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Variety Plus Icon Read Next: Andrea Riseborough Controversy Shares Similarities With 2004 FYC Ad Where Shohreh Aghdashloo Wasn't Disqualified From Oscars
'Broken Circle Breakdown' Actor Veerle Baetens on Her Challenging Directing Debut 'When It Melts'
By Alissa Simon
Alissa Simon
Film Critic
'Broken Circle Breakdown' Actor Veerle Baetens on Her Challenging Directing Debut 'When It Melts' 1 week ago
'Cinema Sabaya' Review: Women Talking (and Filming) in Israel's Excellent Oscar Submission 4 weeks ago
Foreign-Language Screenplays From 'RRR' to 'Corsage' Jostle for Awards Attention 1 month ago
Courtesy of Sundance Film Festival
Versatile Belgian actress Veerle Baetens, known for her incandescent turn as the bluegrass-singing mom whose daughter takes ill in Oscar-nominated "The Broken Circle Breakdown," joins the Sundance World Feature Competition with her provocative feature directing debut, "When It Melts," an unflinching portrait of the lasting impact of untreated trauma. Film screens Jan. 21.
What drew you to adapt Lize Spit's prize-winning novel "The Melting"?
At first, it was an offer a producer made. I read the book and I was touched by young Eva's desire to be valued, to be loved. With the adult Eva, I felt sorry, but I found her difficult to grasp and thus fascinating. I know people who have been silenced and later on silence themselves. By making this movie I wanted to get closer to understanding people who have buried their pain deep inside of them, where no one can see it and where it silently hollows them out. … It is a vengeance story on a human scale.
What were the challenges in adapting the book?
It wasn't easy. The book is written in three timelines and we brought them back to two. It was a question of distilling the most important elements. It took us in total, with breaks of course, six years. Co-screenwriter Maarten Loix and I wanted every character and their decisions to be human, and in a way even understandable. Also, we made Eva a more active character. Last but not least, the book treats some sensitive topics and it took us a long time to find the right balance in how far to go.
You found some really compelling young performers.
None of the kid actors, except for young Tess (Eva's little sister) had any experience in acting. The casting process was very long and very intense, but a beautiful experience. They first sent in tapes. We narrowed them down and invited some to do a face-to-face audition. Again, we narrowed down [the field] and started auditioning in the form of workshops. They would have acting lessons/games for a whole day where you could see them starting to relax and pick up things, really play with each other. They would go home, having learned something. Each time, the group got smaller and smaller until the final cast was formed.
With the final cast we kept doing workshops on acting, not using scenes from the movie, but scenes that somehow touched/treated the same topics. Like scenes from "Lord of the Flies," "Goonies," "Girl Interrupted," "American Beauty," "Stand by Me" and so on. We spent a lot of time together so that trust was built between them and us. I only started to really rehearse scenes from the movie with them a few weeks before shooting.
"When It Melts" by Veerle Baetens. Photos courtesy of Sundance Institute
How did you prepare the kids to shoot the traumatic event that haunts Eva's life?
The kids themselves call it the scene, the sword of Damocles hanging above their heads. It was of course a big thing. To begin with, at the time of the shoot, all of them were over 14. Rosa, who plays Eva, was actually 16 at that time. She is the oldest of the bunch. We were lucky to find such a talent who looked less than 13 years old and yet of an age where she could have a real conversation about it, reflect on it. Not only that, she had read the book before she came to the audition.
I insisted on having someone attached to the project who was familiar with trauma. The psychologist was already involved in the last stage of the casting process. When we finally had our cast together, we spoke with the kids and their parents. We read the script together and talked about their fears, their own lives and experiences and of course the scene. The psychologist pointed out what we should pay attention to for every child. The shooting of the scene was scheduled at the end of the shoot so that they had all the time possible to be together, to become a tight and loving group.
We had three days to shoot it, so time to do it in as gentle a way as possible. Rosa was given an in-ear piece. I would talk to her during the shooting of the scene and tell her a story with different connotations. Also, when she was alone in the image, all the other actors would go out of the room.
The psychologist was on set during the shooting of this scene and after every take she would take them out for games like Tetris or cutting fruits like ninjas or something. Anything to get their minds working in a different way from what they had just been feeling. Apparently, that is how you avoid trauma from settling in. Of course, it was intense; heavy for all the actors. But because there was trust, professional guidance and aftercare, it was managed in the best way possible.
What surprised you most about directing your first feature?
That it felt good. As an actress you are always in a fragile position, always depending on the opinion of others and you need a feeling of safety to be able to do that work. It felt good that I knew that and that I could be the one trying to provide that, so that the cast could give their best. I felt like a parent, very focused, very passionate.
What's next for you? Do you want to continue writing and directing? What is your next acting job?
Oh yes! I am actually discussing the adaptation rights of a play with an English author. I cannot say more about it, but I am very excited to dive into it shortly. I don't know what my next acting job will be. I have been so busy finishing the film that there was no time for acting. But I'm looking forward to diving into a part soon.
Sundance Film Festival,
Veerle Baetens,
When It Melts


Today is the 44th anniversary of the Roger Patterson/Bob Gimlin film. It is the greatest blobsquatch footage ever shot of Bigfoot. Is it real? Like everything else in the Bigfoot arena there is no consensus on the films authenticity. A couple of people have come forward since it was shot claiming to be the guy in the costume. Special Effects experts have claimed that a costume that complex did not exist in 1967. And a number of computer models have been done to determine if a human could walk that way. To add to the confusion, some have said a human could, some have said a human can't.
A second passed and then the first scream let out followed by another and then another. People ran for the exits. My friend and I sat in our seats watching the chaos, all the while hoping the movie would continue. We wanted to see Bigfoot. Our hearts sank; the picture fluttered and then went white. The projectionist stopped the film. People were pushing and shoving each other, squeezing through the doors to the lobby. Still my friend and I sat there. They would start the film again. We knew it. It was just a tornado warning. Central Illinois got dozens of tornado warnings every year. It wasn't going to hit us.
My friend's father walked down the aisle and told us it was time to give up hope. They weren't going to show the rest of the film. We both stood and walked dejected to the exit. A few hours later, Main Street was decimated by more than one small tornado that touched down. Cars were flipped upside down. Windows were shattered. Businesses were crippled, including the movie theater. The film would never make it back to the area. We missed our chance.
That was then. This is now. I've seen the film numerous times. I've even watched it on my phone. M.K. Davis was the first to do an incredible enhancement of the film and stabilize the creature for better viewing. His unusual theories aside, he really is responsible for giving the film a second life. Costume designer Bill Munns has done extensive work on the film trying to determine size and other details that have been discussed for nearly 50 years now.
Christopher Noels posted this video on his Impossible Visits Facebook page, and I have to say it is probably shows the best argument I've seen that this is an actual creature and not a guy in a costume.
This entry was posted in News I Find Interesting and tagged bigfoot, patterson/gimlin film, sasquatch. Bookmark the permalink.


text:
Wirusy Umysłu () esej napisany przez Richarda Dawkinsa w 1991 odnoszący się do memetyki i używający analogii wirusa biologicznego i wirusa komputerowego oraz schorzeń i epidemiologii do analizy rozprzestrzeniania się idei i zachowań (tzw. wirus umysłu). Szczególnie koncentruje się na zagadnieniach wierzeń i zachowań religijnych. Utworzył w nim pojęcie zarażonego wiarą (faith-sufferer). Esej został włączony do książek Dennett and His Critics: Demystifying Mind i A Devil's Chaplain.

Druga część dwuczęściowego programu telewizyjnego Dawkinsa "Źródło wszelkiego zła?" (The Root of All Evil?, 2006) dotyczy podobnych zagadnień i ma podobny tytuł Wirus wiary (The Virus of Faith).

Treść

Dawkins definiuje "objawy" zarażenia "wirusem religii", przedstawiając przykłady i szukając powiązań pomiędzy elementami religii i ich zdolnościami do przeżycia (używając analogii ewolucyjnych w zastosowaniu do wyznawców religii). Opisuje religijne przekonania jako "pasożyty umysłu".

Według niego przekonania religijne w "zarażonym wiarą" zwykle charakteryzują się następującymi objawami:

 żywi głębokie, wewnętrzne przekonanie, że coś jest prawdziwe, właściwe lub zacne, to przekonanie nie wydaje się mieć cokolwiek wspólnego z dowodami lub uzasadnieniem, jednak jest dla wyznawcy całkowicie nie do odparcia i przekonujące
 zwykle dumny jest ze swej mocnej i niezachwianej wiary, choć jej przedmioty nie są oparte na żadnych dowodach
 przekonany jest, że "tajemnica" jest dobrą rzeczą jako taka (per se), wierzy, że nie powinno się rozwiązywać tajemnic, ale je w radości przeżywać i cieszyć się ich zagadkowością
 mogą występować nietolerancyjne zachowania wobec konkurencyjnych religii, nawet zabójstwa lub pochwała zabójstw, wyznawcy mogą być agresywni również wobec apostatów i heretyków (nawet jeśli "heretycy" należą do bardzo niewiele różniącej się religii - jak to było w przypadku podziałów w chrześcijaństwie)
 to jakie konkretne przekonania żywi wyznawca, nie ma nic wspólnego z dowodami, ale jest duże prawdopodobieństwo, że te przekonania będą identyczne jak jego rodziców
 jeśli wyznawca jest rzadkim przypadkiem mającego odmienne przekonania niż jego rodzice, wyjaśnieniem może być nawrócenie przez mającego silną osobowość duchownego
 osobiste doświadczenia mogą wykazywać uderzające podobieństwa do przeżyć zwykle kojarzonych z miłością

Dawkins podkreśla, że przekonania religijne nie rozprzestrzeniają się z powodu wspierających je dowodów, ale zwykle odbywa się to na drodze przekazu kulturowego. To odróżnia religię od nauki, która musi spełniać wymogi metodologiczne "testowalność, dowody, dokładność, intersubiektywność, powtarzalność wyników, uniwersalność, niezależność od kontekstu kulturowego itd.". Pisze również "religia rozprzestrzenia się przy całkowitym braku któregokolwiek z powyższych wymogów".

Zobacz też
 Richard Dawkins
 Metodologia nauk

Linki zewnętrzne
 Viruses of the Mind tekst eseju online

Literatura popularyzująca biologię
Utwory literackie z 1991
Twórczość Richarda Dawkinsa

redpajama_set_name: RedPajamaWikipedia


Apartments Taneski is set in Konjsko, only 300 metres from Lake Ohrid and 6 km from the town of Ohrid, both under UNESCO-protection. Featuring free Wi-Fi and free parking, it offers rooms with a balcony and lake view.
Guests can relax in the garden with a terrace. They can also make use of barbecue facilities in order to prepare meals. Various shops and a restaurant can be found within 500 metres, while cafés and bars are 1 km away.
Ohrid's Old Town is full of sights. Some of them include the ancient theatre, Samuil's Fortress and the mediaeval Saint Panteleimon Monastery. Ohrid International Airport is 17 km from the Taneski Apartments.


text:
Senate GOP Fear-Mongers About 'Spying' Ahead Of DOJ IG Testimony
WASHINGTON, DC - JUNE 05: Senate Finance Committee Chairman Chuck Grassley (R-IA) speaks during a forum regarding the future of health care and drug pricing in America, hosted by Pfizer and Axios, on June 5, 2019 in ... WASHINGTON, DC - JUNE 05: Senate Finance Committee Chairman Chuck Grassley (R-IA) speaks during a forum regarding the future of health care and drug pricing in America, hosted by Pfizer and Axios, on June 5, 2019 in Washington, DC. (Photo by Mark Wilson/Getty Images) MORE LESS
By Nicole Lafond
Prominent Republicans on the Senate Judiciary Committee pre-gamed Wednesday's hearing with appearances on cable news to hype President Trump and Attorney General Bill Barr's "spying" assessment of the Russia report.
Sen. Chuck Grassley (R-IA) made an appearance on Fox Business Network Wednesday morning to peddle accusations that the FBI spied on the Trump campaign, a conspiracy thoroughly debunked by the Justice Department inspector general's report on the launch of the probe released Monday.
"The issue here isn't just spying on the Trump campaign, there (are) a lot of constitutional rights that were compromised to get reasons from the court to spy on the Trump campaign. And if it could happen to Trump it could happen to you, Maria (Bartiromo), or anybody else in America," Grassley said about the FISA application process. "There are civil liberties that are potentially violated because of the FBI having political opposition, at least the leaders of the FBI having, political opposition to the President and want to go keep him from being president even after he became president finding ways to get him thrown out of office."
Grassley goes on unhinged rant about spying pic.twitter.com/8Lc0w5SATc
Sen. Ted Cruz (R-TX) appeared on Fox News' "America's Newsroom" an hour later and didn't even attempt to spin the findings of the report, instead taking a page from Barr's book and outright disagreeing with the conclusions — that there were no political motivations behind the decision to launch the Russia probe.
"I think the real conclusion, when you read all the facts, I disagree with his final conclusion that political motivation didn't play a role," he said. "I think it's clear the senior leadership there were hard Democratic partisans. The only way you justify sending in spies to spy on the Trump campaign when he is the Republican nominee for president. He is the leading contender on the Republican side and the FBI is sending in spies to spy on his campaign."
Ted Cruz argues it's a "sad day" for the DOJ ahead of DOJ IG hearing pic.twitter.com/JC7YRAHKSm
The spin isn't novel coming from Republicans, but it's particularly notable for two sitting committee members to use in the hours before a public hearing with the Justice Department's watchdog to peddle outright fake DOJ IG report conclusions.
Inspector General Michael Horowitz is testifying before the committees that Cruz and Grassley sit on on Wednesday to lay out the findings of his extensive review of the launch of the Russia probe. Horowitz poked holes in most of Republicans' conspiracy theories about the launch of the probe, concluding the investigation was started properly and there was no political motive that influenced the scope or direction of the probe.
Horowitz did rail against the FBI in the report, however, for errors and omissions made in the FISA warrant application process when the agents wanted to surveil Carter Page, a foreign policy adviser on Trump 2016 campaign, because they believed he was in contact with Russia. Republicans have seized on that assessment as proof that the Russia probe into Russian interference in the 2016 election was invalid and political.
Nicole Lafond (@Nicole_Lafond) is TPM's special projects editor, based in New York. She has a master's degree in journalism from Columbia University and previously worked as an education reporter at The News-Gazette in Illinois.
Chuck GrassleyDOJ IG hearingDOJ inspector general's reportTed Cruz

redpajama_set_name: RedPajamaCommonCrawl


Your business's communications objectives are the goals that you need to achieve through all communications, such as public relations, advertising and social media. Your sales objectives are the goals you need to achieve in sales, such as an incremental increase in a particular product or an entire line. Your communications plan can help you achieve that, but it also includes other aspects of your business other than sales, such as communicating both inside and outside your organization. Objectives in both areas should meet the "SMART" test: specific, measurable, achievable, realistic and time-focused.
External communications are what you use to communicate with audiences and markets outside your business. This includes the media, current and prospective customers, analysts, investors and any other stakeholders. In young businesses or for new products, communications objectives may start out very broad, such as "create media awareness about our company and products." This means you design communications to introduce yourself to the media, such as press releases announcing the opening of your business. As your contacts grow, your objectives can narrow, such as "increase media awareness by 10 percent based on a name recognition survey."
Your internal business communications include your employees, sales force and distributors. These communications are important because you want everyone in your business to be consistent in their communications with everyone they meet. You also do not want external audiences to get information before your employees receive it. Internal communications tools may include company web portals, newsletters and weekly meetings. Objectives may include "increase on-time attendance at weekly status meetings," or "improve communications between work groups." You then develop strategies and tactics to meet those objectives, such as providing incentives or training in meeting facilitation.
Your sales objectives are easier to measure than your communications objectives, as long as you keep them specific. You can set them for any time period you like, such as a month, quarter or year. You can break them out by a particular product as well as overall sales. For example, "increase sales of women's shoes by 20 percent the first half of 2013." If you have more than one business location, you need to set specific sales objectives for each geographical area.
One portion of your communications plan should be devoted to your products or services to support your sales objectives. This is where you lay out your strategies -- using public relations and advertising, for example. An example of this communication objective might be "educate prospective customers in the warehouse district about the health benefits of our support shoe inserts." Your strategies and tactics use all communications tools to achieve this objective, such as soliciting testimonials from current customers and posting them on social media sites.


COVELO — The lightning fire burning about 10 miles northeast of Covelo has increased by 6,000 acres since Wednesday.
The Pass Complex is up to 17,820 acres and is just 10 percent contained. One outbuilding has been destroyed and 50 other buildings are threatened.
Evacuations have been ordered in its path. The full evacuation list can be seen here.
The complex is two separate fire, Cal Fire reported today. Pass 1 had burned east into the Mendocino National Forest. Pass 2 has jumped firelines and is burning toward the other fire.
There are 962 people committed to the fire and there have been three injuries.
Also assigned to the fire are 932 engines, 37 bulldozers, 25 water trucks, six helicopters and two airtankers.


text:
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Craig Robinson: the Sausage Party star is having an 'amazing' career moment
EP4PRO, August 17th, 2016, in ep4records
The standup comic spoke with the Guardian about his multiple projects: from Seth Rogens lewd comedy to Morris From America to a car-based karaoke show
Lately, Craig Robinson is prone to saying amazing a lot. Its the word he uses to describe Sausage Party, Seth Rogens hit R-rated cartoon in which talking food items in a supermarket discover the nature of their doomed existence with laughs and sex scenes. (Robinson drolly voices a box of grits named, well, Mr Grits.) Robinson also uses the word amazing to describe his first experience of the Sundance film festival in January, where he won a special jury prize for his performance in Morris From America, in which he plays a widowed, hip-hop loving father to a 13-year-old boy.
In person, Robinson might seem a bit weary from the lengthy promotional blitz for Morris From America (yawns punctuate his every few sentences), but the 44-year-old standup-comedian-turned-actor is nonetheless clearly jazzed to be at this stage in this career, with a packed schedule of projects.
On top of his role in Sausage Party and Morris From America, Robinson has recently appeared in the second season of tech thriller Mr Robot, as the mysterious new addition Ray. Hes also hosting Karaoke Showdown, a Spike TV game show he describes as a karaoke car thing with me driving around saying, Im not James Corden! Hes currently in the midst of preparing its first season, shuffling between Los Angeles and New York, where I meet him at the offices of A24, the hip distribution label that bought Morris From America following its stellar Sundance reception.
Robinsons comedy brand of silly, musical seriousness meant that he stole scenes in The Office, Hob Tub Time Machine and This is the End. However, Morris From America marks a change of pace. He plays Curtis, whose son (newcomer Markees Christmas) is struggling to find his place in the German town his dad has moved them to. Like the film, by writer-director Chad Hartigan, Robinson is warm and understated. He skillfully taps into Curtiss simmering grief, without letting the emotion override whats otherwise a pretty cheery coming-of-age film.
It is a step in a different direction, Robinson says of Morris From America. I relished the challenge.
Robinson doesnt have children himself, so drew on his memories of his parents when researching the role. My father would discipline me, while my mom, shed be the good cop. Shed be playful and have fun – but my father would be like, Hey, this is cause I said so.
Robinson also had music taste in common with his character Curtis, whose comically cringeworthy rendition of the Notorious BIGs Juicy is one of the highlights of the film. Robinson is quick to note, however, that hes no match for Hartigan when it comes to knowledge of the genre. That guy is an onion, marvels Robinson. He sure taught me some stuff.
Where Robinson had to really step outside of his comfort zone, was in learning German for the part a language with which he was not at all familiar. For a handful of scenes in which Curtis converses casually in German with folks around town, Robinson says he prepped for weeks with a buddy from Liechtenstein. I wanted it to look like I had been living there, so I just worked and worked and worked, says Robinson.
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Man of mystery: Craig Robinson in Mr Robot. Photograph: USA Network/NBCU Photo Bank via Getty Images
There was a major benefit to shooting in Germany, though. They do things a little differently there, Robinson recalls. If your schedule has you out by 5pm, then youre actually out by 5pm. They dont mess around with overtime, those Germans.
Its common for comedians to make the transition to more dramatic fare often with great outcomes. Eddie Murphy earned an Oscar nomination for Dreamgirls, in which he played a drug-addicted R&B star on the wane. Most recently, Sarah Silverman played against type as a drug-addicted mother in the intense drama I Smile Back.
However, Robinson says his recent foray into drama wasnt conceived as a calculated ploy to find a new audience. Its all organic, man. These projects found me. After doing Morris, it made other people go: I can trust you with this.
It hasnt all been plain sailing however: NBC canceled his comedy Mr Robinson after its first season in 2015, after underwhelming ratings and <a href="https://www.theguardian.com/film/2016/aug/15/suicide-squad-sausage-party-petes-dragon-us-box-office" data-link-name="in" body link" class="u-underline">poor reviews (it was described in the Guardian as Cheers but without any of the funny parts). Yet Robinson says that the outcome of his failed sitcom led him to the place he is today: content and busy. The stay was a little short but you learn to place that energy elsewhere.
Morris From America opens in select US theaters 19 August
Read more: https://www.theguardian.com/film/2016/aug/16/craig-robinson-sausage-party-morris-from-america-mr-robot
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text:
const oAuthClientRepository = require('../repositories/oAuthClientRepository');
const usersRepository = require('../repositories/usersRepository');
const oAuthTokensRepository = require('../repositories/oAuthTokensRepository');
const jwt = require('jsonwebtoken');
const configs = require('../configs/configs.js');

var oAuthService=function(){

  var _getClientById=function(clientId,successCallback,errorCallback){

    oAuthClientRepository.getClientById(clientId,function(client){
      successCallback(client);
    },
    function(err){
      errorCallback(err);
    });

  };

  var _getUserByUsernameAndPassword=function(username,password,successcallback,errorcallback){
    return usersRepository.getUserByUsernameAndPassword  (username,password,
    function(data){
      successcallback(data);
    },
    function(err){
      errorcallback(err);

    });
  };

  var _getToken=function(token,successCallback,errorCallback){

    oAuthTokensRepository.getToken(token,function(token){
      successCallback(token);
    },
    function(err){
      errorCallback(err);
    });

  };

  const _createUser=function(user,successCallback,errorCallback){

    usersRepository.createUser(user,function(result){

      var userOut={
        username:result.username,
        email: result.email,
        firstname:  result.firstname,
        lastname:  result.lastname
      };

      successCallback(userOut);
    },
    function(err){
      errorCallback(err);
    });

  };

  var _saveToken=function(oAuthToken){
    oAuthTokensRepository.saveToken(oAuthToken);
  };

  var _removeToken=function(oAuthToken){
    oAuthTokensRepository.removeToken(oAuthToken);

  };

  var _removeTokeByUserId=function(userId){
    oAuthTokensRepository.removeTokeByUserId(userId);
  };

  var _login=function(username,password,successCallback,errorCallback){

    usersRepository.getUserByUsernameAndPassword(username,password,
    function(user){

      var expireDate = new Date();
      expireDate.setDate(expireDate.getDate() + 1);

      const token = jwt.sign({
        username: user.username,
        userId: user.userId,
      }, configs.jwtSecret, { expiresIn: '24h' });

      _removeTokeByUserId(user.userId);

      _saveToken({ accessToken: token, accessTokenExpiresOn: expireDate, clientId: '', userId: user.userId });

      successCallback(token);

    },
    function(err){
      errorCallback(err);
    });

  };

  return {
    getClientById:_getClientById,
    getUserByUsernameAndPassword:_getUserByUsernameAndPassword,
    getToken:_getToken,
    saveToken:_saveToken,
    removeToken:_removeToken,
    removeTokeByUserId:_removeTokeByUserId,
    createUser:_createUser,
    login:_login
  };
};

module.exports=oAuthService();

redpajama_set_name: RedPajamaGithub


Is the iPrimio cat litter mat a good choice? We had the opportunity to try out this litter mat, testing its effectiveness, ease of use, and quality.
At first, I wasn't sure if I needed a cat litter mat.
For years I've been going back and forth on the litter mat question. A cat litter mat didn't seem necessary, but the image of a mat cutting down on my cleanup and catching all the mess was really appealing. I procrastinate, though—and a litter mat didn't make it to the top of my priority list. Until recently.
Sometimes I need to be reminded to take care of the little things. That reminder is now sitting under the litter box. Seriously, I would have saved myself so much litter grief if I had taken the five minutes to order a litter mat years ago.
I don't really mind scooping out the litter box. The odor's not that bad, either. But you know what does bother me? The stuff outside the litter box that I can't seem to remember to sweep up every day. I used to be really good about sweeping up stray litter, but as time went on I've become more lax about it and it certainly doesn't happen every day as it should.
It's no fun—as I'm sure you know, stray litter granules + bare feet = ew. And I can't forget to mention the other mess that can get right outside the litter box. Does anyone else have cats that can sometimes go number 1 too close to the side of the box… and it just goes over the side and onto the floor?
The mess was gritty, gross, and I kept forgetting to vacuum every day. Honestly, the litter box mess was stressing me out.
Everything changed when we got the opportunity to try out a cat litter mat.
When iPrimio reached out to us to ask if we'd like to review the iPrimio Cat Litter Trapper EZ Clean Mat, we were already familiar with the litter mat. We had researched cat litter mats in the past and knew the iPrimio mat was well-received by users and considered one of the best cat litter mats available.
We agreed to receive a free litter mat in exchange for an honest review.
The litter mat is shipped flat, not rolled, so it comes in a big flat box. The box is really light, but it sure wasn't about to fit in our P.O. Box. I appreciated that the mat was shipped flat because one common complaint from litter mat reviewers is the presence of lasting wrinkles in their litter mats. Little things like that can be really annoying.
The first thing that impressed me when I removed the iPrimio litter mat from the box was that it's big. It is an ideally sized mat to go under a large litter box or for cats who love to toss litter out of their boxes. A good cat litter mat must be large enough to house the litter box and still include a few inches of protection around the sides of the box. You could fit two medium conventionally-sized litter boxes on this thing.
That's big enough even for you big Rubbermaid litter box users, right?
Let's take a closer look at the iPrimio litter mat's design.
The mat has two layers. The first layer is made of foam material in an open honeycomb pattern. Any stray litter that your cat tosses outside of the litter box will be caught in the holes and settle down on the second layer instead of hanging out on the floor where you'll see it and step on it.
In theory, the honeycomb pattern will also separate your cat's paw pads when they walk on it, releasing the litter from their paws and stopping them from tracking it around the house. Forest and Wessie, however, like to leap out of the litter box and don't really spend much time walking on the mat, even though it's so big.
The bottom layer of the mat features a waterproof plastic film that repels urine and odors. If your cat frequently goes just outside the box, you can place a puppy pad in between the two layers to absorb the liquid.
The two layers are attached on one side so that you can easily dump out the captured litter and clean the bottom layer. The mat feels like it is made of sturdy materials and is well-designed.
How did the iPrimio litter mat work?
Let's say that the iPrimio litter mat sold me on litter mats. I don't want to go back to that extra mess on the floor. It catches most of the litter that our cats toss over the side of the box—certainly not all, our cats are vigorous diggers—but most. I'm stepping in way less gritty stray litter.
Just yesterday I noticed a little puddle on the mat from a too-close-to-the-edge litter box use. I'm glad that puddle is on the easy to clean mat and not the floor.
The only issue I had with the iPrimio litter mat was with dumping out the captured litter. It's supposed to be easy and convenient—and perhaps it is, once you develop the right technique. For me, though, litter-dumping was not as easy as expected. I tried to bend the litter mat into a tube to send the litter into the trash. Because of the mat's stiff material and large size, dumping was a little awkward and unwieldy. Maybe I'll get better at dumping out the litter with a little more practice or larger trash can.
Our conclusion—is the iPrimio litter mat worth it?
The iPrimio litter mat does its job really well. I was flustered about the mess around the litter box, and the iPrimio litter has given me a lot of peace of mind in that area.
The mat does an awesome job of collecting most spilled litter and any small accidents over the edge of the box. Its non-porous texture makes it easy to clean, and I haven't noticed it collecting odors.
The mat's large size allows you to use a larger litter box, such as a Rubbermaid container or Litter Robot. It catches more tossed and spilled litter than smaller mats would.
We only tested the iPrimio litter mat with small-grained clay litter, but I don't see any reason it wouldn't work with most other types of cat litter.
For me, the iPrimio litter mat is definitely worth it. So far it has saved me a lot of clean up time and I worry a lot less about my floor and accidents over the litter box edge.
At $39.95 on Chewy, the iPrimio litter mat is more expensive than many other options. If the mat fits your budget, however, the iPrimio does have features that set it apart from other mats. If you're looking for a jumbo-sized cat litter mat that's easy-to-clean and ready for big messes, the iPrimio litter mat is an excellent choice. It's sturdy, well-made, and has a functional design that I really like.
Where can I buy the iPrimio cat litter mat?
Some of our links are affiliate links and Wildernesscat will receive a percentage of the sale. It doesn't cost any extra but helps us to continue sharing the radical cat parenting message. Thank you for your support!
The iPrimio Cat Litter Trapper is available online from Amazon and Chewy.com.
Do you use a cat litter mat?
Are you in the same camp as I was, not sure whether or not a cat litter mat is really necessary?
Let us know in the comments if you use a litter mat or not, and your favorite tricks to keep the litter box mess at a minimum!
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Somehow I grew up with the love for books. I don't know if this came from hours of both parents and grandparents reading to me or if my imagination just needed to be fueled by others. There are times I get lost in a book because of the story. Those are the ones I hate to put down and it is almost heart wrenching when they end. I know I am not alone. There are many "others" like that out there.
Without Fear or Favor takes the reader on a thrilling hunt for justice. We have seen too many cases go public where fairness and liberty were excluded because of some flare up to appease people and hasty decisions to arrest which backfired. Injustices of any kind are a travesty. These might be highlighted in Without Fear or Favor. (just a hint) You might be inclined to think the book takes you through current American social problems. You will not want to put it down.
Tanenbaum's stories capture the reader and are fast paced with surprising twists. Without Fear or Favor will not disappoint, especially if you like thought provoking substance.
Robert K. Tanenbaum's books are chock-full of thrills and pulled from his experiences. How do I know this? After reading Without Fear or Favor, I had to read more.
The author has a remarkable background and phenomenal career. He spoke to me over the phone for an interview. I could not have been more stoked!
An article reflecting many of the conversation highlights was reported on Law Enforcement Today. This post will not be a repeat of that, so you might want to tune into both to get the scope of all the exciting elements.
His stellar career and life accomplishments are astounding and reflect his justice warrior personality. How many people do you know get involved with that many high profile cases and some of which occurred during significant U.S. social and political events? It's rare. And that expertise is invaluable.
Tanenbaum wants those who commit crimes to be held responsible. Furthermore, he represents strong moral values in his profession while advocating for the justice system to provide due process and to afford the same opportunities to all-whether indigent or wealthy. He and his colleagues have been pioneers in the legal system before Miranda v. Arizona existed. By the way, you might want to read up on that case.
So it would be very obvious Tanenbaum's legal mind and work has been and still is very valuable to our justice system and greatly admired. He was very diligent in seeking details and the truth in its entirety. I only wished I had been able to take some of his courses or work with him in the justice system.
The legal procedures and processes surely improved so much through Tanenbaum's work. He believes in searching for the truth and that truth comes from various aspects, even the defense. I find this to be fact. Tanenbaum says the truth should be found and justice should be done without fear or favor. I encourage you to peek at his background, but really dig into his writings. They represent values. They have depth.
It seems today values and what is right gets lost in certain cases and it is within all of us to keep the justice system pure from political and personal agendas. It is a system we rely on for our moral and social control. These are important things to note, especially when the variables hitting it today come from all different directions and endanger the purity of justice. Every component of the system should strive to keep it impartial while also protecting it from toxicity.
Tanenbaum said, "The justice system reflects our character as a nation."
That statement is so true and resonates with my thoughts and beliefs. Do you agree?
It was also refreshing when he spoke with candor. He expressed the media has been complicit and the false narratives are hurting our country. In fact, they are a catalyst to the division we see and the social unrest which plagues our nation.
Specific examples were brought up regarding the conflicts with the Baltimore area. Marilyn Mosby, who was fast to charge officers in the Freddie Gray case, used the podium to grand stand for her agenda. The city was filled with protests, political pressure, and false narratives from the media.
Additionally, there was racial disparity felt between the citizens and officers. Whether it was actual or perceived does not matter. It was there in some form. The media fueled the problems in Baltimore. The protests and political pressures built up and suddenly officials were struck with the feeling of urgency to quiet the masses.
But you can't rush justice. Investigations must be complete as well as comprehensive. You can't stop with some of the facts, you must seek them all.
The officers who had been formally arrested were later found not guilty and the remainder of the officers were not charged. Now Mosby is faced with several civil lawsuits. Freddie Gray paid the ultimate price. Lives were ruined. The city was labeled and viewed with distrust. Careers were destroyed. Where are we now? Are we learning from these travesties of justice? And this wasn't the first case. We had Ferguson and others like it before that.
Tanenbaum instilled the importance of a prosecutor to stay apolitical and remain steadfast to the work authorized for them to conduct. In fact, he shared his perspective that prosecutors should have very few press releases and remain free from using the legal system as a "political vent".
I truly have learned things from Robert K. Tanenbaum. I have learned to always grow. Strive to do better. He reminded me to be better. You can always do and be better than you are. He inspired me to fight for the truth and to hold steadfast to my values.
"The search for truth matters most," echoes in my mind all the time. It is something I always knew and went after, but saying it out loud and advocating for it makes it bigger.
I encourage you to pick up a copy of Without Fear or Favor. You might want to add more of Robert K. Tanenbaum's authorship to your list after that. I guarantee you will enjoy the books and find substance in the stories!
That's a good take, not JUST on the book, but on the VALUES that seem to be found IN the book (as well as in life).
Gonna be worth a read for THIS Robert...heh.
Tanenbaum has been a favorite of mine for many years. Great review.
I am inspired to go back an read some more of Tanenbaum's books. The few that I have read were very entertaining. He's one of those people who after reading his bio, leave me recognizing how little I have accomplished in life. I am amazed by people that manage multiple career and personal achievements and still have time to write 30+ books.


Meirion is a very accomplished and well-respected sheepdog handler, judge and event organiser.
His Quack Pack provides hilariously entertaining duck herding demonstrations for the general public and corporate clients. The Quack Pack team of Border Collies and comical Indian Runner ducks provide entertaining, educational and interactive displays at local, regional and national shows, as well as private events.
A farmer born and bred, Meirion has been around Border Collies all his life. He started sheepdog trialling at the age of nine and is the third generation of his family to be involved in the art of training, competing and demonstrating with his Border Collies all over the country.
Meirion's duck herding demonstrations are designed to showcase the amazing talents of Border Collies and the communication between handler and dog.
He provides his own humorous commentary as he uses a combination of commands to guide his dogs and cooperative (and sometimes uncooperative) Indian Runner ducks around a course that includes tunnels, slides and pens.
The dogs used in Meirion's Quack Pack demonstrations are all pure bred Border Collies.
Border Collies are widely renowned for their intelligence, agility, energy, hard work, and innate skills in herding animals. They listen and respond to verbal and whistle commands that tell them which direction to go to best move stock.
Watch Meirion's demonstrations and you will be amazed at the wisdom of the Quack Pack Border Collies and experience first- hand what "Come Bye," "Away," "Walk" and "Stand" mean to a Border Collie.
The current Quack Pack Border Collies include Rob, Glen, Tim and Kenny.
The Quack Pack Indian Runner Ducks have instant appeal they are very social, comical, daring, have endless amounts of energy, and are eager to please in every performance.
It's not all about ducks though…….
Since his boyhood start Meirion has gone on to win many trials including the Welsh National Sheepdog Championship and has also captained the Welsh team at the International Sheep Dog Trials.
He is a life member of the International Sheep Dog Society and past Welsh President of the Society.
Judging assignments have taken Meirion all over the globe and in 2002 he was honoured to be invited to judge the very first World (Sheep Dog) Trials in Bala, North Wales.
More recently he headed the organising committee for the very successful 2008 World Trials held in Llandeilo, South Wales.


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Home » baseball player » Joe Knight Net Worth 2018: What is this baseball player worth?
Joe Knight Net Worth 2018: What is this baseball player worth?
Joe Knight was a pro baseball player who played Left fielder. Knight was born on September 28, 1859, in Port Stanley, Ontario. Knight died on October 16, 1938, in Lynhurst, Ontario. This page will take a closer look at Joe Knight's net worth.
Joe Knight Career, Earnings
Knight batted Left and threw Left. Knight debuted in the MLB on May 16, 1884 for the Philadelphia Quakers. In all, Knight played for the Philadelphia Quakers, and Cincinnati Reds. Knight's career ended with the Cincinnati Reds in 1890.
Some of Knight's most prominent statistics in the MLB included a Batting average stat of .309, a Home runs stat of 4, and a Run batted in stat of 69.
Joe Knight Net Worth 2018
Baseball compensation can range widely. In professional baseball, the average player earns around $3 million every year. Top players can make $25 million or more per annum, and lower paid players earn $1 million or less. In the minor leagues, most contracts pay less than $10,000 a year.
Joe Knight net worth: baseball salary distribution
So what was baseball player Joe Knight's net worth at the time of death? Our estimate for Joe Knight's net worth at death is:
Want to see some related net worth articles? Check out these: Frank Grant, Ray Schmandt, Johnny Morrison, Pop Swett, Lee Sang-hoon, Bob Glenn, Tim Pugh, Glenn Sparkman, Ben Taylor, Fred Tauby, and Dan Cortes.


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US20100292345A1 - Therapeutic uses of cannabigerol - Google Patents
Therapeutic uses of cannabigerol Download PDF
cannabigerol
Roger Pertwee
2007-06-25 Priority to GB0712303A priority Critical patent/GB2450493A/en
2007-06-25 Priority to GB0712303.7 priority
2008-06-25 Application filed by GW Pharmaceuticals PLC filed Critical GW Pharmaceuticals PLC
2008-06-25 Priority to PCT/GB2008/002179 priority patent/WO2009001081A1/en
2010-06-07 Assigned to GW PHARMA LIMITED reassignment GW PHARMA LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PERTWEE, ROGER
A61K31/00—Medicinal preparations containing organic active ingredients
A61K31/33—Heterocyclic compounds
A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. cannabinols, methantheline
The present invention relates to the use of the cannabinoid cannabigerol (CBG) in the manufacture of medicaments for use in the treatment of diseases and conditions benefiting from concurrent agonism of the CBi and the CB2 cannabinoid receptors. Such diseases or conditions to be treated are taken from the group: pain, neurodegenerative disease, ischemic disease, brain injury or damage, acquired brain injury, age related inflammatory or autoimmune disease, cachexia, nausea and vomiting, glaucoma, movement disorders, rheumatoid arthritis, asthma, allergy, psoriasis, Crohn's disease, systemic lupus erythematosus, diabetes, cancer, osteoporosis, renal ischemia and nephritis.
The present invention relates to the use of the cannabinoid cannabigerol (CBG) in the manufacture of medicaments for use in the treatment of diseases and conditions benefiting from concurrent agonism of the CB1 and the CB2 cannabinoid receptors.
BACKGROUND TO THE INVENTION
The action of many known cannabinoids can be attributed to their interaction with cannabinoid receptors. Cannabinoid receptors are present in mammalian systems and several classes of G-Protein coupled receptors have been identified. The receptors that are present mainly in the central nervous system are known as CB1 receptors, whereas a different type of receptor, which are found substantially in the immune system, are known as the CB2 receptors.
Cannabinoids are generally known to be cannabinoid receptor agonists. When a cannabinoid receptor agonist binds to a cannabinoid receptor a response is triggered. This response is known as a signalling pathway.
Compounds which are known to bind to the CB1 cannabinoid receptor include delta-9-tetrahydrocannabinol (THC), R-(+)-WIN55212 and anandamide. These compounds are as such described as CB1 agonists as when they bind to the CB1 receptor a specific response is produced.
Agonism at a receptor will often lead to an active response by the cell. Many diseases or conditions can be alleviated by the administration of cannabinoid receptor agonists.
Such diseases and conditions include but are not limited to the following: pain (including but not limited to acute pain; chronic pain; neuropathic pain and cancer pain), neurodegenerative disease (including but not limited to Alzheimer's disease; Parkinson's disease; amyotrophic lateral sclerosis; Huntington's disease; multiple sclerosis; frontotemporal dementia; prion disease; Lewy body dementia; progressive supranuclear palsy; vascular dementia; normal pressure hydrocephalus; traumatic spinal cord injury; HIV dementia; alcohol induced neurotoxicity; Down's syndrome; epilepsy or any other related neurological or psychiatric neurodegenerative disease), ischemic disease (including but not limited to stroke; cardiac ischemia; coronary artery disease; thromboembolism; myocardial infarction or any other ischemic related disease), brain injury or damage (including but not limited to traumatic brain injury is taken from the group: diffuse axonal injury; concussion; contusion; whiplash or any other traumatic head or brain injury), acquired brain injury (including but not limited to stroke; anoxic brain injury; hypoxic brain injury or any other acquired brain injury), age related inflammatory or autoimmune disease, cachexia (including related conditions such as AIDS wasting disease, weight loss associated with cancer, chronic obstructive pulmonary disease or infectious diseases such as tuberculosis), nausea and vomiting, glaucoma, movement disorders, rheumatoid arthritis, asthma, allergy, psoriasis, Crohn's disease, systemic lupus erythematosus, diabetes, cancer, osteoporosis, renal ischemia and nephritis.
The diseases and conditions listed above may all benefit from agonism of either the CB1 and/or the CB2 cannabinoid receptor. Due to the multifactorial nature of many of these diseases and conditions it is credible to suppose that agonism at one or more of the receptors may be beneficial in their treatment.
The ability of a compound to have agonist properties concurrently at both the CB1 and CB2 receptors may be of great use clinically.
It is known that agonism of the CB1 receptor in man can cause side effects, for example a study on the use of dronabinol in clinical trials for AIDS-related wasting disease reported the following side effects: asthenia, palpitations, tachycardia, vasodilation, facial flush, abdominal pain, nausea, vomiting, amnesia, anxiety, nervousness, confusion, depersonalisation, dizziness, euphoria, hallucination, paranoia, somnolence and abnormal thinking.
The CB2 receptor is highly localized in the immune cells and as such agonism at these receptors produces a regulation of immune function and inflammatory pain.
It is thought that concurrent agonism at both the CB1 and CB2 receptors might attenuate the side effects caused by direct agonism of the CB1 receptor.
It has previously been shown that CBG, along with many other natural and synthetic cannabinoids is a CB1 receptor agonist as described by US 2007/0060638. This application describes the use of cannabinoid receptor agonists in combination with a cannabinoid receptor antagonist for use in the treatment of drug or alcohol addictions.
In addition the topical use of cannabinoid extracts as an analgesic has been described in U.S. Pat. No. 6,949,582. The cannabinoid extract of the patent includes all of the naturally occurring cannabinoids, terpenes and flavinoids that are found in cannabis plant extracts. Amongst these is the cannabinoid cannabigerol.
Surprisingly the applicants have shown that the cannabinoid cannabigerol (CBG) is an agonist of both the CB1 and CB2 cannabinoid receptors.
The cannabinoid CBG is a non-psychoactive phytocannabinoid and as such has the dual benefits of being both able to concurrently agonise both CB1 and CB2 receptors whilst not causing the psychoactive side effects of other commonly used cannabinoids such as THC.
CBG is a naturally occurring cannabinoid and is a precursor to the major cannabinoids CBD, CBC and THC and as such is rarely found in cannabis plants in any significant concentration. As such this cannabinoid was not thought to possess pharmacological properties making this finding even more surprising.
According to the first aspect of the present invention there is provided the use of the cannabinoid cannabigerol (CBG) in the manufacture of a medicament for use in the treatment of diseases and conditions benefiting from agonism of the CB1 and/or the CB2 cannabinoid receptors.
Preferably the cannabinoid cannabigerol (CBG) is used in the manufacture of a medicament for use in the treatment of diseases and conditions benefiting from agonism of the CB1 cannabinoid receptor.
Alternatively the cannabinoid cannabigerol (CBG) is used in the manufacture of a medicament for use in the treatment of diseases and conditions benefiting from agonism of the CB2 cannabinoid receptor.
More preferably the cannabinoid cannabigerol (CBG) is used in the manufacture of a medicament for use in the treatment of diseases and conditions benefiting from concurrent agonism of the CB1 and the CB2 cannabinoid receptors.
Preferably the diseases or conditions to be treated are taken from the group: pain (including but not limited to acute pain; chronic pain; neuropathic pain and cancer pain), neurodegenerative disease (including but not limited to Alzheimer's disease; Parkinson's disease; amyotrophic lateral sclerosis; Huntington's disease; multiple sclerosis; frontotemporal dementia; prion disease; Lewy body dementia; progressive supranuclear palsy; vascular dementia; normal pressure hydrocephalus; traumatic spinal cord injury; HIV dementia; alcohol induced neurotoxicity; Down's syndrome; epilepsy or any other related neurological or psychiatric neurodegenerative disease), ischemic disease (including but not limited to stroke; cardiac ischemia; coronary artery disease; thromboembolism; myocardial infarction or any other ischemic related disease), brain injury or damage (including but not limited to traumatic brain injury is taken from the group: diffuse axonal injury; concussion; contusion; whiplash or any other traumatic head or brain injury), acquired brain injury (including but not limited to stroke; anoxic brain injury; hypoxic brain injury or any other acquired brain injury), age related inflammatory or autoimmune disease, cachexia (including related conditions such as AIDS wasting disease, weight loss associated with cancer, chronic obstructive pulmonary disease or infectious diseases such as tuberculosis), nausea and vomiting, glaucoma, movement disorders, rheumatoid arthritis, asthma, allergy, psoriasis, Crohn's disease, systemic lupus erythematosus, diabetes, cancer, osteoporosis, renal ischemia and nephritis.
References to CBG, CBG type compounds or derivatives thereof, particularly with regard to therapeutic use, will be understood to also encompass pharmaceutically acceptable salts of such compounds. The term "pharmaceutically acceptable salts" refers to salts or esters prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids, as would be well known to persons skilled in the art. Many suitable inorganic and organic bases are known in the art.
Cannabinoid biosynthesis begins when a precursor molecule reacts with geranylpyrophosphate to form a ringed structure. As shown in FIG. 1, CBG type compounds are mostly 21 carbon compounds.
Variation in the length of the side chain that is attached to the aromatic ring (bottom right hand side of the structure) can produce different types of CBG compounds. For example when the side chain is a pentyl (5 carbon) chain the compound produced will be CBG. If the pentyl chain is replaced with a propyl (3 carbon) chain the CBD type compound formed is CBGV (cannabigeroldivarin). The propyl variant will be formed if a 10 carbon precursor is reacted at the first stage of the biosynthetic pathway rather than a 12 carbon compound.
Synthetic variants of CBG include dimethylheptyl CBG. This variant also has variations in the side chain of the CBG compound.
The scope of the invention also extends to derivatives of CBG that retain the desired activity of concurrent agonism of the CB1 and CB2 receptors. Derivatives that retain substantially the same activity as the starting material, or more preferably exhibit improved activity, may be produced according to standard principles of medicinal chemistry, which are well known in the art. Such derivatives may exhibit a lesser degree of activity than the starting material, so long as they retain sufficient activity to be therapeutically effective. Derivatives may exhibit improvements in other properties that are desirable in pharmaceutical active agents such as, for example, improved solubility, reduced toxicity, enhanced uptake, etc.
The term concurrent is understood herein to refer to simultaneous and essentially independent binding of cannabigerol to the CB1 and CB2 receptors.
Preferably the cannabigerol is in the form of an extract prepared from at least one cannabis plant.
More preferably the extract from at least one cannabis plant is a botanical drug substance.
Preferably the extract from at least one cannabis plant is produced by extraction with supercritical or subcritical CO2.
Alternatively the extract from at least one cannabis plant is produced by contacting plant material with a heated gas at a temperature which is greater than 100° C., sufficient to volatilise one or more of the cannabinoids in the plant material to form a vapour, and condensing the vapour to form an extract.
Preferably the extract from at least one cannabis plant comprises all of the naturally occurring cannabinoids in the plant.
Alternatively the cannabigerol is in a substantially pure or isolated form.
A "substantially pure" preparation of cannabinoid is defined as a preparation having a chromatographic purity (of the desired cannabinoid) of greater than 90%, more preferably greater than 95%, more preferably greater than 96%, more preferably greater than 97%, more preferably greater than 98%, more preferably greater than 99% and most preferably greater than 99.5%, as determined by area normalisation of an HPLC profile.
Preferably the substantially pure cannabigerol used in the invention is substantially free of any other naturally occurring or synthetic cannabinoids, including cannabinoids that occur naturally in cannabis plants. In this context "substantially free" can be taken to mean that no cannabinoids other than the active cannabigerol are detectable by HPLC.
In another aspect of the present invention cannabigerol is in a synthetic form.
Preferably the cannabigerol is formulated as a pharmaceutical composition further comprising one or more pharmaceutically acceptable carriers, excipients or diluents.
The invention also encompasses pharmaceutical compositions comprising CBG type compound or derivative thereof, or pharmaceutically acceptable salts or derivatives thereof, formulated into pharmaceutical dosage forms, together with suitable pharmaceutically acceptable carriers, such as diluents, fillers, salts, buffers, stabilizers, solubilisers, etc. The dosage form may contain other pharmaceutically acceptable excipients for modifying conditions such as pH, osmolarity, taste, viscosity, sterility, lipophilicity, solubility etc. The choice of diluents, carriers or excipients will depend on the desired dosage form, which may in turn be dependent on the intended route of administration to a patient.
Suitable dosage forms include, but are not limited to, solid dosage forms, for example tablets, capsules, powders, dispersible granules, cachets and suppositories, including sustained release and delayed release formulations. Powders and tablets will generally comprise from about 5% to about 70% active ingredient. Suitable solid carriers and excipients are generally known in the art and include, e.g. magnesium carbonate, magnesium stearate, talc, sugar, lactose, etc. Tablets, powders, cachets and capsules are all suitable dosage forms for oral administration.
Liquid dosage forms include solutions, suspensions and emulsions. Liquid form preparations may be administered by intravenous, intracerebral, intraperitoneal, parenteral or intramuscular injection or infusion. Sterile injectable formulations may comprise a sterile solution or suspension of the active agent in a non-toxic, pharmaceutically acceptable diluent or solvent. Liquid dosage forms also include solutions or sprays for intranasal, buccal or sublingual administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be combined with a pharmaceutically acceptable carrier, such as an inert compressed gas.
Also encompassed are dosage forms for transdermal administration, including creams, lotions, aerosols and/or emulsions. These dosage forms may be included in transdermal patches of the matrix or reservoir type, which are generally known in the art.
Pharmaceutical preparations may be conveniently prepared in unit dosage form, according to standard procedures of pharmaceutical formulation. The quantity of active compound per unit dose may be varied according to the nature of the active compound and the intended dosage regime. Generally this will be within the range of from 0.1 mg to 1000 mg.
According to a second aspect of the present invention there is provided a method for the treatment or prevention of diseases benefiting from concurrent agonism of the CB1 and the CB2 cannabinoid receptors, which comprises administering to a subject in need thereof an effective amount of cannabigerol.
SPECIFIC DESCRIPTION
There are over sixty identified cannabinoids that are known to be produced the by cannabis plant. Of these cannabinoids there are eight different main classes of cannabinoids: cannabigerol-type; cannabichromene-type; cannabidiol-type; tetrahydrocannabinol-type; cannabielsoin-type; iso-tetrahydrocannabinol-type; cannabicyclol-type; and cannabicitran-type.
All of these main classes of cannabinoids are derived from cannabigerol-type compounds and differ mainly in the way the CBG precursor is cyclised.
The structure of cannabigerol is shown in FIG. 1. Cannabinoid production in cannabis plants begins when an enzyme causes geranyl pyrophosphate and olivetolic acid to condense to form cannabigerol. The CBG cannabinoid is then usually converted by cannabinoid synthase enzymes to cannabidiol (CBD), cannabichromene (CBC) or tetrahydrocannabinol (THC).
Due to the nature of the biosynthetic pathway of cannabinoids most cannabis plants do not comprise a large amount of CBG. As such the pharmacology of CBG is largely unknown and it has been postulated that CBG is merely a precursor to other more pharmacologically active cannabinoids.
Due to the biosynthetic pathway of the cannabinoids, it is possible that CBG will share some common properties with its products such as CBD and CBC. Also it is highly conceivable that the combination of CBG with it's products such as CBC, CBD and THC will produce a greater and more beneficial effect than that produced by CBG alone.
It was shown by Elsohly et al. in 1992 that CBG had antimicrobial properties and more recently in 2005 Maor et al. described a synthetic analogue of CBG, CBG-dimethyl heptyl which possessed hypotensive and vasorelaxant properties. Additionally the applicant's co-pending patent application (US 60/813814) describes the antidepressant properties of cannabigerol. Compared with the vast knowledge available on THC or CBD, CBG's properties are relatively unknown.
Some patients have found cannabis to be useful in the treatment of many different diseases or conditions ranging from multiple sclerosis, glaucoma and nausea. However reports on the therapeutic potential of cannabis are often contradictory as they describe the effects of whole, usually smoked cannabis, rather than the actions of the specific cannabinoids themselves.
The example detailed below describes studies undertaken to investigate the properties of CBG at the CB1 and CB2 cannabinoid receptors. In particular the ability of CBG to bind to CB1 and CB2 receptors was investigated.
Certain aspects of this invention are further described, by way of example only, with reference to the accompanying drawings in which:
FIG. 1 shows the structure of cannabigerol;
FIG. 2 shows a graph of displacement of [3H]CP55940 by CBG from specific binding sites in mouse whole brain membranes (CB1); and
FIG. 3 shows a graph of displacement of [3H]CP55940 by CBG from specific binding sites in hCB2 CHO cell membranes.
EXAMPLE 1 Investigation into the Properties of CBG at the CB1 and CB2 Receptors
The major constituent of cannabis delta-9-tetrahydrocannabinol (THC) has been well investigated as a medicinal substance yet its therapeutic usefulness can often be hindered by its additional psychotropic activity. This often limits the amount of THC that can be administered to a patient.
In contrast the naturally occurring plant cannabinoid cannabidiol (CBG) has been less well documented therapeutically, although it is known that CBG is non-psychoactive and has antimicrobial and anti-inflammatory properties.
The current study investigated the effects of CBG at the CB1 and CB2 receptors themselves. CB1 receptors in mouse brain tissue and CB2 receptors in CHO cell membranes transfected with human CB2 receptors were used to compare the properties of CBD with the established CB1 receptor and CB2 receptor agonist CP55940.
The test articles used were: CBG (purified plant extract), and CP55940. The compounds were dissolved in DMSO prior to use.
Whole mouse brain membranes were prepared as described by Thomas et al., 2004. CHO cells were stably transfected with cDNA encoding human cannabinoid CB2 receptors and were maintained at 37° C. and 5% CO2 in Dulbecco's Modified Eagle's Medium nutrient mixture.
Radioligand Displacement Assay
The assays were carried out with the established CB1 and CB2 cannabinoid receptor agonist CP55940. This was radiolabelled to form [3H]CP55940.
Binding of the radiolabelled compound was initiated by the addition of either the brain membranes (33 μg protein per tube) or the transfected hCB2 cells (25 μg protein per tube).
All assays were performed at 37° C. for 60 min before termination by addition of ice-cold wash buffer (50 mM Tris buffer, 1 mg ml−1 bovine serum albumin, pH 7.4) and vacuum filtration using a 24-well sampling manifold and GF/B filters that had been soaked in wash buffer at 4° C. for at least 24 h.
[35S]GTPγS Binding Assay
The assays were carried out with GTPγS binding buffer (50 mM Tris-HCl; 50 mM Tris-Base; 5 mM MgCl2; 1 mM EDTA; 100 mM NaCl; 1 mM DTT; 0.1% BSA) in the presence of [35S]GTPγS and GDP, in a final volume of 500 μl. Binding was initiated by the addition of [35S]GTPγS to the tubes. The drugs were incubated in the assay for 60 min at 30° C. The reaction was terminated by a rapid vacuum filtration method using Tris buffer (50 mM Tris-HCl; 50 mM Tris-Base; 0.1% BSA), as described previously, and the radioactivity was quantified by liquid scintillation spectrometry.
The agonism of the CB1 or CB2 receptors by CP55940 results in a response in the cell. This response is the binding of [35S]GTPγS to the cell membrane.
Changes in the response in the presence of the test compound can be measured in order to determine whether the compound is acting as an agonist, a neutral antagonist or an inverse agonist. An agonist will increase the response, a neutral antagonist will have no effect on the response and an inverse agonist will stop or reverse the response. The KB-value that results from these investigations is therefore an indicator of the cells response.
The test compounds were also tested to determine whether they were able to displace the agonist CP55940 from the binding site of the CB1 or CB2 receptor. The Ki-value that resulted from this investigation gives an insight into how strongly the test compound competes with the agonist for the binding site.
It was shown that CBG can displace [3H]CP55940 from specific binding sites on mouse brain membranes (Ki=439 nM) and stimulate binding of [35S]GTPγS to these membranes, with an EC50 of 0.05 nM as is shown by the graph in FIG. 2.
As shown in the graph in FIG. 3, CBG displaced [3H]CP55940 from specific binding sites on membranes prepared from hCB2-CHO cells (Ki=337 nM) and, at submicromolar concentrations, inhibited the ability of 5 μM forskolin to stimulate cyclic AMP production by these cells, albeit with an efficacy less than that of CP55940. The EC50 was 388 nM with an Emax of 28.3.
To conclude the data presented in the example above show that CBG is a partial agonist at both the CB1 and CB2 cannabinoid receptors. As such this naturally occurring cannabinoid has real potential for use in the treatment or prevention of diseases benefiting from concurrent agonsim of the CB1 and CB2 cannabinoid receptor.
1. Use of the cannabinoid cannabigerol (CBG) in the manufacture of a medicament for use in the treatment of diseases and conditions benefiting from agonism of the CB1 and/or the CB2 cannabinoid receptors.
2. Use as claimed in claim 1, of the cannabinoid cannabigerol (CBG) in the manufacture of a medicament for use in the treatment of diseases and conditions benefiting from agonism of the CB1 cannabinoid receptor.
4. Use as claimed in claim 1, of the cannabinoid cannabigerol (CBG) in the manufacture of a medicament for use in the treatment of diseases and conditions benefiting from concurrent agonism of the CB1 and the CB2 cannabinoid receptors.
5. Use as claimed in any of claims 1 to 4, wherein the diseases or conditions to be treated are taken from the group: pain (including but not limited to acute pain; chronic pain; neuropathic pain and cancer pain), neurodegenerative disease (including but not limited to Alzheimer's disease; Parkinson's disease; amyotrophic lateral sclerosis; Huntington's disease; multiple sclerosis; frontotemporal dementia; prion disease; Lewy body dementia; progressive supranuclear palsy; vascular dementia; normal pressure hydrocephalus; traumatic spinal cord injury; HIV dementia; alcohol induced neurotoxicity; Down's syndrome; epilepsy or any other related neurological or psychiatric neurodegenerative disease), ischemic disease (including but not limited to stroke; cardiac ischemia; coronary artery disease; thromboembolism; myocardial infarction or any other ischemic related disease), brain injury or damage (including but not limited to traumatic brain injury is taken from the group: diffuse axonal injury; concussion; contusion; whiplash or any other traumatic head or brain injury), acquired brain injury (including but not limited to stroke; anoxic brain injury; hypoxic brain injury or any other acquired brain injury), age related inflammatory or autoimmune disease, cachexia (including related conditions such as AIDS wasting disease, weight loss associated with cancer, chronic obstructive pulmonary disease or infectious diseases such as tuberculosis), nausea and vomiting, glaucoma, movement disorders, rheumatoid arthritis, asthma, allergy, psoriasis, Crohn's disease, systemic lupus erythematosus, diabetes, cancer, osteoporosis, renal ischemia and nephritis.
6. Use as claimed in any of the preceding claims, wherein the cannabigerol is in the form of an extract prepared from at least one cannabis plant.
7. Use as claimed in any of the preceding claims, wherein the extract from at least one cannabis plant is a botanical drug substance.
8. Use as claimed in any of the preceding claims, wherein the extract from at least one cannabis plant is produced by extraction with supercritical or subcritical CO2.
9. Use as claimed in any of the preceding claims, wherein the extract from at least one cannabis plant is produced by contacting plant material with a heated gas at a temperature which is greater than 100° C., sufficient to volatilise one or more of the cannabinoids in the plant material to form a vapour, and condensing the vapour to form an extract.
10. Use as claimed in any of the preceding claims, wherein the extract from at least one cannabis plant comprises all of the naturally occurring cannabinoids in the plant.
11. Use as claimed in claim 1, wherein the cannabigerol is in a substantially pure or isolated form
12. Use as claimed in claim 1, wherein the cannabigerol is in a synthetic form.
13. Use as claimed in any of the preceding claims, wherein the cannabigerol is formulated as a pharmaceutical composition further comprising one or more pharmaceutically acceptable carriers, excipients or diluents.
14. A method for the treatment or prevention of diseases benefiting from concurrent agonism of the CB1 and the CB2 cannabinoid receptors, which comprises administering to a subject in need thereof an effective amount of cannabigerol.
US12/666,385 2007-06-25 2008-06-25 Therapeutic uses of cannabigerol Abandoned US20100292345A1 (en)
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PCT/GB2008/002179 WO2009001081A1 (en) 2007-06-25 2008-06-25 Therapeutic uses of cannabigerol
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The online music service We7 has succeeded where many similar companies have failed: it has managed to get its advertising revenues to cover not only its own costs but, more importantly, the cost of the royalties it pays to the artists whose tracks it plays.
It may not sound like cause for celebration but after three years, We7, co-founded by Peter Gabriel, can lay claim to being the first company in the UK to prove that internet advertising can be used to fund a web-based on-demand music service that pays industry-standard royalties to musicians.
We7 has done deals with the big four record companies as well as a host of independent labels and is charged different rates by different labels. As a result, 1m plays of a song on We7 would generate payments to the music industry of between £2,000 and £4,000, according to the company.
In March, for the first time, the advertising revenues generated by We7 met both its royalty costs and its running costs.
"This is our four-minute mile," said the We7 chief executive, Steve Purdham. "We have managed to pay a rate for every song that is being played and listened to on demand and pay for that by a rate of advertising that is just standard run-of-the-mill digital advertising, with nothing exceptional."
"We are not talking about one or two songs by one or two people," he added. "We have 3 million monthly unique users in the UK who come and consume music. And there were no advertising campaigns that were above the norm over the last month and none that were paying advertising rates that were above what you would expect a large scaleable operation to have."
The advertising-backed streaming music market is littered with failures, while other companies have become subsumed into larger organisations. Spiralfrog and Ruckus both collapsed last year despite having backers among the music labels. Rival Qtrax, meanwhile, hit the headlines after a glitzy launch two years ago, only for it to emerge that it did not in fact have the rights to the tracks it was offering. It has still not launched. Last.fm was snapped up by CBS three years ago, while iMeem was shut down after being acquired by MySpace and late last year Apple bought Lala.
We7's biggest rival is Spotify, but the level of royalties paid to artists by that service appears opaque, sparking speculation that some artists – such as Lady Gaga – are being underpaid for their songs. Swedish newspaper Expressen claimed last year that 1m plays of Lady Gaga's hit Poker Face had earned the singer just $167 and earlier this month the British Academy of Songwriters, Composers and Authors accused Spotify of paying "tiny" amounts of money to artists.
In contrast, the payments to the music industry from We7 start with the standard streaming royalty rate as set by collection agency PRS for Music – which collects on behalf of the music publishers – which is currently 0.085p per stream or a share of advertising revenue, whichever is the highest. There is also a larger payment to the record company.
"This really is the first time that an on-demand ad-funded business has actually shown that it can work and at a valuable level for rights holders, so that they get a fair and reasonable rate," Purdham said.
We7 generates its revenues by playing quick "blipverts" before songs and a range of display advertising on its website. Advertising is sold by Yahoo and Purdham said the company is now into the third month in which all display inventory has sold out.
The PRS for Music director of broadcast and online, Jez Bell, welcomed the news that We7 has reached its milestone, adding: "We've worked with We7 since the outset as they wanted to ensure they were licensed to deliver royalties back to the songwriters on whom their service relies.
"It's a great user experience, providing superb choice for music lovers and this news underpins the fact that the ad-funded model can work for online music services."
Earlier this week Spotify announced features that integrate it with Facebook and Twitter, and help synchronise it with users' music collections. While the rival service may have generated a lot of headlines, Purdham said his service already has such functionality, although he bears Spotify no ill will for its success in generating publicity as both companies stream music to users rather than allowing them to download tracks.
"Streaming is the future and the more noise there is about it the better," he said. "But there is a massive difference between Spotify and We7. Spotify is an application you have got to download and you have got to install it and as a result this is their first new version since November 2008.
"We are a web service and we upgrade our facilities every month. People have been able to share their We7 music with Facebook, Twitter and Bebo as well as with anyone who has a web browser, whereas Spotify features are only available to somebody in the Spotify world."