mowing them all down. They began by beating No. 8 Jones County, the followed the next week by giving No. 5 Wayne County its first loss of the season. The fervor ramped up when the Bearcats went to No. 2 Buford and won on a drizzly night, then reached a fever pitch when they returned a squib kick for a touchdown in the final two minutes to stun No. 6 Stockbridge.
That just set up the classic game against No. 3 Warner Robins, the same team that had beaten them 38-0 just a few weeks earlier. But the Bainbridge defense and special teams, which carried the team for must of the postseason, rose up with critical stops and enabled the Bearcats to walk away with its first state championship since 1982.
"The only people that believed was the people on this field," Bainbridge coach Jeff Littleton said.
Here are few other highlights of the 2018 season:
Welcome back, Panthers: Southwest DeKalb regained some of its glory days by going undefeated and winning the region championship. The Panthers rejoined the state rankings in midseason and finished No. 7. But the Panthers crashed in the first round of the playoffs against Loganville to put a damper on things. Still, coach Damien Wimes has the program headed in the right direction.
The Banneker revival: The ending wasn't great – they lost in the first round of the playoffs – but the Banneker Trojans had a tremendous regular season. Coach Mario Allen's club made huge strides in his second season, lost only to Class AAAAAAA quarterfinalist Hillgrove in the regular season, and won the school's first region title. Hard to believe this is the same school that didn't win a game for two years.
The Dutchtown surge: Coach Clifford Fedd brought a tough, defensive-minded mentality to Dutchtown when he took the job in 2017. It paid off this season when the Bulldogs won the region championship – and knocked off Stockbridge in the process – thanks to its bone-jarring defensive style. They gave Rome a full measure in the quarterfinals, ending the season 12-1. Looks like this program will be an on-going contender.
Fromm-to-Jones: The duo of quarterback Tyler Fromm and Marcayll Jones propelled Warner Robins to the state title game. Jones set a state record with 115 catches for 2,047 yards. Fromm threw for 4,274 yards and 46 touchdowns. They'll go down as one of the top pass catching connections in Georgia history.
Best player: Jamious Griffin of Rome rushed for 2,815 yards and 38 touchdowns. Probably could have been a lot more if he'd played in the fourth quarter of most of those lopsided Region 7 games. That's the fourth-best rushing season in GHSA history and only 367 yards off the state record. Griffin has committed to N.C. State, but is being wooed by new Georgia Tech coach Geoff Collins, where he would join his brother Quan.
Looking ahead to 2019: Hey, spring practice will be here before you know it. Who will be No. 1 going into the next season. It may just be Bainbridge, which returns its backfield, but loses some outstanding defensive players in Roman Harrison, Randy Fillingame and Bryce Worthy. But with quarterback Quayde Hawkins, running back Caleb McDowell and defensive end Tahari Tate coming back, don't be surprised to see the Bearcats at the top of the preseason rankings. They certainly won't be an unranked surprise in 2019.
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Information in this section will help you understand advising and registration processes, career development, and student support as it relates to academic integrity, probation, and preparing for graduation.
Academic Advising
Your academic advisor is a faculty member in your area of study. Please note that advising assignments are made by individual academic schools/departments. Incoming first-year students in VPA are likely to be notified of their academic advisor after they arrive on campus and will not necessarily meet with their academic advisor on Opening Weekend.
Registration/Schedule Adjustment
Schedules for incoming first-year students are put together prior to their arrival on campus. First-year students can view schedules upon move-in and may schedule adjust as outlined by the Registrar's Office. After this first semester, students are responsible for managing their own registration and schedule adjustment and do so through a web portal known as MySlice.
External transfer students meet with an advisor during Opening Weekend and can then add classes on MySlice. Student Success staff will be available to assist as outlined in the orientation schedule.
Returning undergraduate students are eligible to register and schedule adjust as outlined by the Registrar's Office.
Note: Most College of Visual and Performing Arts students are required to meet with their faculty advisor before they can register for classes.


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The new Silver Z range that was introduced last year broadens in early 2019. We proudly present the third pure fiberglass Silver, the Tiger BRz. Tiger BRz, which is the only Bow Rider in the Z range, is made onto the same hull as its sister model Tiger DCz. This novelty model will be launched at the Helsinki Vene19 boat show in stand 6h50.
The hull design of the new Tiger BRz follows closely in the footsteps of the two Z models already published. The hull uses the unique Swedish Petestep® technology, thanks to which the boat runs higher on the water than traditional V-hulled boats, with a smaller wet surface, making the rides both smoother and more quiet. Simultaneously the Petestep® hull makes the boat surprisingly dry from sea sprays. Interior-wise the color scheme is calm and timeless in a sophisticated greytone, and the materials overall are high-quality. The stylish brown-toned composite teak deck is a more environmental friendly alternative to real teak, at the same time as it's easier to clean and maintain.
The open bow is ample and versatile, and includes large storage compartments and additional seating. There is also a separate decked storage box for mooring lines. The sturdy bow rails and distinct steps make it safe to embark the boat, and the standardly fitted bumper in the very bow overlooks small bumps when beaching. As additional accessory it is possible to get an effective spotlight for the bow that can help you navigate in the dark.
The pilot's area has been designed with ergonomics and practicality in mind. All meters, switches and the standardly fitted 9" Raymarine Axiom chartplotter have been mounted perfectly into the pilot's field of view, but without masking viewability forward. The streamlined windshield that extends along the sides of the boat effectively helps keep airflow away from the passengers travelling in the back.
The stern has been fitted with a U-shaped sofa, which is easy to transform into a large sunbed using the separate table that is part of the standard equipment. All passengers fit comfortably around the table and underneath the sofa there's plenty of storage space for bags and equipment. The storage compartments are lockable with ready-installed Abloy locks, so rest assured that you can leave belongings in the boat even for longer periods of time. The pantry in the co-pilot's console adds to the comfort as it can be fitted with a tap and a portable gas stove (additional accessories). The decked fender storage compartments in the aft corners are a familiar detail from the other Silver Z models.
The standard accessory set of the Tiger BRz is very comprehensive. The price includes e.g. the table for the stern (including the sunbed), a 9" Raymarine Axiom chartplotter with touch display, a 2-part stern canopy, hydraulic steering, the fenders with fender lines, the stern cushion set and the bow bumper. For added comfort you can choose between several additional accessories, such as a drawer fridge, a Webasto heater, a fresh water system, a double battery system and the luminous spotlight for the bow.
Silver Tiger BRz is a modern and welcome addition to the segment of fiberglass Bow Riders. The boat is quite an extraordinary boat in its size range, especially thanks to its patented Petestep® hull, but also because its apprearance clearly sets it apart from the other bow riders on the market. The new Tiger BRz brings a tad of animalistic power into the bow rider segment.
Original article, attachments and high-resolution images


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Loading game seconds left
Date Added:
Game Title:
Tom and Angela Family Portrait
Game Description:
Angela's baby is crying and she needs your help to take care of him and make him happy. Follow the steps and help Angela feed the baby, sing to him and show her love. After the baby stops from crying you can make a family photo with Tom, Angela and their cute baby. Enjoy the game!
© Yokogames 2009-2018. All Rights Reserved


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Businesses looking to borrow this year may find themselves facing a tougher credit climate amid an aging cycle and a recent investor exodus from loans to already indebted companies.
The Bank of Canada's latest senior loan officer survey found that, while business lending conditions had eased, approval rates for Canadian corporate borrowers were lower in the fourth quarter of 2018, "because some respondents appear to be less willing to undertake deals with looser terms and conditions."
Those deals included so-called "covenant-lite loans," the central bank said on Dec. 21, such as ones that may have fewer restrictions around the payment terms or income levels.
"Companies will continue to be able to access financing in 2019," said Bill Wolfe, an analyst and senior vice president in the corporate finance group at Moody's Investors Service. "It'll just be a little bit tighter than it was in 2018 and 2017."
Those tighter credit conditions could stem from higher interest rates or slower economic growth, with Moody's saying in its outlook for North American, non-financial corporate borrowers for 2019 that "gradual monetary tightening will temper the cost and availability of credit."
Corporate borrowers also watched reportedly record-breaking outflows from so-called "leveraged" loan funds in the United States to close out 2018.
Loans are dubbed "leveraged" when they are made to companies whose ratios of debt to assets or earnings are well above industry norms, according to blog post penned by International Monetary Fund staffers in November.
The loans are usually arranged by a syndicate of banks and issued to firms who already possess a significant amount of debt or weaker credit ratings, they added.
As of November, issuance of leveraged loans had hit an annual rate of US$745 billion, with the majority of the year's total borrowed to help bankroll mergers and acquisitions, leveraged buyouts, dividends and share buybacks, the IMF staffers noted.
The borrowers are also spread across various sectors (albeit the bulk of the loans are tied to U.S. issuers), with most being from the technology, energy, telecom and health-care industries.
Leveraged loans have also become an area of interest for those watching for bubbles. The debts can be packaged into what are known as collateralized loan obligations (or CLOs), securities that bear a similarity to the collateralized debt obligations, stuffed with mortgages, that contributed to the global financial crisis a decade ago.
"A sharp rise in defaults could have a large negative impact on the real economy given the importance of leveraged loans as a source of corporate funding," the IMF blog post said.
For borrowers, a concern would be if investor demand and lender interest in issuing the loans drop for a sustained period, or if borrowers struggle paying them back in a rising interest-rate environment.
Lisa Kwasnowski, a senior vice-president at DBRS, said they are keeping an eye out for any issues around the refinancing of leveraged loans, where a company would perhaps be unable to renew a loan or issue new debt.
"If we started to see that happen, maybe … becoming more common, we'd see that as a concern," she said.
Wolfe said their sense is that the market is searching for "equilibrium" after a long period of low interest rates and quantitative easing that saw the U.S. Federal Reserve buy up securities at a steady clip.
"That asset allocation that unfolded from 2011 to 2016 is now reversing," Wolfe added. "These funds that have had the benefit of these inflows for a long period of time, now they're struggling to attract the same degree of funding that they've become accustomed to. And so … that's how it affects these pools of capital that have supported leveraged loans."
• Email:[email protected]| Twitter:GeoffZochodne


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PURPOSE: The Greek-American Historical Museum of Washington State is sponsoring a competition that will provide a means by which stories of the Greek and Greek-American experience in Washington State will be documented. A number of young people have prepared similar documents and the intent is to encourage these inspirational stories. For more information about the Museum, please visit www.greeksinwashington.org GREEKHISTORYCOMPETITION-PDF
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TODAY is your LAST opportunity to buy early bird tickets for BIMA National Conference 2017.
Saturday 18-Sunday 19th March 2017
Book now at: http://www.britishima.org/conference/
Are you a Muslim healthcare professional seeking inspiration?
Do you want to hear from leading academics and professionals on topics that matter to you?
Need a spiritual boost to reconnect your faith to your profession?
Don't miss out on the incredible 2 day conference at King's College London bringing together like-minded Muslim healthcare professionals and students from all over the UK and abroad. Our programme of leading academics and healthcare professionals will leave you feeling inspired, informed and motivated.
Conference Themes:
Ethics, Medicine and Faith
Professional Development
Community Service and Public Health
Islamic Medical History
There will also be a 3 course dinner in the evening in celebration of the great achievements of Muslim healthcare professionals at Zaza's restaurant.
We hope to see you there!
_ #WhatsYourLegacy #BIMA2017Last modified on Thursday, 19 January 2017 22:43


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LHOOQ Mona Lisa with moustache by Marcel Duchamp
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by Jeremy on 2010-11-26
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This is a great piece of art. I have never seen anything so hairy. As a moustache enthusiast i praise this artist....
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The title of this painting is a joke by Marcel Duchamp. Spelling LHOOQ in french makes "Elle a chaud au cul", which can be translated as "She has a h...
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EDITOR — I am alarmed at the rate at which women and especially children are being sexually violated by shameless individuals in our society.
Everyday, reports of rape of both minors and women flood our media, and police stations while many others are unreported.
I call upon the responsible authorities to take sterner measures to curb this evil.
The victims, especially women, should speak out on this issue instead of keeping quiet about it.
To make matters worse some women even go as far as to say that women who are raped bring it upon themselves.
If this war is to be won both men and women should raise their voices against rape.
The government needs to impose even stiffer penalties on sexual offenders and carry out intensive awareness campaigns against this vice.
These campaigns should reach even the most remote areas in our country were many other cases go unreported.
Non-governmental organisations and other donors also need to play their part as they are in this fight.
To all men out there, let us be a source of protection for our children and women of Zimbabwe.
Let us stand behind them especially the little ones who look up to us for guidance, inspiration, comfort and protection.
This evil definitely scars someone for life and in some cases even counselling does not completely deal with this problem.
As Zimbabweans we should all speak up against the sexual abuse of women and children and even some men.


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Michael Naccache supports economic experts through all stages of consulting and litigation work related to antitrust matters, with a focus on healthcare provider and insurer issues. His review of discovery materials, analysis of large claims and other complex data sets, and organization of report submissions contributes to clear assessments of anti-competitive conduct and antitrust risk for government and industry clients. Michael also has experience working on mergers and monopolization cases involving technology and consumer goods markets, including AT&T-Time Warner, Arista v. Cisco, and GE-Electrolux.
BA, Economics, Political Science, Mathematical Methods in the Social Sciences, Northwestern University


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Home » Experiences »
UNICEF Summer Gala 2021 : Friday 6th August 2021, Porto Cervo, Sardinia
The third annual UNICEF Summer Gala, presented by LUISAVIAROMA, will take place on August 6th in Porto Cervo, Sardinia. This evening in paradise will include a languorous cocktail hour, gala dinner, and a live auction under the stars while raising funds for UNICEF's programs helping children in need. This will truly be a magical evening not to be missed.
Last year Event Chairs included Adrian Brody, Alicia Silverstone, Andrea Panconesi, Caroline Scheufele, Christopher Walken, Claire Foy, Devon Windsor, Elsa Hosk, Emily Ratajkowski, Georgia Fowler, Georgia Gibbs, Halima Aden, Jasmine Sanders, Jordan Barrett, Leonardo Del Vecchio, Lily Aldridge, Martha Hunt, Noel Capri Berry, Shanina Shaik, and Zoe Saldana.
Ticket & Table Options
Ticket Options
- Friend Tickets £3,000 per person
(Preferred dinner seating, "Friend" listing on printed materials)
- Backer Tickets £6,000 per person
(Premium dinner seating, "Backer" listing on printed materials)
- Patron Tickets £10,000 per person
(Prime dinner seating, "Patron" listing on printed materials)
Table Options
- Youth Benefactor Package at £25,000
(Preferred dinner seating for 10 guests and "Youth Benefactor" listing on printed materials)
- Child Protector Package at £50,000
(Premium dinner seating for 10 guests, "Child Protector" listing on printed materials)
- Children's Rights Crusader Package at £100,000
(Prime dinner seating for 10 guests, "Children's Rights Crusader" listing on printed materials, Prime full page ad in programme)
Reception 7:30pm, Dinner at 9:00pm
Please note:
Preferred seating will be slightly further back but with good views of the stage.
Premium seating will be very well placed in the room (central but not the front rows).
Prime seating will be the best seating in the house in the front rows.
All prices are subject to VAT at 20%.
Click here if you wish to download last year brochure.
For more information email firstname.lastname@example.com or call Mini Vohra and the Cornucopia Events™ team on +44 (0)871 288 3965 or 07863 240 513


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Plantar Warts
Plantar warts are growths that typically appear on the heels or other weight-bearing areas of the feet. These warts are caused by the human papillomavirus (HPV). The virus enters the body through breaks in the skin, such as cuts, that are on the bottom of the feet. Plantar warts are more likely to affect children and teenagers, people with weakened immune systems, people who have a history with plantar warts, and people who walk barefoot in environments exposed to a wart-causing virus.
If you suspect you have plantar warts, you may have the following symptoms: pain or tenderness while walking, a lesion that interrupts the ridges in the skin of your foot, small fleshy lesions on the bottom of the foot, or a callus where a wart has grown inward over a well-defined spot on the skin.
HPV causes plantar warts to form and is very common. There are more than 100 kinds of the virus in existence. However, only a few of them cause warts on the feet. The other types of HPV are likely to cause warts on other parts of the body.
If you have plantar warts, your podiatrist may try different treatment methods depending on your specific case. Some treatments for plantar warts are peeling medicines (salicylic acid), freezing medicines (cryotherapy), or surgical procedures. Laser treatments and vaccines are also used to treat plantar warts.
Where Are Plantar Warts Located?
The virus that causes most warts to develop is known as the human papillomavirus (HPV). This includes plantar warts, which grow into the heel of the foot as a result of constant pressure the foot endures from walking and standing. This type of virus generally enters the body through tiny cracks in the skin and is known to thrive in warm and moist places, which may include public pools, locker rooms, and surrounding areas. Plantar warts appear as a small and thickened area on the heel or sole of the foot and may have small blood vessels in the center, which appear as miniscule black dots. Small warts of this nature will generally produce minimal discomfort and will typically diminish on its own. If there are many warts, which may span a large portion of the sole of the foot, the pain and discomfort may be more severe. If you are afflicted with plantar warts, it is advised to consult with a podiatrist who can provide knowledge about correct treatment options.
Plantar warts can be very uncomfortable. If you need your feet checked, contact Dr. Rick L. Simon from Lansdale, Pennsylvania. Our doctor will assist you with all of your foot and ankle needs.
About Plantar Warts
Plantar warts are the result of HPV, or human papillomavirus, getting into open wounds on the feet. They are mostly found on the heels or balls of the feet.
While plantar warts are generally harmless, those experiencing excessive pain or those suffering from diabetes or a compromised immune system require immediate medical care. Plantar warts are easily diagnosed, usually through scraping off a bit of rough skin or by getting a biopsy.
- Lesions on the bottom of your feet, usually rough and grainy
- Hard or thick callused spots
- Wart seeds, which are small clotted blood vessels that look like little black spots
- Pain, discomfort, or tenderness of your feet when walking or standing
- Freezing
- Electric tool removal
- Laser Treatment
- Topical Creams (prescription only)
- Over-the-counter medications
To help prevent developing plantar warts, avoid walking barefoot over abrasive surfaces that can cause cuts or wounds for HPV to get into. Avoiding direct contact with other warts, as well as not picking or rubbing existing warts, can help prevent the further spread of plantar warts. However, if you think you have developed plantar warts, speak to your podiatrist. He or she can diagnose the warts on your feet and recommend the appropriate treatment options.
If you have any questions please feel free to contact our office located in Lansdale, PA. We offer the newest diagnostic and treatment technologies for all your foot and ankle needs.Read more about Plantar Warts
Causes Symptoms and Treatment for Poor Circulation in the Feet
The purpose of the body's circulation system is to transport blood, oxygen, and nutrients throughout the body. A reduction of blood to a specific part of the body may cause one to experience symptoms of poor circulation. The most common causes of poor circulation in the feet are obesity, diabetes, and heart conditions such as peripheral artery disease (PAD). Common symptoms of poor circulation include tingling, numbness, throbbing, pain and muscle cramps.
Peripheral artery disease is a common cause of poor circulation in the legs. Symptoms of PAD are cramping, pain or tiredness in the leg or hip muscles while walking or climbing stairs. This pain tends to go away with rest and starts back up when you begin to walk. It is a condition that causes the blood vessels and arteries to become narrow. Although PAD is more common in adults over the age of 50, it may also occur in younger people. A similar condition called atherosclerosis causes arteries to stiffen up due to a buildup of plaque in the arteries and blood vessels.
Blood clots are also a common cause of poor circulation in the feet. Clots may obstruct blood vessels and if they occur in the legs, they may eventually lead to pain and discoloration. This occurrence is commonly known as deep vein thrombosis (DVT) and it may travel to the lungs. Varicose veins are another condition that may lead to poor circulation, and it is caused by incompetence of the valves in the veins. Women who are overweight are prone to developing this condition. Lastly, diabetes, which is correlated with poor blood sugar metabolism may lead to chronic poor circulation. Those with diabetes often suffer from cramping in the legs, calves, thighs and buttocks.
If you are looking for ways to avoid poor circulation there are some tips you can follow. One tip is to avoid sitting for too long. If you plan to sit down for a long period of time, you should try standing up occasionally, to improve your circulation. Another great way to avoid poor circulation is to exercise. Exercise is an excellent way to pump the heart and increase blood flow. Those who suffer from poor circulation should also avoid smoking, reduce their salt intake, and try to lose weight.
If you are experiencing symptoms from poor circulation in your feet, you should consult with your podiatrist to determine the best method for treatment for you. He or she may prescribe medication in addition to recommending specific lifestyle changes to improve your circulation.
Symptoms of Poor Circulation In the Feet
Research has indicated that high blood sugar levels may be a common reason for poor circulation to occur in diabetic patients. Diabetes may cause blood vessels to gradually become damaged, and this may lead to decreased circulation. There are several symptoms that are associated with this condition, including a loss of sensation, which may begin with a feeling of pins and needles in the lower extremities; an awareness of hot or cold temperatures in the feet; or a decreased pain level, which may make it difficult to notice any sores or wounds. There are certain measures that may be taken to possibly prevent or help this ailment, including performing mild exercises and stretching techniques, wearing supportive shoes and socks, and keeping your cholesterol and blood pressure at normal levels. If you believe you have poor circulation, it is advised to speak with a podiatrist who can determine what the best course of treatment is for you.
While poor circulation itself isn't a condition; it is a symptom of another underlying health condition you may have. If you have any concerns with poor circulation in your feet contact Dr. Rick L. Simon of Lansdale, Pennsylvania. Our doctor will treat your foot and ankle needs.
Poor Circulation in the Feet
Peripheral artery disease (PAD) can potentially lead to poor circulation in the lower extremities. PAD is a condition that causes the blood vessels and arteries to narrow. In a linked condition called atherosclerosis, the arteries stiffen up due to a buildup of plaque in the arteries and blood vessels. These two conditions can cause a decrease in the amount of blood that flows to your extremities, therefore resulting in pain.
Some of the most common symptoms of poor circulation are:
- Numbness
- Tingling
- Throbbing or stinging pain in limbs
- Pain
- Muscle Cramps
Treatment for poor circulation often depends on the underlying condition that causes it. Methods for treatment may include insulin for diabetes, special exercise programs, surgery for varicose veins, or compression socks for swollen legs.
As always, see a podiatrist as he or she will assist in finding a regimen that suits you. A podiatrist can also prescribe you any needed medication.
If you have any questions, please feel free to contact our office located in Lansdale, PA. We offer the newest diagnostic and treatment technologies for all your foot care needs.Read more about Causes Symptoms and Treatment for Poor Circulation in the Feet
Everything You Need to Know About Gout
Gout, typically found in diabetic patients, is an unusually painful form of arthritis caused by elevated levels of uric acid in the bloodstream. The condition typically strikes the big joint on the big toe. It has also been known to strike the knees, elbows, fingers, ankles and wrists—generally anywhere that has a functioning, moving joint.
The high level of uric acid in a person's bloodstream creates the condition known as hyperuricema—the main cause of gout. Genetic predisposition occurs in nine out of ten sufferers. The children of parents who suffer gout will have a two in ten chance of developing the condition as well.
This form of arthritis, being particularly painful, is the leftover uric acid crystallizing in the blood stream. The crystallized uric acid then travels to the space between joints where they rub, causing friction when the patient moves. Symptoms include: pain, redness, swelling, and inflammation. Additional side effects may include fatigue and fever, although reports of these effects are very rare. Some patients have reported that pain may intensify when the temperature drops, such as when you sleep.
Most cases of gout are easily diagnosed by a podiatrist's assessment of the various symptoms. Defined tests can also be performed. A blood test to detect elevated levels of uric acid is often used as well as an x-ray to diagnose visible and chronic gout.
Treatment for gout simply means eliminating symptoms. Non-steroid anti-inflammatory drugs or NSAIDs (Colchicine and other corticosteroid drugs, etc.) will quell the redness, the swelling, and the inflammation. However, managing your diet, lifestyle changes, and using preventative drugs are all helpful toward fully combating the most severe cases.
Those that lead an inactive lifestyle are at a higher risk for gout. Any amount of exercise decreases the probability of repeat encounters with the condition. Reducing your consumption of red meat, sea food, and fructose-sweetened drinks also reduces the likelihood of chronic gout as well.
Ingesting Vitamin C, coffee, and particular dairy products can help with maintaining a healthy lifestyle. There are new drugs out on the market that inhibit the body's production of uric acid-producing enzymes. However, reducing or eliminating your overall levels of uric acid is the best remedy to ensuring you lead a gout-free life.
Causes of Gout
The medical condition that is referred to as gout is a form of arthritis, which may affect the joints in the big toe. This condition may typically be associated with severe pain and discomfort and is the result of excess uric acid in the blood levels. Crystals will form in the joints of the big toe and the pain may be debilitating until this ailment subsides. There are several causes for this condition to develop, including a family history of gout and ingesting foods that are high in purine levels. These foods may include eating excess shellfish, red meat, or drinking an overabundance of alcohol. Research has shown that stress, specific medications, or a prolonged illness may play a significant role in developing gout. If you feel you have this condition, it is advised to speak with a podiatrist who can properly treat this uncomfortable condition.
Gout is a foot condition that requires certain treatment and care. If you are seeking treatment, contact Dr. Rick L. Simon from Lansdale, Pennsylvania. Our doctor will treat your foot and ankle needs.
What Is Gout?
Gout is a type of arthritis caused by a buildup of uric acid in the bloodstream. It often develops in the foot, especially the big toe area, although it can manifest in other parts of the body as well. Gout can make walking and standing very painful and is especially common in diabetics and the obese.
People typically get gout because of a poor diet. Genetic predisposition is also a factor. The children of parents who have had gout frequently have a chance of developing it themselves.
Gout can easily be identified by redness and inflammation of the big toe and the surrounding areas of the foot. Other symptoms include extreme fatigue, joint pain, and running high fevers. Sometimes corticosteroid drugs can be prescribed to treat gout, but the best way to combat this disease is to get more exercise and eat a better diet.
If you have any questions please feel free to contact our office located in Lansdale, PA. We offer the newest diagnostic and treatment technologies for all your foot and ankle needs.Read more about Everything You Need to Know About Gout
Treating Heel Pain with Shockwave Therapy
Shockwave therapy is one treatment option for plantar fasciitis, a condition that causes heel and foot inflammation and pain. This type of injury is often caused by overworking the feet. Heel pain is most common in people that exercise often, individuals who are overweight, and people whose profession require them to stand for long periods of time.
Heel pain can be caused by a number of problems including ill-fitting shoes, strenuous exercise routines or work hazards. Simple treatment options involve buying new shoes, taking ibuprofen, doing heel and foot exercises, and resting your feet. For severe cases, shockwave therapy can be considered a more viable form of treatment.
Shockwave therapy should be considered for patients that have had unsuccessful treatment or whose heel pain has lasted for more than six months. In shockwave therapy, a device delivers shockwaves to the patient's body, which jumpstart the body's repair mechanisms. These mechanisms then begin working more effectively to repair damage done to the heel area.
Shockwave therapy also helps eliminate pain in the heel area. When the body's natural repair mechanisms are triggered, tissue healing in the body is sped up. This leads to pain reduction after pain transmission nerves are stimulated.
Shockwave therapy eliminates the risk factors associated with surgery, such as the use of anesthetics, and is less invasive. Since this technique also helps improve the body's natural healing techniques, recovery time should be shorter than surgical procedures.
Discomfort issues can also be a side effect of treatment. Short-term issues normally include skin bruising, minor pain during and after treatment, swelling of the heel, and discolored tissue. However, these side effects of shockwave therapy usually disappear after a few days. The fast recovery time of shockwave therapy makes it easy for patients to return to their daily routines.
Like most types of treatments, surgeries, and medications, shockwave therapy is not for everyone. Potential patients with heart conditions and people with pacemakers should not be considered for this technique. People on certain types of medications, usually medications affecting blood clotting, would be ineligible for shockwave therapy. Children and pregnant women should avoid this treatment option as well.
Overall, shockwave therapy could be a great option for heel pain. It is less invasive than surgery, helps trigger natural healing mechanisms, and should be considered by people who have had long bouts of heel pain or tried conventional treatment options that were unsuccessful.
There Are Two Types of Shockwave Therapy
Shockwave therapy may be an option that may provide moderate relief for people who are afflicted with specific types of foot pain such as plantar fasciitis or chronic tendon conditions. This type of treatment may aid in initiating the healing response in the body and may help to heal the affected areas. Research has shown there are two types of this type of treatment that may be implemented, which are referred to as low and high energy treatment. The latter is given in one session and may require the use of general anesthesia to reduce the sensation of pain. Low energy shockwave therapy is typically administered in several treatments and may generally produce little or no pain. Many patients are satisfied with the results of this noninvasive treatment, even though it may be costly. If you are suffering from this type of foot pain, please speak with a podiatrist for addition information about shockwave therapy.
Shockwave therapy is a treatment commonly used to treat various injuries and conditions, particularly plantar fasciitis in the feet. To learn more, consult with Dr. Rick L. Simon from Lansdale, Pennsylvania. Our doctor can provide the care you need to keep you pain-free and on your feet.
Shockwave Therapy
Shockwave therapy is a new treatment option designed to treat bone conditions such as tennis elbow, shoulder pain, and others. Shockwave therapy uses high intensity sound waves that are directed to the affected tissues of the body with pinpoint accuracy. The effects are very beneficial, leading to a production of collagen fibers, eliminating inflammation.
Who Benefits from Shockwave?
Shockwave is recommended for patients suffering from heel pain and associated problems. Heel pain is a common condition which can be caused by obesity, overexertion, and spending a substantial amount of time on hard floors with your feet exposed and unsupported.
Fast and Easy
The therapy is actually a simple process that can leave patients feeling better the very next day. Shockwave therapy is not as dramatic as it sounds. It enables more blood flow to effected areas, addressing the source of the problem and allowing treatment to last for a long time.
Treatment & Recovery Time
Shockwave treatment will enable your feet to recover quickly. This is especially important since surgery is not required. It is cost effective and does not require the use of anesthesia. This treatment is a better option to surgery, since it is proven safe.
If you have any questions, please feel free to contact our office located in Lansdale, PA. We offer the newest diagnostic and treatment technologies for all your foot and ankle needs.Read more about Treating Heel Pain with Shockwave Therapy


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This Stockholm rental is just the enlargement of a single room. Whether you may need to or not, it's a ought to to consider it, due to that's the actual fact. The small, however cozy, condominium is an trustworthy and fashionable metropolis crib. The most important dwelling area has the entertaining area, consuming room and mattress room, 'multi helpful giant room'.
The mattress occupies an alcove close to the kitchen, however this carry out makes it incomparably fascinating. At the very best of the hallway, we've got acquired a updated stroll-in-closet, giving the residents the prospect of utilizing your full area; the closet has wardrobe fittings as rather a lot as a result of the ceiling. The area maintained its distinctive parquet flooring. This magnificence eclipses the truth that the fridge is positioned contained in the closet contained in the hallway. Stucco ceilings in white are visually brightened by pure delicate coming from huge-paned residence house home windows.
While taking inventory of this Stockholm condominium, a criticism might probably be raised that that is small, however it has many storing selections similar to the stroll-in closet contained in the hallway, closets and storage beneath the mattress. Having direct entry to the inside courtyard, the house encourages the inhabitants to profit from as a lot present air as attainable, inviting them to the floor, the place patio furnishings and a barbeque await. Though one-roomed, this dwelling area earlier take a look at supplies sufficient area for the inhabitants to profit from homely comforts to their brim, contained inside the crib together with outside. This house is an impressive evaluation in how small areas is perhaps metamorphosed into huge locations of calm and opulent, offered we have got now the requisite ideas and inclination.
Stockholm Penthouse is an Exquisite Apartment