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rom scratch in my portfolio area, you can review and measure my quality of work. Moreover, I am pretty much flexible in terms of time for communication so please feel free to contact me whenever you want. Thanks!


These plates are issued to carpool commuter vans transporting passengers to work, such as the "Easy Street" vans seen around the state.
This type started in 1980. The officially-issued plates have always been blue on white, changing to the generic "blue fade" base in 2000.
Shortly after this type was introduced, Van Pool became Vanpool.


text:
Q: How to open multiple pages in the same app? I know that Aurelia is a framework for an SPA but I need to open multiple pages at the same time inside the browser.
I want to host each page (view/viewmodel) within a draggable div and have more than one open at the same time. They will be selected by the User from a menu.
I have looked at viewPorts but cannot see how they will help in this problem.
Is there another way to do this?

A: Yes, there is a way to do this.
You say pages, but basically they are components. Every component has a HTML (view) and JS (view-model) file. They can be included as custom-elements.
So if you want multiple possible components on one page, all you need to do is create one component that has a placeholder for those views.
Probably, you would want something looking like this:
running Gist example
<template>
  <require from="./page1"></require>
  <require from="./page2"></require>

  <page1></page1>

  <page2></page2>
</template>

You can create loop for all elements you want to display, if you need multiple instances of the same page, and put a repeat.for on the elements:
HTML:
<template>
  <require from="./page1"></require>
  <require from="./page2"></require>

  <page1 repeat.for="i of page1instances"></page1>

  <page2 repeat.for="i of page2instances"></page2>
</template>

JS:
export class App {
  const page1Instances = 4;
}

Making them drag&droppable works like every other element, there are many solutions for that to be found. Just make the <page1> and <page2> draggable.

redpajama_set_name: RedPajamaStackExchange


text:
Q: MarketingCloud SDK - iOS turn on/off for GDPR? can I disable the salesforce SDK in my iOS application if the user chooses to not share their data with respect to the GDPR?
Basically, how does MarketingCloudSDK handle GDPR?

A: The SDK handles GDPR in response to changes in the Marketing Cloud system itself - the server communicates the state of contact privacy (Do Not Track, Right to be Forgotten, Restriction of Privacy) to the SDK daily and the SDK will take the appropriate action (deleting PII, turning off services, etc.).
Fully documented here: https://salesforce-marketingcloud.github.io/MarketingCloudSDK-iOS/sdk-implementation/data-privacy-iOS.html


The bunting and flags were out and excitement was buzzing around St George's as we waited for the arrival of the Bishop of Nottingham - The Right Reverend Patrick Mckinney S.T.L. On Tuesday 8th March, Mass was celebrated at St George's Catholic Academy Derby by the Bishop to bless our memorial garden and new office buildings. Staff, governors, parents, parishioners and pupils all enjoyed a special mass, con- celebrated with the Bishop by Canon Alan and Fr Jude and we were even able to go out to the garden for the blessing as, although it was a cold March day, the sun shone down at the end of mass as the whole congregation processed out to the garden. The memorial garden has been created in memory of the six children who tragically died in a house fire. They were all pupils, at St George's and St Benedict Academies and many of our ex pupils from St. Benedicts who knew the children personally joined us. The garden, designed by pupils, was started over three years ago with funding from the Lottery and Toyota and donations from parents, parishioners and the local community. Then Derby Garden centre kindly offered to plant the garden for us. Mass was followed by refreshments and cake with the Bishop and an extra special afternoon was planned for pupils. They had fun decorating pebbles, creating Bishop's hats, composing poems and prayers, making crosses and wind chimes, decorating biscuits, painting flags and they even enjoyed doughnuts and juice.
A wonderful day which has created some lovely memories for all.


text:
<?php

namespace Reflection\Tests\Validator;

use PHPUnit\Framework\TestCase;
use Reflection\Validator\FunctionValidator;
use Reflection\Validator\ArgumentSpecification;

class FunctionValidatorTest extends TestCase
{
    use Data;

    protected $firstArgument;
    protected $secondArgument;

    /**
     * {@inheritdoc}
     */
    protected function setUp()
    {
        parent::setUp();
        $this->setUpArguments();
    }

    protected function setUpArguments()
    {
        $this->firstArgument = (new ArgumentSpecification('string'))
            ->setOptional(false)
            ->setPassedByReference(false)
            ->setType('string');

        $this->secondArgument = (new ArgumentSpecification('iterator'))
            ->setOptional(false)
            ->setPassedByReference(false)
            ->setType(\Iterator::class);
    }

    public function testPositive()
    {
        $validator = (new FunctionValidator(new \ReflectionMethod($this, 'reflectionMethod')))
            ->setReturnByReference(true)
            ->setReturnType('int')
            ->addArgument($this->firstArgument)
            ->addArgument($this->secondArgument);

        $this->assertAttributeCount(2, 'arguments', $validator);
    }

    /**
     * @dataProvider providerWrongNumberOfArguments
     * @expectedException \Reflection\Validator\Exception\BadFunctionDefinitionException
     */
    public function testWrongNumberOfArguments(array $arguments)
    {
        $count = count($arguments);
        $validator = (new FunctionValidator(new \ReflectionMethod($this, 'reflectionMethod')))
            ->setReturnByReference(true)
            ->setReturnType('int');

        foreach ($arguments as $argument) {
            $validator->addArgument($argument);
        }

        $this->assertAttributeCount($count, 'arguments', $validator);
        $this->expectExceptionMessage(
            sprintf(
                'The "Reflection\Tests\Validator\FunctionValidatorTest::reflectionMethod()" ' .
                'method must have %s arguments, 2 given.',
                $count
            )
        );
    }

    /**
     * @dataProvider providerWrongReturnType
     * @expectedException \Reflection\Validator\Exception\BadFunctionDefinitionException
     */
    public function testWrongReturnType(string $method, string $expectedExceptionMessage)
    {
        $this->expectExceptionMessage($expectedExceptionMessage);

        (new FunctionValidator(new \ReflectionMethod($this, $method)))
            ->setReturnByReference(true)
            ->setReturnType(\Iterator::class)
            ->addArgument($this->firstArgument)
            ->addArgument($this->secondArgument);
    }

    /**
     * @expectedException \Reflection\Validator\Exception\BadFunctionDefinitionException
     */
    public function testWrongReturnReference()
    {
        $this->expectExceptionMessage(
            'The "Reflection\Tests\Validator\FunctionValidatorTest::reflectionMethod()" ' .
            'method must not return a value by reference.'
        );

        (new FunctionValidator(new \ReflectionMethod($this, 'reflectionMethod')))
            ->setReturnByReference(false)
            ->setReturnType('int')
            ->addArgument($this->firstArgument)
            ->addArgument($this->secondArgument);
    }

    public function providerWrongReturnType()
    {
        $this->setUpArguments();

        return [
            [
                'reflectionMethod',
                'The "Reflection\Tests\Validator\FunctionValidatorTest::reflectionMethod()" ' .
                'method must return a value of "Iterator", but at the moment it is "int".',
            ],
            [
                'reflectionMethodWithoutReturnType',
                'The type of returning value for "Reflection\Tests\Validator\FunctionValidator' .
                'Test::reflectionMethodWithoutReturnType()" method is not specified.',
            ],
        ];
    }

    public function providerWrongNumberOfArguments()
    {
        $this->setUpArguments();

        return [
            [[]],
            [[$this->firstArgument, $this->secondArgument, $this->secondArgument]],
        ];
    }
}

redpajama_set_name: RedPajamaGithub


The SereneLife Portable Infrared is our pick for the best home sauna because of its portability, ease of setup and its inclusion of a chair that can allow you to sit for hours with more comfort. It is ideal for home detoxification.
Our step-up pick is the Durasage Portable Indoor and this one is very easy to put together at only 5 minutes, and can be used at home or anywhere. It has a chair and a foot pad included and has a large size that fits most people.
The budget pick is the Hindom Box Portable and this one is also portable and comes with carbon heating panels that are all ETL approved and eco friendly. It comes with 5 temperature settings for you to use depending on your needs.
A sauna can be found in either private areas or public places. The difference between private and public types is that the private ones are usually smaller and can fit somewhere from 1 to 3 people at once. The public ones, however, are those that can fit up to 10 people or more. The public ones can be larger than 5 feet while the private and home ones can be just around 4 feet or less.
Those who do not want to always have to go to a public place can enjoy the pleasures of home therapy. If you don't enjoy being in a public area due to certain issues then you can buy yourself a home sauna for you to feel warm in the comfort of your home and also feel its benefits.
It can be found anywhere in the world but the most common place can be in Europe or north Asia. Finland is known to be the best in this field of activity. In Finland, this kind of heating room is an important part of their culture so they will usually have these rooms in nearly any home and public area. They usually have traditional types that use the water and stone method.
Remember that excessive heat can lead to dehydration, so make sure you get sufficient recovery time first, especially if you are a beginner and not very used to high heat temperatures. Dehydration can be combated with properly drinking and the right time of using the room.
Construction of body and door: the body and the door can be made of different materials. Some have a wooden door but most today have a tempered glass door that is durable and see-through and can also be scratch-free. For home type rooms, they can either be made of glass or wood. The wood material for the body can be usually made out of red cedar wood and Canadian hemlock, and they should be sustainably harvested.
Heating method: the heating method can be different from each other, such as carbon and ceramic for heating types, and the traditional heating method for those who want to make use of stones to heat up and add humidity. Infrared heaters are less hot compared to the traditional types, and this is why they are preferred by those who just want an at-home system that is easy to set up. The traditional types are most ideal for public areas.
Ease of installation: usually, if you want a home type heating room then you should consider one that is simple to set up with its construction. It should come with a user's manual so that it will be simpler to install for you and the electrician. The plugs should be compatible with your current electric system and vents, if present, should be simple to install as well.
Number of heaters: consider the number of heaters that are present in your home heating room. Most can have 6 to 7 heaters depending on whether it is ceramic or carbon, but some higher end ones can go for up to 10 heaters at once, usually those that are priced above $2,000.
Indoor or outdoor use: you need to consider whether your home heating room will be used for indoor or for outdoor use. Indoor ones are usually the most ideal for home use, but those that are for outdoor use can be situated in patios and the like. Indoor ones are easier to install with your current and existing system but outdoor use may take some time and effort to install all in all.
Method of delivery: some can accept curbside delivery while some may be difficult when it comes down to the delivery options. You should ask the manufacturer first on where they deliver, depending on the size of your unit and where you live. Usually, the bigger ones that have more features can be harder to deliver so you need to consider various factors with this criteria first.
Added features: consider those with added features such as chromotherapy, ionizer, music player, lights, backrests and many more. You can have these additional stuff if you have the budget and the needs for it, so it is important that you pick one for your best preferences. Usually, more added features means a higher price tag, so you should consult your wallet first.
Warranty policy: some companies offer a longer warranty period but this depends on the product that you order and its size and features. Some can offer 5 to 7 years of limited warranty policies but some can go for as much as 10 years of warranty. Know all of the factors to consider in the warranty such as the return methods and the like.
As our top pick, the SereneLife Portable Infrared is very portable and easy to use and move from one place to another. It comes with a foot pad and a chair for comfort and is easy to control as well. It can heat up within 5 to 10 minutes and it also comes with timers and the like.
While not a deal breaker, the SereneLife Portable Infrared is only for 1 person, but there are other models out there that are meant for 2 people or more.
The Durasage Portable Indoor is our step-up pick, which uses infrared technology and can be set up to 60 minutes of maximum operating time. It only takes 5 minutes to heat up the surroundings and it comes with a chair and heating foot pad as well.
The Hindom Box Portable is our budget pick, which can be set up to 150 degrees F of temperature. It is made with ETL approved carbon panels for heating and can be set up to 5 levels of temperatures for your added convenience.
The ALEKO PIN15SY is a personal home use type of heating room mechanism that comes with a foot pad and folding chair for your convenience. It can be used for up to 60 minutes and can heat up to 140 degrees Fahrenheit.
If you want a portable one then you should consider the Anfan 2L Portable, which you can bring anywhere for additional weight loss and detoxification in your lifestyle. It comes in 2 colors and also comes with an adjustable timer to time your stay there.
Made for a 2-person configuration, the DYNAMIC SAUNAS Andora is great for those who enjoy a bigger sized one. It uses Canadian hemlock for the panels and plugs into any standard 110-volt system. It also comes with mp3 player compatibility.
The Almost Heaven Grayson is a great 4 person unit that can be used for indoor areas. It has a hemlock and fir combination for the wood and comes with a stainless steel heater that is at 6 kW in its power consumption. It has a delay factor option for up to 8 hours.
For those who want a dome shape, the Crystal Ray KOREA is a good choice, which is foldable and portable. It consumes less energy than other units and it has a unique design. It is designed for home use and can be folded when not needed.
The Almost Heaven Bluestone has enough space up to 3 people and comes with a stainless heater at 4.5 kW. It has an LED lighting system and comes complete with a set of stones, a bucket and a ladle for that traditional feeling.
The Empava 2-3 Person is powered by carbon heaters totaling to 8 in the whole unit, and is protected by durable Canadian hemlock wood. It can be set up to 141 degrees Fahrenheit and can take 15 minutes to heat up. It can be set up with your mp3 player and has a radio and Bluetooth speakers as well as an ionizer and lights for reading.
While others looked promising, they were not in this list because they were not very durable with their material. Also, they were hard to install with lack of user's manual and they had less features for a higher price, which is not really economical.
Q: What should I wear when using the sauna?
a. Towel – the most basic thing of all is to just wrap a towel around you, especially for those with private rooms. In public rooms, this can be a bit awkward, especially in a mixed room, so most people wear towels only in private rooms. However, the benefits of using a towel instead of other garments is that it helps your skin breathe and maximizes the added benefits of being in this kind of heating room.
b. Loose swimsuit – if you don't like the idea of towels because you feel embarrassed or awkward and you need to protect your privacy, especially in a public area, a loose swimsuit would do the trick. It should be made of natural fibers so that it will not leak out any dye from the tremendous heat produced by the room. Again, like with towels, you need to make yourself clean first by rinsing before going inside.
c. Cotton – if you need to consider more coverage because of cultural cues, such as in conservative parts of the world, such as in Asia, consider any cotton shirt, shorts or any garment to help you experience a similar breathability with having a towel wrap. Underwear should be left out – this also means lingerie.
d. Don't wear "sauna suits" – because these suits don't really have natural fibers and they can interfere with the environment of the room due to the heat potentially exposing the plastic and synthetic fabrics of your suit. Consider any natural fabric instead so that it will be eco-friendly and more breathable.
e. Don't wear shoes or footwear – this can make the flooring dirty and can be blown into the air, contaminating the inside of the room. They also hold heat which can make your foot irritated with athlete's foot and similar foot problems.
f. Don't wear sweaty clothes – they can contain all of the dirty stuff and can leach into the air of your heat room. This is why you need to ditch them to avoid contaminating the surroundings, especially if you are in a public room. They will also make the air smell bad if you keep wearing them for your session.
g. Clean your items with vinegar – cleaning your towel or sauna garment with a harsh detergent can make the inside of the room less pleasant. Do consider washing it with a milder detergent, if you really need to get it clean.
Q: What are the benefits of using this heating room?
1. Added relaxation – using this kind of room helps your entire body to relax, much like with getting a back and neck massage. The heat from the room can penetrate your skin and become a soothing feeling that can help you to relax. If you have been stressful lately due to some problems at work or in school or at home then unwinding with this kind of activity in the heating room can help alleviate your stress.
2. Relief from joint, body and muscle pains – one of the key benefits of this kind of heating room is that your muscle pains can be relieved, especially after an exercise. Those with problems in their joints and body aches can also feel the therapeutic effects of this kind of heating room. The heat that is generated can help with your various body pains so that you can work or study effectively later on, or do your other activities better.
3. Helps with blood flow – it is important to have a healthy blood flow so that you will be less likely prone to heart problems, hypertension and the like. One way of doing so is by getting into this kind of heating room so that your blood flow will be regulated and will not become stagnant, which can lead to various illnesses and problems in your body. Aside from regular exercise, adding this kind of heating therapy helps a lot.
4. Alleviates negative feelings – aside from its relaxation benefits, it has a great way of relieving your stress, anxiety and other bad feelings you have felt lately. For those who are going through any form of depression or negativity in their life, a great way to relax and loosen up is with this kind of heating activity to improve their mental and emotional health as well, which are also both important in anyone's life and daily activities.
5. Adds endurance to your physical and mental health – it helps you to become stronger in various physical activities such as with exercise, sports and the like. It also adds more positivity to your mental health when you endure the heat of this kind of room. Endurance and immunity can be boosted with this kind of room because it releases endorphins, much like with exercise, for you to feel good inside and out as a person.
Q: Why is Finland considered the sauna region of the world?
a) It's part of their culture. Finns are very much known to be the origin for this kind of activity simply because it is an integral part of their culture, history and everything in between. It is like an identity for their country so it is no wonder that you will find this kind of heating room almost anywhere, from private homes up to the public areas, in which many people treasure the heritage and gather in them.
b) Nearly 3 million saunas are in the country. In most cases, you will more likely find these kinds of rooms more than you will even find automobiles in the country. This shows their extraordinary love for this kind of activity more than any other country in the world. Their immense support to this kind of health activity is so deep that there is roughly one to two persons per room, which is pretty lucky.
c) They like to dip in cold, icy lakes afterwards. This is known to be a custom in this country and in this kind of activity, and is a true test of power for most Finns. They also do it in other parts of the world, but it originated in this country. It can be dangerous if you are not physically fit, however, but for those who want to test endurance, it will feel good and is a great experience.
d) They promoted whisking – using a birch twig. This kind of activity is mostly done by the Finns but is now being adapted by the rest of the world when it comes down to this kind of heating room. This whisking activity is done for adding more blood circulation while you are in the public or private room.
e) They have their own terminology with sauna stuff. One of the really cool things about the Finns is that they call the stove, the ladle, the rocks, the water, etc. with specific terminology that only they use and understand. Simply put, their obsession with this kind of heating room is very deep indeed.
Q: Why should I add a sauna to my home?
A good way to detoxify is to add this kind of heating mechanism to your home. It helps if you want to get rid of all the bad stuff from your body so that you will feel healthier inside and out.
It helps if you have trouble with pains in your muscles after any exercise or physical activity. For those people with constant muscle pains and the like, it can help alleviate these pains similar to that of a massage due to the heat.
For those people who have been plagued with stressful activities, events and the like. This is a great stress reducer activity that you can do to help reduce your anxiety, stress and various negativity in your life.
It pays to have a healthy circulatory system so it can really help if you add this kind of heating room to your home area. It helps to add vigor to your circulatory system so that your blood flow will be regularized and maintained well.
This kind of activity can help boost your metabolism so that the fat in your body doesn't always stay there, leading to some manner of weight loss or management. It is a supplementary type of activity that heats up your body and makes you sweat even more to help burn some fat and calories along the way.
One of the greatest benefits for using this kind of room at home is that it improves your skin quality and is great for those who may have acne problems and skin irritations. It helps your skin to breathe better so that it does not get clogged with bad bacteria and dirt all the time.
Those with respiratory problems such as allergies, clogged nose, sinus problems and the like may benefit from this kind of heating room activity. It helps if you can control the steam and humidity to add to the vaporization method to help alleviate such respiratory problems.
Q: What should I watch for or consider when using these rooms?
Because things can get hot in this kind of room, it is important that you stay safe by staying away from really hot stuff so that you won't risk burning yourself or any part of your body, which can be a traumatic experience for most people. Consider staying safe while you are using this kind of heating room.
For men, it can be dangerous to stay inside this kind of heating room all the time because it can take its toll on the sperm count of a man. This is why you should always make sure to only stay at reasonable amounts of time and take breaks in between to avoid infertility problems.
Just as with men, women may also have problems when it comes down to the amount of heat in this kind of heating room. Pregnant women may experience problems with their offspring if they use it while they are pregnant or even when they have given birth and are nursing.
This is a problem for most people who go in the room with their shoes on. Wearing shoes can most likely give you athlete's foot so make sure you walk barefooted at the very most. Do consider not using it if you have such fungal infections to avoid spreading it into the air and the area.
Because feeling thirsty is something that can potentially happen if you are in this kind of indoor heating room, it is inevitable that you may start to feel thirsty. However, sauna water is absolutely not that safe to drink, especially if you're a person with a sensitive stomach with water. Consider getting fully hydrated before or after the session in this case.
Dehydration can happen if you spend too much time in this kind of room due to the excessive heat. Consider drinking a lot more before you get inside the hot room to avoid the risks of dehydration and likely fainting or dizziness. Dehydration is a very dangerous situation so you should address it properly.
While it is a fun activity and an added challenge for most people, especially the Finns who take pride in this kind of activity, it can be dangerous for those who are not properly trained for it and are not physically fit to do the activity.
There can be sudden death if there is complication with dehydration and other factors. It pays to stay safe in this kind of heating room and not to spend too much time in it. Remember that it is not a contest of manliness but it is supposed to be a relaxing activity, which has limits as well, like the human body.
Q: What are the sizes of rooms to choose from for this kind of room?
1. Single Tier – this is a smaller room that is intended for those who are potentially solo or just for one person when it comes down to a heating room.
Q: Why are these heating rooms made of wood?
a. It tolerates heat very well. One of the key points as to why these kinds of heating rooms are made with wood is that heat doesn't melt away unlike other materials. The heat inside this kind of room is no joke and this is why you need a quality wood that can do well with this heating mechanism.
b. It doesn't retain moisture. Compared to other materials that do not do well with moisture, some wood types are good with such moisture and humidity. It is important that the wood does not retain moisture because it can help prevent the likelihood of mold, bad bacteria and the like that can harm the air quality. This is also why some of these units may also have an air purifier and ionizer alongside it.
c. It uses natural oils and preservatives to combat mildew. These natural oils can vary depending on the type of wood that you have, so it is important to pick high quality wood that is not only sustainably harvested, but is legitimately rich in oils that can keep the mold and mildew away while being used for a long period of heating time.
d. It eliminates bad odor from people when they sweat. We all know that when people sweat due to really hot environments, the result is either a sweaty sports like odor or even body odor that is caused by germs and viruses. This is why you need something that gives off a more natural scent that will make you feel like in a forest instead of being in a clumped room full of sweaty smells.
Q: What kinds of wood materials are used for this kind of heating room?
a. Cedar – this is the most common kind of wood type for either infrared or traditional types due to the fact that it is great against mold, mildew and moisture. It has a reddish color that has a darker brown shade, and it is best known for not easily expanding or contracting compared to other wood types. If you see one that is made for commercial use then it is most likely made out of cedar due to its durability.
b. Basswood – if you are not good with wood residue of other wood types then basswood is a great choice for you. It is also applicable for commercial use and it has a lighter color. It is also quite durable with any kind of temperature adjustment and does not emit any harmful toxins that can potentially cause allergies to people.
c. Hemlock – any hemlock made room is usually darker in color, and it is usually Canadian hemlock that is used to make it. Hemlock is a choice for those who don't have a lot of budget for cedar or basswood, and you will most likely see it in infrared types.
d. Pine – pine is another type of wood that can be seen in low-end types as well as in infrared types. Pine has a lighter color than hemlock and it makes the cost of the unit slightly cheaper.
e. Spruce – where spruce is available much like pine, it can be a cheap alternative for basswood and cedar due to its lower price value.
f. Eucalyptus – this is a good wood type that can be great for outdoor use due to its durability as well. It is also a cheaper alternative and it also does not emit any harsh fragrances that may make you allergic to it. This type of wood is also very good in its texture and just-right brown shade.
Q: What are the different door types for this room?
Q: There are many different types of this heating room – what are they?
1. Traditional or wood burning – these ones are the most commonly found in Finland due to their simplicity and traditional factor.
2. Electric type – these can either be mounted on the floor or on the wall and are mostly used by a lot of countries out there. It can come with a remote control and it is usually safer to operate.
3. Manufactured types – these are the ones that are custom built and you can buy directly from a manufacturer and have it delivered and installed to your home easily.
4. Savu Sauna – also called the smoke sauna, this is a type of heating room that uses much more wood to burn and it requires a lot of time and patience to prepare it. These are only most commonly found in Finland and not so much in other countries.
5. Infrared room – these are the most commercially available today because of their ease of installation, price and convenience. They don't use traditional stone heating methods and rely on infrared technology, which is either fueled by ceramic heaters or carbon heaters.
6. Steam room – this is also called the wet heater because it is mostly used for adding humidity to the air to give off a steam bath experience instead of a dry feeling. It has a lower temperature compared to a dry type room so it is best for those who don't want too much heat in general.
Q: How much calories can you burn in it?
A: When it comes down to the total calories burned, on the average, with this kind of room, the average number of calories you can burn with it is about 63 to 84 calories in 30 minutes. That is when computed with the average weight but this can vary depending on the time you spend there and your body weight.
Q: How much does it take to operate this kind of room?
Q: How does the sauna compare to a hot tub?
a. It is less likely to be a problem when it comes down to maintenance.
b. It can help your skin to become healthier and better cleansed.
c. Insomniac people can help get relief from their wakefulness.
d. They tend to be cheaper in terms of unit and maintenance fees.
e. They consume less energy in the long run.
f. It is good for your immune system overall.
g. Your home resale value can potentially increase.
a. It is not recommended for pregnant women.
b. Installation can be difficult in general.
c. Male infertility problems can potentially happen.
d. You may need a lot of space at home for it.
e. Installation fees tend to be on a higher scale.
a. They can be easier to install overall.
b. It helps with people who have insomnia and the like.
c. It helps for those with muscle aches and pains.
d. Installation costs are cheaper.
e. It helps with maintaining better blood sugar levels.
a. It may not have a good resale value at all.
b. Materials can cost more.
c. Like with saunas, they may have bad effects for pregnant women and the sperm count of men.
d. Energy efficiency is not very good compared to the hot room.
e. Maintenance can be troublesome overall.
Q: How much do I need to spend for installation costs?
Q: Is it possible to build your own sauna?
1. Consider the wiring of your heating room system.
2. Add insulation so that it will reduce on the operating costs.
3. Reflection of the heat can be done with a foil vapor barrier.
4. Add the wood panel, preferably cedar wood for a quality finish and durability.
5. Install the heater onto the wall inside the room itself.
6. Mounting the heater depending on the preferences or manufacturer's recommendation comes next.
7. For traditional types, you can add the rocks next.
8. Install the benches depending on the size of the interior and the position it is configured for.
9. The door should be installed next and this depends on the type of door you have.
10. Adding trim can help make your room look better finished and cleaner in the looks.
11. Install the flooring as recommended.
Q: How do I practice sauna etiquette?
1. Don't bring unnecessary electronic gadgets inside, which can distract others.
2. Talk in a soft manner so as not to disturb others.
3. Close the door quickly.
4. Public rooms shouldn't be used for drying clothes.
5. Make sure you shower first before going in.
6. Bathing should be done with a towel wrap or less clothes.
7. Shaving shouldn't be done publicly – only in an at-home unit.
8. Performing exercises in a public room can be distracting for others.
9. Ask others on how much water should be poured on the rocks.
10. Be courteous towards other people.
Q: What's the difference between a steam room and this kind of hot room?
Steam room: this one is usually meant for wet and humid conditions, which is great for respiratory problems and allergies.
Sauna: this one is for those who want a dry condition, and is great for backaches, muscle pains and joint aches, as well as for casual relaxation.
Q: How do I stay safe in this kind of heating room?
1. Keep each session from 15 to 20 minutes only, unless you're an expert with heat endurance and want to keep up to 30 minutes.
2. Make sure you have 10-minute breaks in between sessions to avoid the risks of dehydration.
3. Adding a cold shower afterwards can help you to cool down in between sessions.
4. Make sure jewelry are out of the room because they can cause irritation to your skin.
5. Consider bringing someone with you in case something bad happens.
6. Make sure you get hydrated before you get there and after each session. A good amount is around 2 to 4 glasses of cold water or any drink that can hydrate you.
7. Don't force yourself to stay in, even with peer pressure. By all means get out if you feel uncomfortable so that your condition will not get any worse.
Q: Does it help alleviate acne?
A: Yes, in most cases, it can help alleviate acne. This is because your pores become more opened when you sweat more while you are in the heat of the room. This helps your skin to breathe better. However, you should go for a shower quickly to avoid breakouts because sweat can get stuck in between the pores of your skin.
Q: Can it help with detoxing my body?
A: Yes, this kind of heating room can help with body detoxification because of its therapeutic benefits. When combined with other therapies such as herbal medicine and the like, you can achieve a fully detoxified feeling inside and out.
Overall, the SereneLife Portable Infrared is our pick for the best home sauna due to the ease of use, portability and great design that can be set up in any part of your home.


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Q: Limiting no-load output voltage of a tube amp power supply I am designing a power supply for my tube amp. Here's what I have come up with:

Duncan's PSU designer shows that it should work OK (and provide 256V at 320mA). However, should one or both output tubes fail, the voltage would rise to 550V, which the other tubes may not like. Also, since the rectifier is directly heated, it will warm up much faster than the output tubes, probably resulting in too high voltage for a brief time after turn on.
So, I need to somehow limit the output voltage. However, I do not want to use any semiconductors anywhere in the amp. So far, I have come up with one way to do it and want your opinion on it or other suggestions:

simulate this circuit – Schematic created using CircuitLab
R3 is made up of 10x 100Ohm 10W resistors, R2 value calculated so the relay turns on when the voltage is too high and turns off when the voltage gets too low (output tubes warmed up etc).
This would probably oscillate if R2 is not calculated precisely enough or with line voltage variations. Also, it would result in an overload of the power supply when the relay is active and the output tubes start working.
Are there any better ways of doing this?

A: Use a vacuum tube time delay relay. (Check Ebay)
Hook it up across the mains, with the NO contacts in series with the HV output.
Then, when you turn on the amp, the heater in the relay will close the contacts some time after the tube filaments/heaters warm up and supply HV when everything is ready for it.

A: I have solved the problem. Because I need a low current stabilized voltage too (for the input selector - the cold cathode thyratrons I am using self-start at 260V), I used a gas stabilizer SG-1P (140-150V) and a 10K resistor. In addition to making the input selector work properly it now makes the voltage at start not go over 460V. If I want to bring it down still, I guess I can just add a bleeder resistor.


How is financial stress affecting Canadians?
A national survey conducted by Leger has found that 42% of Canadians rank 'money' as their greatest stress. That stress is driving Canadians to lose sleep, reconsider past financial decisions, argue with partners and lie to family and friends. Women report more financial stress than men.
The Canadian Consumer Tax Index tracks the total tax bill of the average Canadian family from 1961 to 2015. Including all types of taxes, that bill has increased by 1,939% since 1961.
The average Canadian family now spends more of its income on taxes (42.4%) than it does on basic necessities such as food, shelter, and clothing combined (37.6%). By comparison, 33.5% of the average family's income went to pay taxes in 1961 while 56.5% went to basic necessities.
In 2015, the average Canadian family earned an income of $80,593 and paid total taxes equaling $34,154 (42.4%). In 1961, the average family had an income of $5,000 and paid a total tax bill of $1,675 (33.5%).


SUPPLEMENT PLAN CUSTOMIZED JUST FOR YOU!
Add this plan to help support your body. The right supplements can make such a big difference! You'll get a list of quality supplements with background info. You'll also get links so you can be sure to get the right types.


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Lawmakers want better treatment for women inmates
Sheyanne N Romero
The United States houses one-third of the world's female prison population and the majority of incarcerated women are mothers.
On Tuesday, law makers and prison reform activists from around the country met in Washington D.C. to discuss the issues surrounding the growth of incarcerated women and how the prison system can be more responsive to women and their needs.
The forum, entitled "Women Unshackled," was hosted by Justice Action Network, the nation's largest bipartisan group working to reform the justice system.
Women have more complex needs and at least half of the prison population have experienced at least one traumatic event — a quarter-to-half have a history of child abuse, said Holly Harris, executive director of Justice Action Network.
During a visit to a women's facility, Holly Harris asked prisoners a few questions.
"I asked the women how many of them had children, every one of them raised their hand," she said. "When I asked how many actually see their children, the room went silent."
Holly Harris went on to say that one in four incarcerated women are pregnant or the mother of a child under the age of 1. Additionally, women are the fastest growing demographic in prison, according to the ACLU.
"Where is the outrage?" she said. "Why aren't people talking about this?"
Substance abuse is a common driving factor, even more so than for men — 25 percent of women compared to 15 percent of men. California Department of Corrections and Rehabilitation stated that the female population declined immediately following the implementation of Proposition 47, which reclassified felony drug and property crimes to misdemeanors.
Officials expect the population of incarcerated women to increase by 2.9 percent over the next five years.
During the forum, Senator Kamala Harris (D-Calif.) announced the creation of new legislation aimed at meeting the needs of women in prison.
The Dignity for Incarcerated Women Act would serve as a series of "common-sense" reforms to how the prison system treats women.
"There is so much we can do to fix what is broken," Kamala Harris said. "Law enforcement has such a profound and direct impact on the most vulnerable among us. Law enforcement has a responsibility to be a voice for the voiceless."
Recently, the senator toured Chowchilla's Central California Women's Facility. There are roughly 5,800 women incarcerated in California prisons — nearly half of the female population is housed in Chowchilla.
More:Sen. Kamala Harris meets with Central Valley farmers
"The drastic increase in the women's prison population has destroyed communities, torn families apart and done little to promote public safety," Kamala Harris said. "It has also had a deep impact on children. In order to create lasting improvements to public safety, we have a responsibility to not only reunite women inmates with their families but to also support the rehabilitation and re-entry of these women inmates into society"
The Dignity for Incarcerated Women Act would:
Require the Bureau of Prisons (BOP) to consider location of kids when placing incarcerated people in facilities
Require BOP to create better visitation policies for primary caretaker parents.
Ban the shackling of pregnant women.
Prohibit the solitary confinement of women
Require BOP to provide tampons and pads free of charge to prisoners.
Restrict correctional officers from entering restrooms of incarcerated people of the opposite sex, except in exigent circumstances.
"We need to be smarter on crime," said Kamala Harris, who served as the state's attorney general before winning her seat in Washington D.C. "Especially when it comes to this population."

redpajama_set_name: RedPajamaCommonCrawl


We throw the word "king" around loosely in the church.
The Point: We serve our king Jesus by serving others.
Good morning! Did you know that this is the last Sunday in the church year?
Buzter hummed to himself. He was happy in his work, and he always hummed when he was happy.
Ezekiel illustrates spiritual leaders as shepherds leading sheep.
Jesus must be with us right now wherever we are here on earth, but we don't recognize him.
Oystein Brinch of Oslo, Norway, wrote a devotional for the Upper Room on May 18, 2014.
It's a dream we all have.
Keisha does not tolerate dishonesty in her employees.
In Colonial America each household was required to keep a leather bucket next to the front door.
"Your children are so talented -- and yet they're so nice!" people often exclaimed to Janet.
During the exile, God's people are scattered like abandoned sheep.
Leader:God! We come to thank and enjoy You.
Imagine yourself in a remote location, separated from familiar faces and places.
The scriptures are replete with striking symbols.
When I was in high school, I had a bad case of acne. Many teenagers did then and many still do now.
The Parable of the Sheep and the Goats is the last parable in Series A of the Lectionary.
I used to know a man who claimed to be able to make himself invisible.
Every day newspapers, magazines, and radio stations report how "bad" things are getting.


Equipments to capture biometrics information under Aadhaar. Image from Flickr by Julian Correa. Public Domain.
Last week, a nine-judge bench of India's supreme court issued a unanimous ruling that Indian citizens have a fundamental right to privacy .
The historic decision could have significant implications for India's biometric identity scheme or Aadhaar  (Hindi for "foundation"), the world's largest biometric identification programme.
Aadhaar was launched in 2009 in a stated effort to eliminate ghost, duplicate and fraudulent IDs that its proponents said were disrupting the delivery of financial and other social services and causing "leakages " in government revenue. Aadhaar is implemented by the Unique Identity Authority of India (UIDAI ).
Last week's judgment must be seen within the context of a series of citizen petitions to the court attempting to challenge the implementation and linkage of the biometric ID to various government welfare schemes and services.
On September 23, 2013, the Supreme Court of India passed an interim order in response to a batch of petitions  that argued that Aadhaar violates fundamental rights of equality and privacy.
The petitions specifically challenged the linkage of Aadhaar with various welfare schemes. In their response, the court held that "no person should suffer for not getting the Aadhaar card inspite [sic] of the fact that some authority had issued a circular making it mandatory." Since then, the court has stated several times  that Aadhaar cannot be mandatory until all the cases are heard in court and disposed of.
Theoretically, this made Aadhaar optional. However, various government bodies continued to link Aadhaar to more benefits and services.
In 2015, citizens petitioned the court challenging  the constitutionality of Aadhaar. Then-Attorney General Mukul Rohatgi, representing the central government, argued  before a three-judge bench of the supreme court that privacy is not a "guaranteed right," and that there were "inconsistencies" in the previous apex court orders, despite nearly thirty years of jurisprudence on privacy  in India to the contrary.
The government went on to argue that citizens will have to waive certain fundamental rights  in order to have access to government benefits. To settle the matter, the court decided  that the challenge would have to be resolved by a nine-judge constitution bench that would consider the overarching question of whether Indian citizens have a fundamental right to privacy or not.
But it took many months for the court to assemble this bench to hear the case.
In the meantime, more than 108 services – ranging from bank account access, to key healthcare procedures, to school enrollment — that citizens cannot access without an Aadhaar ID. Yet the UIDAI still maintains that the scheme is voluntary.
While petitioners continued to wait for the court to form this bench, in March 2016 the government passed the Aadhaar Act .
Soon after, the law was reported to have disrupted welfare schemes  across the country, 'leaked' citizens' data , and from some advocates' perspectives, become an instrument of surveillance . At one point, Aadhaar even had an officially sanctioned trolling programme  to attack critics of the scheme on social media.
Government proponents of the scheme, including Prime Minister Narendra Modi,  made several claims about the benefits of Aadhaar as a tool for combating identity fraud in welfare schemes. But civil rights activists and researchers have shown these claims to be dubious .
The magnitude of the Aadhaar scheme and its increasingly broad application to the many processes of everyday life left many advocates concerned  that even if the court finally heard the case and upheld petitioners' arguments, Aadhaar would have bcome so pervasive that it would become impossible for anyone to reverse the process.
Nearly two years after  petitioners challenged the constitutionality of Aadhaar, the supreme court finally convened a nine-judge constitution bench to determine whether Indian citizens will have a right to privacy was formed in July 2017.
During the course of the hearing, the tone of the government shifted  to endorsing a 'Data Protection Act' instead of a full-fledged fundamental right to privacy. This was yet another attempt on the part of the government to dilute  the right.
On top of that, it suggested some names for a committee that would formulate the law, the composition of which raised some eyebrows.
In spite of such heavy odds stacked against the petitioners, the supreme court delivered a unanimous verdict  that Indian citizens do have a fundamental right to privacy.
Twitterati were quick to point out that Aadhaar is still around.
Just a reminder that the larger case of Aadhaar is still going on in SC and the right to privacy hearing was just a key element of it.
While the 547-page judgment  will have implications on a host of pending cases, the government's response to the judgment is telling.
The law minister was quick to state that the judgment does not affect the biometric scheme. However, a day after the judgment, government officials close to the development feel that they will need to "ring-fence"  Aadhaar and demonstrate to the supreme court that the scheme does protect privacy of Indian citizens.


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What are the Symptoms of Addiction? How to Tell If Someone is on Zolpidem (Ambien)
HomeSubstanceAmbien Abuse, Treatment and Withdrawal TimelineWhat are the Symptoms of Addiction? How to Tell If Someone is on Zolpidem (Ambien)
Ambien Basics
Signs of Addiction
Finding Help for Ambien Abuse
In 2009, a man walked into a nursing home and opened fire. According to an article in the Huffington Post, during the man's trial his lawyers suggested that Ambien (zolpidem) was to blame, as the drug has a tendency to cause amnesia. The lawyers went on to say that people on the drug might say or do all sorts of strange things and that when under the influence, they aren't really responsible for their actions.1
Reports like these might lead family members and friends to believe that spotting an Ambien addiction in a loved one is easy. Watching for strange behaviors when someone is abusing the drug should make addiction easy to spot. In reality, identifying a true Ambien addiction is more difficult. Families can certainly spot the warning signs, but professional help is needed to diagnose and treat an Ambien addiction.
Ambien (Zolipidem) is used to treat insomnia and is a central nervous system (CNS) depressant. CNS depressants slow down the nervous system enabling users to fall asleep faster. The medication is also formulated to help the person stay asleep throughout the night. Ambien comes in tablet or spray form, is typically prescribed for short-term use, and should not be used for more than two weeks. Using this medication for longer periods of time or in larger amounts that prescribed by a physician can lead to dependence and addiction.2
People who struggle with Ambien dependence become acclimated to the medication and may not show signs of intoxication. Rather than seeming sedated or high while they are under the influence of the drug, people who abuse Ambien often appear normal. Families that see Ambien side effects on a regular basis might actually be dealing with an addiction. Some of these side effects include the following:
Daytime drowsiness, tiredness and a feeling of being "drugged"
Dizziness, loss of coordination and balance problems
Stuffy nose or nasal irritation
Digestive issues like nausea, stomach upset, diarrhea and constipation
Visual changes3
Those who are dependent on Ambien might find it difficult to stop using the drug. When the drug is stopped, those who struggle with Ambien addiction may experience withdrawal symptoms like gastrointestinal upset, uncontrolled crying, insomnia, nervousness and feelings of panic.
While the physical and mental signs of an Ambien addiction might be difficult to ignore, those who abuse this drug may also develop unhealthy and unusual habits as they attempt to keep the addiction a secret. If you or a loved one struggles with Ambien dependence, look for these signs of addiction:
Becoming preoccupied with getting and using the drug
Needing more of the drug before the next dose is due
"Doctor shopping" to get new prescriptions for the drug
Engaging in dangerous activities, like driving, while under the influence of Ambien
Participating in illegal behaviors, like stealing, to get and use the drug
Changes in physical appearance and a reduction in personal hygiene
Becoming more secretive about daily activities and spending more time alone
If any of these signs of addiction are present in a friend or loved on who uses Ambien, it's time to get help.
If you know someone who is abusing Ambien and you're not sure what to do, we'd like to help. Call Black Bear Lodge 24 hours a day to learn about our treatment programs and other services. Call now to find out more.
1 Chan, Amanda L. "The Disturbing Side Effect Of Ambien, The No. 1 Prescription Sleep Aid." The Huffington Post. 15 Jan. 2014. Web. 10 Aug. 2017.
2 "Zolpidem (Oromucosal Route, Sublingual Route) Description and Brand Names." Mayo Clinic. Mayo Foundation for Medical Education and Research, 01 Mar. 2017. Web. 11 Aug. 2017.
3 "Common Side Effects of Ambien (Zolpidem Tartrate) Drug Center." RxList. N.p., n.d. Web. 10 Aug. 2017.
Substance Abuse Side Effects and Treatment
Ambien Abuse, Treatment and Withdrawal Timeline
An Overview of IV Drug Abuse
Klonopin Withdrawal: A Timeline for Treatment
Oxycodone Abuse, Withdrawal Timeline and Treatment
OxyContin Treatment, Abuse and Withdrawal Timeline
Overdose: How It Happens and How to Prevent It
Prescription Drug Abuse: Symptoms and Treatment
Further Reading About What are the Symptoms of Addiction? How to Tell If Someone is on Zolpidem (Ambien)
Alternatives to Zolpidem (Ambien) for Anxiety Disorders
Ambien (Zolpidem) Abuse Health Risks
How Long Does It Take to Become Addicted to Zolpidem (Ambien)?
How Long Does It Take to Detox from Zolpidem (Ambien)?
How Much Is Too Much? Zolpidem (Ambien) Overdose
How to Detox or Get Off Zolpidem (Ambien)
How to Help a Family Member with a Zolpidem (Ambien) Addiction
The Issues of Recreational Use of Zolpidem (Ambien)
The Prescribed Uses for Zolpidem (Ambien)
What Can Happen When You Mix Zolpidem (Ambien) with Other Drugs or Alcohol?


With the prevailing wisdom changing on an almost daily basis, Burton G. Malkiel's reassuring and vastly informative volume remains the best investment guide money can buy.
In a time of increasing inequality, when high-frequency traders and hedge-fund managers seem to tower over the average investor, Burton G. Malkiel's classic and gimmick-free investment guide is now more necessary than ever. Rather than tricks, what you'll find here is a time-tested and thoroughly research-based strategy for your portfolio. Whether you're considering your first 401k contribution or contemplating retirement, this fully-updated edition of A Random Walk Down Wall Street should be the first book on your reading list.
In A Random Walk Down Wall Street you'll learn the basic terminology of "the Street" and how to navigate it with the help of a user-friendly, long-range investment strategy that really works. Drawing on his own varied experience as an economist, financial adviser, and successful investor, Malkiel shows why an individual who buys over time and holds a low-cost, internationally diversified index of securities is still likely to exceed the performance of portfolios carefully picked by professionals using sophisticated analytical techniques. In this new edition, Malkiel provides a brand-new section on the recent bubble in cryptocurrencies like Bitcoin, as well as valuable new material on "tax-loss harvesting"—the crown jewel of tax management. He also presents a critical analysis of two recently popular investment-management techniques: factor investing and risk parity.
On top of all this, the book's classic lifecycle guide to investing, which tailors strategies to investors of any age, will help you plan confidently for the future. You'll learn how to analyze the potential returns, not only for basic stocks and bonds but for the full range of investment opportunities—from money market accounts and real estate investment trusts to insurance, home ownership, and tangible assets like gold and collectibles. Individual investors of every level of experience and risk tolerance will find throughout the book the critical facts and step-by-step guidance they need to protect and grow their hard-earned dollars.


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Colombian On-Demand Delivery Unicorn Rappi Raises $1B From SoftBank
Mary Ann AzevedoNatasha Mascarenhas
Mary Ann Azevedo bayareawriter
Colombian on-demand delivery startup Rappi confirmed Tuesday afternoon an investment of "up to $1 billion" from SoftBank. The raise was done at a pre-money valuation of $2.5 billion, according to a Bloomberg report.
Last month, we reported that SoftBank Group Corp. (SBG) had unveiled plans for a $5 billion SoftBank Innovation Fund, or what it described as "the largest-ever technology fund focused exclusively on the fast-growing Latin American market." The funding marks the first investment from SoftBank's new innovation fund and was made alongside SoftBank's Vision Fund. SoftBank Group and the Vision Fund will each invest up to $500 million in Bogota-based Rappi, according to a release by the company.
The investment also marks the largest technology financing to date in a Latin America-based company, according to Rappi.
Since its inception in 2015, Rappi has now raised a total of about $1.4 billion—most recently, bringing in around $200 million in a Series D last August that took it to unicorn status, according to the startup's Crunchbase profile. Yuri Milner's DST Global led that round, which included participation from existing investors including Sequoia Capital and Andreessen Horowitz (a16z).
The chart below highlights recent funding rounds for Rappi.
According to the Latin American Venture Capital and Private Equity Association (LAVCA), Rappi focused on delivering beverages and first, and has since expanded into meals, groceries, tech goods, and medicine. The company also offers a cash withdrawal feature, allowing users to pay with credit cards and then receive cash from one of Rappi's delivery agents. To help keep costs efficient, the company's fleet of couriers use only motorcycles and bikes, according to LAVCA.
Rappi says that last year, it "expanded the number of products delivered by seven times, and registered a monthly growth of 20 percent" in the seven countries where it operates: Brazil, Colombia, Mexico, Argentina, Chile, Uruguay and Peru.
Simón Borrero, Sebastian Mejia, and Felipe Villamarin launched the company in 2015, graduating from Y Combinator the following year. A16z's initial investment in July 2016 was the Silicon Valley firm's first investment in Latin America, according to LAVCA.
Marcelo Claure, SoftBank Group's COO, CEO of SoftBank Group International and CEO of Innovation Fund, said of the company:"Rappi's founders have a bold vision to create the premiere multi-service 'super-app' for Latin America, improving the lives of millions in the region. In less than four years Rappi has become one of the fastest growing start-ups in Latin America. This rapid growth demonstrates the immense opportunity in the Latin American region."
In general, the Latin American region has seen a surge in VC investment and increased interest from global investors, which you can read more about it here.
Editorial note: The funding round was confirmed after this piece was published. We have revised the headline and the article to reflect this change.
TagsRappi Softbank
DraftKings Plans Public Listing Via Reverse Merger
$1.6M Worth Of Grafiti, Female-Founded Unicorns Make History, And A Sweet Spot For VC


Mark has nearly 40 years of global arbitration and mediation experience, having served in both executive and senior executive positions at the American Arbitration Association (AAA) and International Centre for Dispute Resolution (ICDR), leaving ICDR/AAA as Senior Vice President, EMEA in December of 2015.
Mark is thoroughly familiar with arbitration, mediation and conflict management practice and procedure, with 30 years of experience in training arbitrators, mediators, process users and advocates on four continents on behalf of various arbitral/ADR institutions, government ministries, Courts and NGOs.
While serving as a Regional executive for AAA, he personally administered or was responsible for the administration of thousands of commercial arbitrations, facilitating arbitral pre-filing and preliminary hearings which routinely addressed issues including jurisdiction, arbitrator appointment/conflicts, scheduling and information exchange in a wide variety of commercial settings, with individual case claims up to 1 Billion USD. Mark has also successfully mediated cases, including complex multi-party cases, in various industries including Construction/Infrastructure, Energy, Technology, Commercial Finance, Joint Venture/Partnership, Real Estate and Equipment Leasing.
In consultation with companies, governments and industry experts, Mark has drafted multiple sets of bespoke arbitration and ADR procedures, including online, "desk" arbitration procedures and AAA's first set of Dispute Review Board procedures and model contract specifications.
Mark is a founding, now honorary, Director of the International Mediation Institute.
"We are delighted to welcome Mark Appel as an International Member of Chambers. Mark enjoyed a stellar career with ICDR and we now look forward to working with him to further develop his arbitration, mediation and dispute board practice".


At Jono Hardware, we use a Shed Mule to deliver your shed to you. It allows us to get into tight spaces while also protecting your yard from tracks from heavy equipment. Watch the video to see how your shed will be delivered.


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Drug Interactions with Calcium Channel Blockers: Possible Involvement of Metabolite-Intermediate Complexation with CYP3A
Bennett Ma, Thomayant Prueksaritanont and Jiunn H. Lin
Drug Metabolism and Disposition February 2000, 28 (2) 125-130;
Bennett Ma
Thomayant Prueksaritanont
Jiunn H. Lin
The inhibitory effects of six commonly used calcium channel blockers on three major cytochrome P-450 activities were examined and characterized in human liver microsomes. All six compounds reversibly inhibited CYP2D6 (bufuralol 1′-hydroxylation) and CYP2C9 (tolbutamide methyl hydroxylation) activities. The IC50 values for the inhibition of CYP2D6 and CYP2C9 for nicardipine were 3 to 9 μM, whereas those for all others ranged from 14 to >150 μM. Except for nifedipine, all calcium channel blockers showed increased inhibitory potency toward CYP3A activities (testosterone 6β-hydroxylation and midazolam 1′-hydroxylation) after 30-min preincubation with NADPH. IC50 values for the inhibition of testosterone 6β-hydroxylase obtained in the NADPH-preincubation experiment for nicardipine (1 μM), verapamil (2 μM), and diltiazem (5 μM) were within 10-fold, whereas those for amlodipine (5 μM) and felodipine (13 μM) were >200-fold of their respective plasma concentrations reported after therapeutic doses. Similar results also were obtained based on midazolam 1′-hydroxylase activity. Unlike the observations with mibefradil, a potent irreversible inhibitor of CYP3A, the NADPH-dependent inhibition of CYP3A activity by nicardipine and verapamil was completely reversible on dialysis, whereas that by diltiazem was partially restored (80%). Additional experiments revealed that nicardipine, verapamil, and diltiazem formed cytochrome P-450-iron (II)-metabolite complex in both human liver microsomes and recombinant CYP3A4. Nicardipine yielded a higher extent of complex formation (∼30% at 100 μM), and was a much faster-acting inhibitor (maximal inhibition rate constant ∼2 min−1) as compared with verapamil and diltiazem. These present findings that the CYP3A inhibition caused by nicardipine, verapamil, and diltiazem is, at least in part, quasi-irreversible provide a rational basis for pharmacokinetically significant interactions reported when they were coadministered with agents that are cleared primarily by CYP3A-mediated pathways.
Calcium channel blockers (CCBs)1have been used widely for the treatment of hypertension, angina pectoris, and other cardiovascular diseases since first introduced in the 1960s. With such widespread use, there have been a number of reports on significant pharmacokinetic and pharmacodynamic drug interactions associated with CCBs (Hunt et al., 1989; Kirch et al., 1990; Schlanz et al., 1991; Rosenthal and Ezra, 1995; Lamberg et al., 1998). Most recently, numerous cases have been reported in patients receiving mibefradil, a newly introduced CCB, which ultimately motivated the voluntary withdrawal of the compound from the market (Welker et al., 1998). Inhibition of cytochrome P-450 (P-450) activities by CCBs has been suggested as one of possible explanations for such interactions. However, little has been reported in the literature on inhibitory effects of CCBs on human P-450s' activities other than those of CYP3A. Close examination of the data available on CYP3A indicated that, except for mibefradil, CCBs are not very potent P-450 inhibitors. Values for IC50or Ki for inhibition of CYP3A activities in human liver microsomes ranged from ∼10 μM for nicardipine to 100 μM for diltiazem (Tjia et al., 1989; Pichard et al., 1990; Wrighton and Ring, 1994; Zhao and Ishizaki, 1997). These values are over 100-fold greater than typical plasma concentrations of CCBs reported after clinical doses (Kelly and O'Malley, 1992). Recently, diltiazem has been shown to be a quasi-irreversible inhibitor of CYP3A both in vitro and in vivo in rats (Bensoussan et al., 1995). Although these results have not been confirmed with human liver microsomes, they appeared consistent with several significant drug interactions reported for diltiazem in vivo (Lin and Lu, 1998). To date, there have been limited data on mechanisms of CYP3A inhibition by other CCBs in animals or humans.
Chemically, CCBs (Fig. 1) are classified into three classes, benzothiazepines (e.g., diltiazem), dihydropyridines (e.g., amlodipine, felodipine, nicardipine, and nifedipine), and phenylalkylamines (e.g., verapamil). Like diltiazem, most of these CCBs contain an amine functional group and undergoN-dealkylation; both features are common for metabolic intermediate (MI) complexing agents such as diltiazem and several other amine-containing compounds (Pershing and Franklin, 1982; Bensoussan et al., 1995). However, possible formation of such a complex has not been reported for any of the amine-containing phenylalkylamines and dihydropyridines.
Structures of CCBs.
In this study, we examined and characterized the in vitro inhibition profiles of six commonly used CCBs (amlodipine, diltiazem, felodipine, nicardipine, nifedipine, and verapamil) on three major P-450 isozymes (CYP3A, CYP2D6, and CYP2C9) in human liver microsomes. Mibefradil, the CCB recently shown to be a potent mechanism-based inhibitor of CYP3A (Prueksaritanont et al., 1999), also was included in the study for comparison. In addition, the ability of diltiazem, as well as the amine-containing dihydropyridine nicardipine and phenylalkylamine verapamil, to form the MI complex with human P-450 enzymes was examined using human liver microsomes and recombinant P-450 enzymes.
Chemicals and Reagents.
Testosterone, midazolam, tolbutamide, diltiazem, nicardipine, nifedipine, verapamil, troleandomycin (TAO), 17α-ethynylestradiol, quinidine, sulfaphenazole, and NADPH were purchased from Sigma Chemical Co. (St. Louis, MO), whereas 6β-hydroxytestosterone and ketoconazole were purchased from Steraloids Inc. (Wilton, NH) and Research Diagnostics Inc. (Flanders, NJ), respectively. 3-Methylhydroxytolbutamide, 1′-hydroxymidazolam, bufuralol, and 1′-hydroxybufuralol were obtained from Ultrafine Chemicals (Manchester, England). Felodipine and amlodipine were obtained in house (Merck Research Laboratories, Rahway, NJ). Human liver microsomes pooled from 10 or 15 subjects were obtained from the International Institute for the Advancement of Medicine (Exton, PA) and In Vitro Technologies Inc. (Baltimore, MD). Human liver microsomes known to contain high levels of CYP3A activity (used in the P-450-iron (II)-metabolite complex formation experiment) were obtained from Gentest Corp. (Woburn, MA). Microsomes prepared from insect cells with cDNAs of human CYP3A4 and NADPH-dependent reductase coexpressed were prepared and characterized at Merck Research Laboratories (West Point, PA).
Assays for P-450 Activities.
Assays for CYP3A (testosterone 6β-hydroxylation and midazolam 1′-hydroxylation), CYP2D6 (bufuralol 1′-hydroxylation), and CYP2C9 (tolbutamide methyl hydroxylation) activities were described previously (Prueksaritanont et al., 1996). Testosterone, midazolam, tolbutamide, and bufuralol were used at concentrations (50, 10, 100, and 10 μM, respectively) comparable to their reportedKm values. Human liver microsomes were preincubated with CCBs for 30 min at 37°C, either in the presence or absence of 1 mM NADPH, before assaying for P-450 activities. Known selective inhibitors for P-450 CYP3A (TAO and ketoconazole), CYP2D6 (quinidine), and CYP2C9 (sulfaphenazole) were included as positive controls. Time- and concentration-dependent inhibition of testosterone 6β-hydroxylation was performed by preincubating human liver microsomes with CCBs in the presence of 1 mM NADPH for up to 45 min at 37°C. The reaction mixtures were then diluted 5-fold for the determination of testosterone 6β-hydroxylase activity, using 250 μM testosterone.
Dialysis Experiment.
Human liver microsomes (0.5 mg) were incubated with 1 mM NADPH and CCBs or known CYP3A inhibitors for 30 min at 37°C, in a final volume of 0.5 ml. Incubation mixtures were immediately transferred in to "slide-a-lyzer" dialysis cassettes (10,000 molecular weight cutoff; Pierce, Rockford, IL) and dialyzed against 1.5 liters of 0.1 M sodium phosphate buffer containing 5 mM sodium EDTA, pH 7.4, for ∼16 h. The dialysis buffer was changed once after 4 to 6 h. Undialyzed and dialyzed samples were diluted 5-fold and determined for their testosterone 6β-hydroxylase activities using 250 μM testosterone. Protein contents of dialyzed samples were subsequently measured using Lowry's method (Lowry et al., 1951).
Formation of P-450-Iron (II)-Metabolite Complexes.
Spectral differences (400 to 500 nm) between the reference and sample cuvettes were obtained using Perkin Elmer UV 20 double-beam UV-visible spectrophotometer. Incubation mixtures containing 1 mg/ml (P-450 content = 0.53 nmol/mg protein) human liver microsomes or 0.25 μM insect cell expressed recombinant CYP3A4, 0.1 M sodium phosphate, pH 7.4, 10 mM magnesium chloride, and 1 mM NADPH were placed in both cuvettes. CCBs were added at a final concentration of 0.1 mM to the sample cuvette and incubated at room temperature. Spectral differences were monitored every 4 min for up to 28 min. To prevent carbon monoxide complex formation (Franklin, 1991), the incubation mixture in the sample cuvette was bubbled with air briefly every 10 min. The extent of P-450-iron (II)-metabolite complex formed was quantified based on a previously reported extinction coefficient (455–490 nm) value of 64,000 M−1/cm−1 (Pershing and Franklin, 1982; Franklin, 1991). In the experiment with CYP3A4, spectral differences also were monitored after the addition of potassium ferricyanide (50–200 μM).
Data Analysis.
The concentration of CCBs producing a 50% decrease in the activities of P-450 (IC50) values were estimated using nonlinear regression analysis (PCNONLIN; Scientific Consulting, Cary, NC), based on the following relationship:E=Emax×[1−(C/C+IC50)] where E and Emax are the effects measured in the presence of CCBs (at concentrationC) and in the absence of CCBs, respectively.
Inhibitory Effects of CCBs on CYP3A Activity.
Concentration-dependent inhibitory effects of the six CCBs as well as those of known inhibitors of testosterone 6β-hydroxylation in the absence and presence of NADPH during the 30-min preincubation period are shown in Fig. 2, A and B, respectively. Both ketoconazole and TAO produced inhibitory profiles consistent with their mechanisms of inhibition. The potent reversible inhibitor ketoconazole did not show an increased inhibitory effect after preincubation with NADPH (Table 1). In fact, a decreased inhibition was observed (∼3-fold, Table 1). This was consistent with the fact that ketoconazole is a substrate for CYP3A. Also as expected, the quasi-irreversible inhibitor TAO showed increased inhibitory potency when preincubated in the presence of NADPH (Fig. 2, A and B; Table 1). In addition, IC50values obtained in the present study for both ketoconazole and TAO agreed well with those reported previously (Wrighton and Ring, 1994;Eagling et al., 1998; McKillop et al., 1998).
Concentration-dependent inhibition of testosterone 6β-hydroxylation after a 30-min preincubation with various concentrations of CCBs in the absence (A) or the presence (B) of NADPH.
Activities were determined by incubating human liver microsomes with 50 μM testosterone for 10 min after the 30-min preincubation period. Control activities (mean ± S.D., n = 6) = 2.7 ± 0.3 nmol/min/mg for preincubation either with or without NADPH.
IC50 values (μM) for inhibition of CYP3A activities in human liver microsomes
Among the six CCBs examined and after preincubation without NADPH, nicardipine was the most potent inhibitor (IC50 = 1.7 μM) of testosterone 6β-hydroxylase activity. All other CCBs showed comparable inhibitory potencies, with IC50values ranging from ∼20 to ∼80 μM (Fig. 2A, Table 1). The IC50 values of verapamil, diltiazem, and nifedipine for 6β-testosterone hydroxylase were comparable to those reported earlier using cyclosporin, quinine, or midazolam as a CYP3A probe (Tjia et al., 1989; Pichard et al., 1990; Wrighton and Ring, 1994; Sutton et al., 1997; Zhao and Ishizaki, 1997). With the exception of nifedipine, the inhibition effects of all CCBs were increased (from 2-fold for nicardipine to >10-fold for verapamil and diltiazem) when preincubated in the presence of NADPH, similar to the observation with mibefradil (Fig. 2B, Table 1). In the preincubation experiment with NADPH, nicardipine also was the most potent inhibitor (IC50 = ∼0.9 μM), whereas nifedipine was the least potent inhibitor (IC50 = ∼30 μM). Under similar conditions, the IC50 value for mibefradil was 0.3 μM (Prueksaritanont et al., 1999).
The inhibitory profiles of these CCBs and the known inhibitors on midazolam 1′-hydroxylase activity, another commonly used CYP3A marker, were very similar to those of testosterone 6β-hydroxylase activity (Table 1). In most cases, values for IC50obtained for the two markers were within 2-fold of each other (Table1). This similarity in the IC50 values, which were obtained at their Km values, were consistent with the fact that both markers are substrates for CYP3A. As was observed with testosterone 6β-hydroxylation, nicardipine also was more potent than the other CCBs tested, but was less potent than mibefradil in inhibiting midazolam 1′-hydroxylation.
Inhibitory Effects of CCBs on CYP2D6 Activity.
Unlike the observations on CYP3A activity, none of the CCBs examined showed increases in inhibitory potencies or decreases in IC50 values toward CYP2D6 activity (bufuralol 1′-hydroxylase) after preincubation with NADPH (Table2). Among the CCBs studied, the most and the least potent inhibitor were nicardipine (IC50= ∼3 μM) and diltiazem (IC50 > 150 μM), respectively (Table 2). The inhibitory potencies of verapamil, amlodipine, felodipine, and nifedipine were comparable, with IC50 values ranging between 40 and 70 μM. The results obtained with nicardipine were similar to those reported previously (Fonne-Pfister and Meyer, 1988). Under the present conditions, the IC50 value (0.06 μM) of quinidine, a known CYP2D6-selective inhibitor, on CYP2D6 activity also was comparable to that reported earlier (Halliday et al., 1995).
IC50 values (μM) for inhibition of 2D6 activities in human liver microsomes
Inhibitory Effects of CCBs on CYP2C9 Activity.
Similar to the above findings on CYP2D6 activity, inhibitory effects of the CCBs on CYP2C9 activity (tolbutamide methyl hydroxylase) were not increased by preincubation in the presence of NADPH (Table3). In either experiment, nicardipine was the most potent inhibitor (IC50 = 7–9 μM), whereas verapamil and diltiazem were much less potent inhibitors than any CCBs tested as indicated by their IC50 values of >140 μM (Table 3). In agreement with previous reports (Eagling et al., 1998; von Moltke et al., 1998), the known CYP2C9-selective inhibitor sulfaphenazole yielded an IC50 value of 0.5 μM.
IC50 values (μM) for inhibition of 2C9 activities in human liver microsomes
Characterization of CYP3A Inhibition.
To characterize the apparent NADPH-dependent inhibition observed on CYP3A activity, nicardipine, verapamil, and diltiazem were chosen for additional studies. As shown in Fig. 3, the inhibition of testosterone 6β-hydroxylation by nicardipine, verapamil, and diltiazem was both time- and concentration-dependent. Nicardipine was a fast-acting inhibitor, whereas diltiazem was a much slower inhibitor. Values for the maximal inhibition rate constant and apparent KI of nicardipine, verapamil, and diltiazem were estimated, based on reciprocal plots of the initial inhibition rate constant and CCB concentration, to be 2, 0.03, and 0.01 min−1 and 0.6, 0.5, and 0.5 μM, respectively.
Time- and concentration-dependent inhibition of testosterone 6β-hydroxylase activity by the CCBs nicardipine (A), verapamil (B), and diltiazem (C) obtained in the presence of NADPH during preincubation.
Activities were determined using 250 μM testosterone and after a 5-fold dilution of the incubation mixture. Control activities (mean ± S.D., n = 3) = 3.4 ± 0.1 nmol/min/mg.
Reversibility of CYP3A Inhibition.
Reversibility of the inhibition of CYP3A activity by nicardipine, verapamil, and diltiazem was examined by dialysis. As expected, the activity of CYP3A that was inhibited by all of the inhibitors examined after preincubation without NADPH was virtually restored by dialysis (Table 4). In the experiment with NADPH present during preincubation, CYP3A activity inhibited by nicardipine and verapamil also was fully recovered after dialysis (Table 4). However, dialysis only partially (∼80%) restored the inhibited CYP3A activity by diltiazem (Table 4). In a parallel experiment with mibefradil and ethynylestradiol, both potent irreversible inhibitors of CYP3A (Guengerich, 1988; Prueksaritanont et al., 1999), only 14 to 31% of the control activity was recovered after dialysis (Table 4).
Inhibitory effects of CCBs on testosterone 6β-hydroxylase activity in human liver microsomes before and after dialysis
Formation of P-450-Metabolite Complex.
In vitro studies were further conducted to investigate whether the NADPH-dependent inhibition of CYP3A activity by nicardipine, verapamil, and diltiazem was via the formation of MI complex. The three CCBs all contain an amine functional group, formed P-450-iron (II)-metabolite complex, as evident by a Soret peak at around 455 nm (Buening and Franklin, 1976; Pershing and Franklin, 1982; Bensoussan et al., 1995) when incubated with human liver microsomes in the presence of NADPH (Fig. 4, A–C). Under the conditions used (which yielded ∼40% complex formation for TAO, data not shown), the extent of complex formation was estimated to be ∼30, 20, and ∼6% for nicardipine, diltiazem, and verapamil, respectively. Similar results also were observed with recombinant CYP3A4 (Fig. 4, A–C), but not CYP2D6 or CYP2C9 (data not shown). Addition of ferricyanide reduced absorbance at the maxima, consistent with dissociation of the complex and regeneration of P-450-iron (III) (Fig. 4, A–C). These results are in agreement with the aforementioned NADPH-dependent inhibition of nicardipine, diltiazem, and verapamil on CYP3A, and not CYP2D6 or CYP2C9 activity, and supported that this inhibition was due, in part, to the complex formation between their metabolites and CYP3A.
Metabolite-P-450 complex spectra for nicardipine (A), verapamil (B), and diltiazem (C) in human liver microsomes (HLM) and CYP3A4.
Spectra were recorded after a 28-min incubation of HLM or CYP3A4 with 100 μM nicardipine, diltiazem, or verapamil in the absence or presence of 1 mM NADPH, and in the presence of NADPH and 200 μM potassium ferricyanide.
Mechanisms of CYP inhibition of a compound can be divided into three categories: reversible, quasi-irreversible, and irreversible (Lin and Lu, 1998). Quasi-irreversible and irreversible inhibitors require at least one cycle of the CYP catalytic process, and are thus signified by both NADPH- and time-dependent inhibition. Experimentally, mechanisms of inhibition of inhibitors could be assessed initially by comparing their inhibitory effects obtained in the presence and absence of NADPH during a preincubation period. In the present study, the IC50 values obtained for all CCBs tested on CYP2D6 or CYP2C9 activity in the presence of NADPH were not lower than those observed in the absence of NADPH during preincubation. This NADPH-independent inhibition suggests that all six CCBs are not quasi-irreversible or irreversible, but rather reversible inhibitors for these isozymes. In contrast, except for nifedipine, all CCBs tested showed increased inhibitory potencies (up to 16-fold) toward CYP3A activities when preincubated in the presence of NADPH. The results suggest that these CCBs may be converted, at least in part, to reactive intermediates or products that contribute to the overall inhibition, either reversible, quasi-irreversible, or irreversible, of CYP3A activities.
To characterize this apparent NADPH-dependent CYP3A inhibition, nicardipine, verapamil, and diltiazem, representatives of dihydropyridines, phenylalkylamines, and benzothiazepines, respectively, were selected for additional studies. Based on the finding that NADPH-dependent inhibition was completely reversible on dialysis (Table 4), both nicardipine and verapamil are not irreversible inactivators for human CYP3A. The finding of ∼20% irreversible inhibition on dialysis after preincubation of diltiazem with NADPH (Table 4) suggests that diltiazem might act in part as an irreversible inhibitor of CYP3A. A possibility also exists that highly potent metabolite(s) of diltiazem, such as N-desmethyl diltiazem and N, N-didesmethyl diltiazem (Sutton et al., 1997), due possibly to tight binding, could remain in the incubation mixture after the 16-h dialysis period.
Subsequent studies showed that nicardipine, verapamil, and diltiazem were able to form P-450-iron (II)-metabolite complex in human liver microsomes and in recombinant human CYP3A4, indicating that they are quasi-irreversible inhibitors of CYP3A4. These results were not unexpected considering that N-demethylated metabolites, all shown to be mediated by CYP3A (Kroemer et al., 1993; Sutton et al., 1997; Fukunaga et al., 1998), have been observed after administration of the three CCBs, and that N-dealkylation of a secondary or tertiary amine has been suggested as the first step leading to formation of P-450-iron (II)-metabolite complex. The smaller extent of the complex formation observed with verapamil (∼6%) as compared with that obtained with nicardipine (30%) or diltiazem (20%) suggests that the MI complex formation contributed relatively less to the overall NADPH-dependent inhibition for verapamil than for nicardipine or diltiazem. Considering that verapamil exhibited lower IC50 values (Table 1) and higher maximal inhibition rate constant/KI ratio than diltiazem, the relatively low level of MI complex observed for verapamil suggests that metabolite(s) of verapamil might also be potent, but reversible inhibitor(s). It is also interesting to point out that the metabolite complexes observed with these CCBs were relatively unstable on dialysis because virtually complete restoration of testosterone 6β-hydroxylase activity was observed after dialysis in the case of nicardipine and verapamil (Table 4). A similar observation was also obtained in our laboratory with TAO, a known P-450-metabolite complex-forming agent (Table 4). It is presently unclear whether the P-450-iron (II)-metabolite complex formed by diltiazem was more stable than that those complexes formed by nicardipine, verapamil, or TAO.
Based on the above observations and considering typical plasma concentrations of ∼0.1 to 0.4 μM for nicardipine, verapamil, diltiazem, and nifedipine, and of ∼5 to 50 nM for amlodipine and felodipine (Kelly and O'Malley, 1992), all CCBs tested, with the exception of nicardipine, could be considered as weak reversible inhibitors for CYP2D6 and CYP2C9. Significant degree of metabolic inhibition on CYP2D6 and CYP2C9 activities may not be expected after a therapeutic dose of verapamil, diltiazem, nifedipine, amlodipine, or felodipine. However, the present study suggested, based on their IC50 values (0.9–5 μM) obtained in the presence of NADPH preincubation relative to their therapeutic concentrations (0.1–0.4 μM), that nicardipine, verapamil, and diltiazem are relatively potent inhibitors of CYP3A in humans. Inhibition of CYP3A activities likely contributed, at least in part, to the previously observed decreased clearances or increased plasma concentrations of CYP3A substrates after concomitant administration with nicardipine, diltiazem, and verapamil (Kirch et al., 1990; Schlanz et al., 1991; Rosenthal and Ezra, 1995; Azie et al., 1998; Kantola et al., 1998; Lamberg et al., 1998). The above conclusion is additionally supported by the present finding that the three CCBs are quasi-irreversible inhibitors of CYP3A, eliciting inhibitory effects, in part, via MI complex. In vivo, such a complex is known to be so stable that the CYP involved in the complex formation would be unavailable for drug metabolism. As a result, the inhibitory effects of quasi-irreversible inhibitors are more prominent after multiple dosing and last longer than those of reversible inhibitors (Murray and Reidy, 1990; Lin and Lu, 1998). Consistent with these, there have been several cases of significant interactions noted after repeated doses of nicardipine, verapamil, or diltiazem with CYP3A substrates as compared with after other CCBs (Kirch et al., 1990; Schlanz et al., 1991;Rosenthal and Ezra, 1995; Azie et al., 1998; Kantola et al., 1998;Lamberg et al., 1998). The relatively fewer cases of pharmacokinetic interactions reported for felodipine and amlodipine also appeared to be consistent with the present finding that their IC50 values obtained in the presence of NADPH were >200-fold higher than reported plasma concentrations after a therapeutic dose. Noteworthy, the potent and irreversible CYP3A inhibitor mibefradil, which was recently withdrawn from the market due to drug-interaction potential, exhibited lower IC50 value (0.3 μM) relative to its therapeutic concentrations (0.5–1 μM) than all six CCBs studied (Prueksaritanont et al., 1999).
To conclude, the present results revealed that among six CCBs tested, only nifedipine was a reversible inhibitor of CYP3A, CYP2D6, and CYP2C9. All other CCBs reversibly inhibited CYP2D6 and CYP2C9, but not CYP3A activities. Based on ratios between IC50values obtained in the presence of NADPH during preincubation and the respective therapeutic concentrations, nicardipine, verapamil, and diltiazem are relatively potent inhibitors of CYP3A. In addition, the three CCBs inhibited CYP3A activities, at least in part, through the formation of MI complex, and thus are classified as quasi-irreversible inhibitors. The results provide a rational basis for significant pharmacokinetic interactions reported between these CCBs and P-450 substrates, and support the notion that an understanding of the underlying mechanism of inhibition is important to provide valuable insights into drug-drug interactions observed in vivo (Lin and Lu, 1998).
We thank Dr. Anthony Y. H. Lu of Rutgers University for a critical review of the manuscript and Dr. Magang Shou for providing insect microsomes expressed with human CYP3A4 and NADPH-dependent reductase.
Send reprint requests to: Thomayant Prueksaritanont, Ph.D., Department of Drug Metabolism, WP 75–100, Merck Research Laboratories, West Point, PA 19486. E-mail:thomayant-prueksaritanont{at}merck.com
Abbreviations used are::
CCBs
cytochrome P-450
metabolic intermediate
troleandomycin
Accepted October 13, 1999.
The American Society for Pharmacology and Experimental Therapeutics
Azie NE,
Brater DC,
Becker PA,
Jones DR,
Hall SD
(1998) The interaction of diltiazem with lovastatin and pravastatin. Clin Pharmacol Ther 64:369–377.
Bensoussan C,
Delaforge M,
Mansuy D
(1995) Particular ability of cytochromes P450 3A to form inhibitory P450-iron-metabolite complexes upon metabolic oxidation of aminodrugs. Biochem Pharmacol 49:591–602.
Buening MK,
Franklin MR
(1976) SKF 525-A inhibition, induction, and 452-nm complex formation. Drug Metab Dispos 4:244–255.
Eagling VA,
Tjia JF,
Back DJ
(1998) Differential selectivity of cytochrome P450 inhibitors against probe substrates in human and rat liver microsomes. Br J Clin Pharmacol 45:107–114.
Fonne-Pfister R,
Meyer UA
(1988) Xenobiotic and endobiotic inhibitors of cytochrome P-450db1 function, the target of the debrisoquine/sparteine type polymorphism. Biochem Pharmacol 37:3829–3835.
(1991) Cytochrome P450 metabolic intermediate complexes from macrolide antibiotics and related compounds. Methods Enzymol 206:559–573.
Fukunaga Y,
Miyashita A,
Iwatsubo T,
Noguchi K,
Higuchi S
(1998) Identification of the human liver cytochrome P-450 isozymes involved in nicardipine metabolism. ISSX Proc 13:124.
Guengerich FP
(1988) Oxidation of 17α-ethynylestradiol by human liver cytochrome P-450. Mol Pharmacol 33:500–508.
Halliday RC,
Jones BC,
Smith DA,
Kitteringham NR,
Park BK
(1995) An investigation of the interaction between halofantrine, CYP2D6 and CYP3A4: Studies with human liver microsomes and heterologous enzyme expression systems. Br J Clin Pharmacol 40:369–378.
Hunt BA,
Self TH,
Lalonde RL,
Bottorff MB
(1989) Calcium channel blockers as inhibitors of drug metabolism. Chest 96:393–399.
Kantola T,
Kivistö KT,
Neuvonen PJ
(1998) Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther 64:177–182.
Kelly JG,
O'Malley K
(1992) Clinical pharmacokinetics of calcium antagonists: An update. Clin Pharmacokinet 22:416–433.
Kleinbloesem CH,
Belz GG
(1990) Drug interactions with calcium antagonists. Pharmacol Ther 45:109–136.
Kroemer HK,
Gautier J-C,
Henderson C,
Wolf CR,
Eichelbaum M
(1993) Identification of P450 enzymes involved in metabolism of verapamil in humans. Naunyn-Schmiedeberg's Arch Pharmacol 348:332–337.
Lamberg TS,
(1998) Effects of verapamil and diltiazem on the pharmacokinetics and pharmacodynamics of buspirone. Clin Pharmacol Ther 63:640–645.
Lin JH,
Lu AYH
(1998) Inhibition and induction of cytochrome P450 and the clinical implications. Clin Pharmacokinet 35:361–390.
Lowry OH,
Rosebrough NJ,
Farr AL,
Randall RJ
(1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275.
McKillop D,
Wild MJ,
Butters CJ,
Simcock C
(1998) Effects of propofol on human hepatic microsomal cytochrome P450 activities. Xenobiotica 28:845–853.
Murray M,
Reidy GF
(1990) Selectivity in the inhibition of mammalian cytochromes P-450 by chemical agents. Pharmacol Rev 42:85–101.
Pershing LK,
(1982) Cytochrome P-450 metabolic-intermediate complex formation and induction by macrolide antibiotics: A new class of agents. Xenobiotica 12:687–699.
Pichard L,
Fabre I,
Fabre G,
Domergue J,
Saint Aubert B,
Mourad G,
Maurel P
(1990) Screening for inducers and inhibitors of cytochrome P-450 (cyclosporin A oxidase) in primary cultures of human hepatocytes and in liver microsomes. Drug Metab Dispos 18:595–606.
Prueksaritanont T,
Gorham LM,
Hochman J,
Tran L,
Vyas KP
(1996) Comparative studies of drug-metabolizing enzymes in dog, monkey and human small intestines, and in Caco-2 cells. Drug Metab Dispos 24:634–642.
Ma B,
Tang C,
Meng Y,
Assang C,
Lu P,
Reider PJ,
Baillie TA
(1999) Metabolic interactions between mibefradil and HMG-CoA reductase inhibitors: An in vitro investigation with human liver preparations. Br J Clin Pharmacol 47:291–298.
Rosenthal T,
Ezra D
(1995) Calcium antagonists: Drug interactions of clinical significance. Drug Saf 13:157–187.
Schlanz KD,
Myre SA,
(1991) Pharmacokinetic interactions with calcium channel antagonists. Clin Pharmacokinet 21:344–356.
Sutton D,
Butler AM,
Nadin L,
Murray M
(1997) Role of CYP3A4 in human hepatic diltiazem N-demethylation: Inhibition of CYP3A4 activity by oxidized diltiazem metabolites. J Pharmacol Exp Ther 282:294–300.
Back DJ,
Breckenridge AM
(1989) Calcium channel antagonists and cyclosporine metabolism: In vitro studies with human liver microsomes. Br J Clin Pharmacol 28:362–365.
von Moltke LL,
Greenblatt DJ,
Grassi JM,
Granda BW,
Duan SX,
Fogelman SM,
Daily JP,
Harmatz JS,
Shader RI
(1998) Protease inhibitors as inhibitors of human cytochromes P450: High risk associated with ritonavir. J Clin Pharmacol 38:106–111.
Welker HA,
Wiltshire H,
Bullingham R
(1998) Clinical pharmacokinetics of mibefradil. Clin Pharmacokinet 35:405–423.
Wrighton SA,
Ring BJ
(1994) Inhibition of human CYP3A catalyzed 1′-hydroxy midazolam formation by ketoconazole, nifedipine, erythromycin, cimetidine and nizatidine. Pharm Res 11:921–924.
Zhao X-J,
Ishizaki T
(1997) Metabolic interactions of selected antimalarial and non-antimalarial drugs with the major pathway (3-hydroxylation) of quinine in human liver microsomes. Br J Clin Pharmacol 44:505–511.
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Q: LINQ Group By with subquery I am trying to make a query on LINQ using a GroupBy, where on the Select statement I try to make some kind of subquery. The idea is that I have 7 days to look for, I need to get the average value of these last 7 days but also the current value for the current day. So I have tried the following code:
        var oDate = DateTime.UtcNow;
        var startDate = oDate.AddWorkingDays(-7);
        var endDate = oDate.AddWorkingDays(-1);

        var races = RaceTimes.Where(
            x =>
                x.ODate >= startDate && x.ODate <= oDate && x.Status == "Finished")
            .GroupBy(x => x.Athletes.Name).Select(x => new
            {
                Name = x.Key,
                Description = "Just a Random Description for now",
                ODate = oDate,
                SevenDaysAvg = (int?)x.Where(y => y.ODate >= startDate && y.ODate <= endDate).Average(y => SqlFunctions.DateDiff("s", y.StartTime, y.EndTime)),
                RaceTime = (int?)x.Where(y => y.ODate == oDate).Average(y => SqlFunctions.DateDiff("s", y.StartTime, y.EndTime))
            }).ToList().Where(x => x.RaceTime!= null).ToList();

The SevenDaysAvg (average) works fine, it returns me the average of the last 7 days races. However, Latency is always returning me null.
I am trying to make the translation of my query from SQL, which works fine:
...
AVG(case when h.ODate BETWEEN '20140219' AND '20140227' then DATEDIFF(SECOND, h.StartTime, h.EndTime)  else null end) AS SevenDaysAvg,
AVG(case when h.ODate = '20140227' then DATEDIFF(SECOND, h.StartTime, h.EndTime) else null end) AS RaceTime,
...

So what am I doing wrong in my LINQ query? This what I am doing is not possible? I've also tried another aproach. First calculate all averages, and then in the main query have something like:
SevenDaysAvg = averages.Where(y => y.Name== x.Athletes.Name).Select(y => y.SevenDaysAvg).FirstOrDefault()

Once again, this approach didnt work, it keeps giving me empty results. Whats wrong here?


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