text:
User talk:Rajachandra

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-- utcursch | talk 09:53, 27 September 2005 (UTC)

You deserve a barnstar!! :)
namaskAra mattu vaMdanegaLu saravagnya avare

Odeyar
OK...

Now if "Odeyar", "Wadiyar" or "Wodeyar" all there word will lead to the same page.

Thanks for the comment. I am new to wiki.

Sorry, If I messed up. —The preceding unsigned comment was added by Mahesh b s (talk • contribs) 08:16, 6 January 2007 (UTC).

Rajendra, I put my opinion on Talk:Wodeyar too, A persons name must be spelt the way they spelt it in their lifetime. If this Odeyar spelling is retained, would lead to confusion. Wikipedia would perhaps be part of a minority of sources that would use that spelling. I think the spelling must be restored to the way they were in Revision as of 13:15, 5 January 2007 -- Hgkamath 17:08, 9 January 2007 (UTC)

[Kaveri dispute]
Rajachandra avare, tumba sorry. I was starting another round of cpedit of the article and also cleaning up the references. So 'sadhyakke' tegdiraNa aMta tegede. I always meant to bring it back. I wanted to leave a note saying this when I removed it, but I forgot. Very sorry about that. Also, there are few concerns about those contents. You will find them here. Please add your comments when you find time. Once I finish another round of copyedit and clean up the refs, we can surely bring it back. Sorry once again that I forgot to leave a note. Thanks. Sarvagnya 18:42, 14 February 2007 (UTC)

Can you provide references?
Thank you for your interest in the article on the Sritattvanidhi. Can you add any book references for the material you have added? We are trying to upgrade the quality of references on many of the Hinduism articles, which are often without citations now. Also, the picture you added has no associated documentation on file explaining where it is from or what the connection is. Can you help with that? I would also love to find an ISBN or book supplier for reproduction of the work that may still be available. It is a classic that needs wider attention. Buddhipriya 18:30, 27 February 2007 (UTC)

In order to keep conversations in one place on Wikipedia, I will transfer a copy of your remarks here. Thank you so much for replying! If you could upload pictures of all 32 forms showing the text it would be a great contribution. These pictures often appear in degraded forms in devotee publications, often with incorrect identification as to which form is which. If you read the script, could you upload the pictures and also doocument exactly which form appears in each picture, as you did with Mahaganapati? Having the original pictures on file with a systematic documentation of the names of the forms as given in the text would be invaluable to researchers, whc generally cannot obtain access to the source text directly. We could then work together to get the 32 forms integrated into the article. Please reply to this here, on your talk page, to keep the discussion in one place. I will add this page to my watchlist. Also, please sign your comments by typing four tildes ~ which will add your name and a link to here in all your submissions. It saves time for the readers.

Repost of reply: You can get the book from: Director prasaranga University of Mysore Manasagangothri Mysore-570006

you can also get the books from online sources like https://www.dkagencies.com/doc/Home.html and serch for mummadi.

I also feel the title srittavanidi for your post on ganapati is not right.

If you need any more info ot if you feel i should post all the 32 paintings along with the original kannada texts, kindly let me know. raja

Buddhipriya 17:40, 28 February 2007 (UTC)

i have since corected a bit of your post:

1. Maharaja died on 28 march 1868. 2. The first page, the author states thus: May the work sri tattvanidi, which is illustrated and contains secrets of mantras and which is authored by king sri krishna raja, be written without any abstacle. Salutation to Lord ganapati and goddess chamundambika...

Hence we cannot today doubt the authorship and say it was done at his command !

Rajachandra 17:55, 28 February 2007 (UTC)

i have added two pictures today. i will upload a new pic of mahaganapati later. i will also transliterate the kannada texts as i progress.

Rajachandra 19:34, 1 March 2007 (UTC)

 * You are doing great work, thank you. Regarding changing statements that are in published sources, if you have a source that gives a different version, as in the case with authorship, rather than change a cited sentence please add an additional reference with the other point of view, or raise the subject on the talk page so we can work together to get both in.  The citation to Martin-Dubost would be considered a  reliable source and thus should not be removed.  Also, I recommend that we continue further dialog about this on the talk page for the article rather than here, to make it easier for other editors to find these remarks.  I will copy this entire thread to there now to preserve some of the good points you have made. Buddhipriya 19:28, 2 March 2007 (UTC)

Sritattvanidhi
Thanks for your continued work on Sritattvanidhi. Can you please reply on the talk page regarding some questions I posted about references? Also, I would like to standardize the use of IAST so please reply on the talk page for the article. Buddhipriya 18:36, 14 May 2007 (UTC)

i think i have answered all the questions ! if still there are any outstanding issues let me know. thanks for your encouragement and support

Rajachandra 19:08, 15 May 2007 (UTC)

Problem with image licensing
Another editor has identified a problem with the documentation for the images that have been uploaded from the Sritattvanidhi, noting that they lack exact source information. Unless this problem is corrected, the images could be subject to deletion. The problem should be easy to fix by adding text such as "Scan of page from Sritattvanidhi, originally published in 18??" to each of the image pages. Note that the issue here is which publication the scans are actually from. Are they from the orignal copies of the work, which would date to some publication date in 18??, or are they from a reproduction of later date? The complete citation data for the work from which they were scanned is needed. Please reply on the talk page for the Sritattvanidhi, where I have raised this issue. Buddhipriya 23:56, 1 July 2007 (UTC)

Sritattvanidhi
I am sorry if my actions have hurt you. But the issue of slokas (in non-standard notation - not IAST) included is of utmost importance. So I have started a discussoion at the Wikiproject Hinduism talk page.I promise you that the slokas will remain until a concensus is reached on that talk page.--Redtigerxyz 12:09, 1 August 2007 (UTC)

 * I have offered to convert the material to IAST and was in the process of doing that conversion at the time the material was removed. Buddhipriya 21:46, 1 August 2007 (UTC)

 * Rajachandra avare, your contributions to wikipedia truly have been invaluable. I request you not to lose heart at what was only a simple case of vandalism.  You should really simply have reverted the vandalism instead of losing heart.  I have restored all the shlokas and will also add the kannada transliterations in due course.  Thanks.  Sarvagnya 22:39, 1 August 2007 (UTC)

Rajacchandra, I second/third the sentiment expressed in the above posts and sincerely hope that you will resume editing here and contributing to Sritattvanidhi and other articles. Editing on wikipedia can sometimes be a exhausting experience, but in my view worth the effort. So I do hope you'll join in the discussion and not let a single unpleasant experience drive you away. Regards Abecedare 23:55, 1 August 2007 (UTC)

 * I have started a discussion at the WP:IN too as there have no comments on Wikiproject Hinduism. Please participate in the discussion there--Redtigerxyz 13:37, 10 August 2007 (UTC)

i am overwhelmed by your collective response. Thanks. Redtigerxyz, sorry if i sounded a bit harsh. But no offense meant.

I will get back ASAP! Regards Rajachandra 19:02, 11 August 2007 (UTC)

Image source problem with Image:BAlagaNapati1.bmp.jpg
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Speedy deletion of Image:KRWIII.JPG
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Musicians of Mysore Kingdom
Hi. I noticed you were adding links in the middle of this article. Please avoid this. Links should be put in the external links or reference section. I authored this article after lots of research and would like to maintain wiki guidelines.thanks.Dineshkannambadi 19:21, 11 November 2007 (UTC)

The links you are adding must be in the see also section actually, unless they have already been linked to in the main article.Dineshkannambadi 19:27, 11 November 2007 (UTC)

Hi. I own a book published by Dr Meera Rajaram Pranesh and any published book can be referenced, so long as the citations prove that the credit for the information goes to the author, in this case Dr. Meera. This is a wiki guideline. I dont need explicit permission from the author, or wikipedia would not exist. Also, being a summary style article, all info on every king is difficult to provide and infact discouraged. I appreciate your individual articles on the respective kings. Better yet, you could link the kings name with Jayachamaraja Wodeyar kind of name link in the main article, if you dont like the "see also" section. The Kingdom of Mysore is a featured article now after a 2 month long research. Hope you enjoy it.thanksDineshkannambadi 19:39, 11 November 2007 (UTC)

I have converted your image link to a displayed image in Mummadi Krishnaraja Wodeyar. Please see how it is done (syntactically) so you may use the same syntax in the future.thanks.Dineshkannambadi 19:55, 11 November 2007 (UTC)

I saw that article. I feel the origin theory of Mysore Kings is insufficient. some well know scholars feel that the dynasty originated from the Tonnur Hoysala clan or by persons from the Vijayanagara court. The theory that the Wodeyars were immigrants from Dawarka may well be a myth, considering how royal families concocted dazzling connections to royal families in North India, during medieal times. However, being an encyclopedia, all popular theories need to be furnished.Dineshkannambadi 20:05, 11 November 2007 (UTC)

Dear Rajachandra, I did not write that sub-article.Dineshkannambadi 20:18, 11 November 2007 (UTC)

I hope I did not seem assertive in any way. If I did, sorry about that. If you have valuable published sources that can add value, we should discuss it along with the Karnataka work group here in wiki and make all the additions. After all, an encyclopedia is meant to grow.cheersDineshkannambadi 20:22, 11 November 2007 (UTC)

Regarding the origin theories, its best we dont decide which is reliable and which is not. Origin theroies were always controversial and hence left to the readers view point. This is the best we can do on wikipedia.thanks.Dineshkannambadi 20:25, 11 November 2007 (UTC)

I have mentioned that Hyder and Tipu were never officially coronated. This is why I use the term de facto. I have also mentioned the names of those kings that Haider served, though he was in control of the administraton. Nowhere have I mentioned that Haider and Tipu were the kings of Mysore. BTW, only 6 out of 135 citations are from a newspapers or a web page. yet you claim most of the citations are from newspapers. Are we looking at the same article?Dineshkannambadi 21:49, 11 November 2007 (UTC)

Wodeyars
Hello Rajachandra, I have observed the discussion between you and Dinesh in Dinesh's talk page, and requested him to move that discussion to Wodeyar talk page. You can see the discussion in this page, talk:Wodeyar. I request you to continue involve in this discussion, and help resolve the issues. Thanks for all your contributions! - KNM Talk 20:42, 12 November 2007 (UTC)

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files with pink borders
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Hi

I am the son in law of the Maharaja of Mysore and all that I load is from the family's original collections and as such no copy right is infringed.

raja

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Article on Wodiyar Palace
Hello, Rajachandra, Please co-operate thanks Decan.reporter (talk) 19:11, 23 February 2018 (UTC)

July 2020
Hello. This is a message to let you know that one or more of your recent contributions, such as the edit you made to H. S. Doreswamy, did not appear constructive and has been reverted. Please take some time to familiarise yourself with our policies and guidelines. You can find information about these at our welcome page which also provides further information about contributing constructively to this encyclopedia. If you only meant to make test edits, please use the sandbox for that. If you think I made a mistake, or if you have any questions, you may leave a message on my talk page. Thank you. Tayi Arajakate Talk 12:18, 2 July 2020 (UTC)

It is stated by you that: In 1947, during the Political integration of India, the Maharaja of Mysore was reluctant to accede to the Indian Union, which resulted in the "Mysore Chalo" movement to pressurize the maharaja into acceding.

I have stated:

People who don't know history edit posts here. To say mysore Chalo movement was to pressurise the maharaja into acceding itself unequivocally proves that there was either blatant misinformation at that time to mislead the people to join the movement or bulk of the people did not know anything about India Independence Act 1947 and its effect on Indian states. For the record Maharaja was the first to announce his decision to accede to the Indian dominion even before 15-8-1947 and even signed it on 9th august itself. Mysore chalo was nothing but an agitation to gain executive power by Mysore Congressmen in the name of seeking Responsible Government.

I stand by my statement. I can provide you the original instrument of accession copies which as i have stated was signed on 9th aug 1947 and accepted by Governor General of India on 16-8-1947.

Rajachandra (talk) 13:15, 31 July 2020 (UTC)

Hello user:Tayi Arajakate

I reiterate: To say mysore Chalo movement was to pressurise the maharaja into acceding itself unequivocally proves that there was either blatant misinformation at that time to mislead the people to join the movement or bulk of the people did not know anything about India Independence Act 1947 and its effect on Indian states. For the record Maharaja was the first to announce his decision to accede to the Indian dominion even before 15-8-1947 and even signed it on 9th august itself. Mysore chalo was nothing but an agitation to gain executive power by Mysore Congressmen in the name of seeking Responsible Government.

If you want to educate yourself please read: V.P. Menoon's book : The Story of the Integration of the Indian States, India Independence Act 1947, White Paper on Indian states and the original Instrument of accession copy itself at https://abhilekh-patal.in/

I stand by my statement. I can provide you the original instrument of accession copies which as i have stated was signed on 9th aug 1947 and accepted by Governor General of India on 16-8-1947.

I stand by my statement. Stop being petulant and reverting my post. If you have proof and knowledge challenge me

Rajachandra (talk) 19:28, 15 September 2020 (UTC)

title: User talk:Rajachandra


text: File:UniversityChallengeNZ.jpg

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: File:UniversityChallengeNZ.jpg


text:
Tom Veivers

Thomas Robert Veivers (born 6 April 1937) is an Australian former cricketer, teacher, politician and public administrator who played in 21 cricket Test matches between 1963 and 1967. He is the great-uncle of Jack Wildermuth.

Cricket career
Veivers was an all-rounder who bowled right-arm off-spin and batted left-handed. Educated at Downlands College, in Toowoomba in southeastern Queensland, he attended the University of Queensland, whom he represented in club cricket. In 1955, playing for Downlands College in a match against Gregory Terrace at the Brisbane Oval, he scored 155 runs. He was made the captain of the Queensland Colts and scored 126 against the New South Wales Colts in 1958/59, their first win in the interstate Gregory Cup in 8 years.

He made his first-class debut in 1958–59 against the touring English cricket team and made his Sheffield Shield debut that season also. He did not command a regular spot in the Sheffield Shield team until the following season. He was selected for his first Australian squad in 1962, playing in an Australian XI against the visiting English team, in which he was hit for two sixes by Ted Dexter in his opening over.

John Woodcock of The Times wrote: "I doubt if it is possible to hit a cricket ball any harder than Dexter did today. Melbourne is a huge ground and no one who hits a six here is likely to forget it. Against Veivers, an off-spinner, Dexter twice cleared the sightscreen, once by a good 20 yards." In the 2 matches against the MCC, his figures were 3 wickets for 310 and he was considered for the Test matches.

Veivers was selected for the Test team the following season to make his debut against South Africa in the First Test in Brisbane, in which he scored 14 batting at number 8 and took 1/48. He was omitted for the third and fourth Tests, but managed to defy the South Africans with stubborn batting in the fifth Test in Sydney, salvaging a draw. He toured England in 1964, playing all Tests and scoring two half-centuries and three three-wicket hauls. He followed this with 2 more half-centuries and a career-best of 4/68 on the tour to India. While scoring 74 in Chennai he hit Bapu Nadkarni, often considered an unhittable bowler, for 3 sixes.

He scored his Test best of 88 against Pakistan in Australia the following season but was unavailable to tour the West Indies in 1965 for personal reasons. He had a difficult 1965-66 Ashes series back home against England, taking just four wickets and one half-century. He went on the 1966-67 tour of South Africa, which was his last international representation for Australia. He retired from first-class cricket the following year.

His bowling was economical but not penetrative, with a Test average of over 40. He bowled one of the longest known bowling spells in Test cricket - 55 six-ball overs in England's innings of 611 at Old Trafford in 1964. Veivers bowled 75 of the last 80 overs delivered from the City end and finished with figures of 95.1-36-155-3. This is the highest number of balls bowled in an innings of a Test match by an Australian and included a single unbroken spell of 51 overs and one ball. Veivers was the non-striker when Simpson reached the 300 and, one Test later, when Fred Trueman took his 300th wicket by dismissing Neil Hawke.

Later career
Veivers was a Brisbane radio station executive before serving as the secretary of the Queensland Cricket Association from 1974 to 1977 and a state selector from 1977 to 1982.

He had a brief political career, holding the seat of Ashgrove in the Legislative Assembly of Queensland from 1983 to 1986 for the Labor Party. He was Commissioner-General of the Australian Pavilion at World Expo 88 in Brisbane in 1988. He was Chairman of the Queensland Institute of Medical Research Trust from 1991 to 2000 and was appointed a Fellow of the Institute in 2000.

He was the president of the QCA from 1989 to 1992. He was made a Life Member of Queensland Cricket in 2006.

His cousins, Mick and Greg Veivers, both represented for Australia at rugby league, Greg captaining the national team. Mick went on to become a Queensland state politician. His great-nephew, Jack Wildermuth, has played Twenty20 International (T20I) cricket for Australia.

title: Tom Veivers


text:
Wikipedia:Articles for deletion/Mongo (hehu)

 * The following discussion is an archived debate of the proposed deletion of the article below. Please do not modify it. Subsequent comments should be made on the appropriate discussion page (such as the article's talk page or on a Votes for Undeletion nomination).  No further edits should be made to this page.

The result of the debate was DELETE. Linuxbeak | Talk 22:22, 16 October 2005 (UTC)

Mongo (hehu)
Subject is non-notable, a one-liner, and has no references (except for link to a swedish bbs.) bjelleklang 12:05, 10 October 2005 (UTC)
 * Delete as non-notable.--Isotope23 16:13, 10 October 2005 (UTC)
 * Delete No references to prove notability. Solarusdude 23:27, 10 October 2005 (UTC)
 * The above discussion is preserved as an archive of the debate. Please do not modify it. Subsequent comments should be made on the appropriate discussion page (such as the article's talk page or in an undeletion request). No further edits should be made to this page.


text:
User talk:Marskell/Archive 3

Slim, Tim and happy Gibbon:

Dear fellow primate
I'm really perplexed by your anger over edits to primate and ape. I avoided duplication one-page-to-the-other but absolutely no info was removed. In fact, taken together, the concept has been expanded upon, particularly given that the ape page previously made no mention of the topic. I also tried to make clear that Ape is not synonomous with Primate. It's an important point which people often miss. To address a few of things:

 * "It strikes me that you're personally dismissive of the idea and therefore feel it has no place here..." Not at all! It's an absolutely fascinating topic which deserves a mention. Two things. First, again, apes are not primates in the same way dogs are not wolves and my main concern was which page does this belong on. Secondly, great pains have been taken (particularly by Uther, who deserves a lot of credit for his fastidiousness on animal articles) to cover taxonomy and biology comprehensively first and then get into other considerations. He actually moved legal considerations back down, not myself.
 * "If you've inserted it wholesale into Ape, you'd better adjust the figures in it to cover only apes." I didn't insert it wholesale and mentioned no figures. I moved the expanded paragraph about what the "Great Ape Project" is to ape because it makes sense there and left the stats about research on primates on primate (and for what it's worth I never added the "there is no discomfort" line which is indeed a joke as you said).
 * "And yes, people are very serious about extending the notion of personhood, a legal concept, to lemurs." I have read around this topic and I have honestly not seen any reference to lemurs and monkeys being included (as I recall I have encountered comments about dolphins in this regard!). I apologize if it came off as glib to say "Source?" as a single sentence, but I'd honestly be curious for the source. I did search around and can't find one.
 * "You're now engaged in WP:POINT, deliberately inserting false material elsewhere." I'm sorry but that's just not true. I really haven't inserted false material anywhere.

As an ancillary point, do we have a "grandfather" article along the lines of Legal status of animals which we could point to in discussions of this sort? Can't find one in the animal cat. It's certainly an interesting topic and I'd help if you want to make an article. Marskell 00:44, 6 October 2005 (UTC)

Apologies from this (barely human) primate

 * I'm sorry, Tim. I've not had a good wiki-day (lots of annoying WP-related e-mails) and I was short-tempered with you for that reason. I also got annoyed by the "no discomfort" sentence, which I know wasn't you, and I was unfairly reading your posts as coming from the same place, which I see now they weren't. I do apologize. Regarding lemurs, I can't give you a source offhand, but there are many animal-rights groups focusing on trying to achieve rights for all the primates, and lots of people doing PhDs on the legal implications of extending personhood beyond human beings.

 * I like the idea of a "Legal status of animals" page. We already have Animal rights, but that doesn't quite cover details of the current legal status. I'd be happy to work with you on a page like that, though I don't have time right now, but maybe in a few days. Or feel free to start one, and I can catch up with you later. If you want to look through our animal rights articles, they're in Category:Animal liberation movement. Some of them are okay, some aren't. I've been going through them in the last few weeks trying to tidy them a little.

 * I'm not quite sure I understood your point about apes not being primates though. They are, as are we. Or am I wrong about that?

 * Once again, I do apologize, especially for my WP:POINT remark, which I take back, of course. And thank you for sending such a nice note despite my poor behavior. SlimVirgin (talk) 01:14, 6 October 2005 (UTC)

Long-winded follow-up point
Apes are primates but the term ape is not synonomous with primate (like again, dog is not synonomous with canine). That is, apes are one type of primate (and actually a quite limited one, if you exclude the 6 billion us). If there is a truly mis-apprehended word in this regard, it is "monkey". We are not monkeys. Apes are not monkeys. But of course, an off-the-top-head discussion of evolution inevitably includes "hey, we're monkeys!" Anyhow, there is some POV on my part and I'll admit that the previous edit summary "placing legal status at bottom and removing great ape project ref. should lemurs be considered persons under law? a) no b) i don't care. save it for the ape page" was hasty and sarcastic. But again, it goes back to apes versus primates. To go over quickly what I view as a starting point for discussion. To my mind, if you pass both tests you are a person (POV obviously, but not out of nowhwere). Trees don't pass either. Dogs don't pass either (place a mirror in front of them and they get ready to fight the "intruder"). And the vast majority of primates (as far as I know and I'm not claiming expert knowledge) may pass the first but not the second test. Only chimps come close. The Great Ape Project says this without saying it IMHO. Their declaration is clear but their reasoning is not and they don't clarify the "before this why not before that point" (ie, you include chimps so then you include gorillas and orangs—why not all primates, why not all mammals, why not insects, and on and on until hydrogen ought to have personhood...). My getting uptight about the edits has a lot to do with this reasoning; again it's POV but it's not non-thought-out or over-general. I really do think the paragraph I placed on ape makes more sense there than on primate because the project has, to this point, only sought to demand rights for apes. Anyway, I'll chew over the suggested addition of Legal status of animals. It shouldn't be added in the "just a stub everybody add an incidental point" fashion because it could wind-up badly. Well-done it could be a good addition. Finally, after much long-windedness, thanks for your gracious comments on my talk page! Marskell 02:17, 6 October 2005 (UTC)
 * 1) Apes (or maybe just chimps--disputed) appear to have self-recognition, passing the "mirror test."
 * 2) Apes may have theory of mind (again disputed); that is they appear cognizant of what another is thinking and will act on that knowledge. Knowing "you" basically being the step after knowing "I".

SlimVirgin2

 * Okay, I'm finally getting round to responding. First, the apes versus primates point. I put the material on Primate because we're primates too, and I wanted to have a section showing the huge discrepancy in treatment between human and non-human primates. If it were up to me, that section would be a lot longer and more detailed, so I felt I was being quite restrained in what I wrote. ;-) Regarding which types of primates are used in research, it's not just monkeys or great apes, but all the non-human primates, so again, the primate page seemed appropriate.

 * Regarding your points about theory of mind. First, I feel this is a dodgy concept in general, and while interesting, it's important not to make too much of it. People with severe autism don't have a theory of mind, according to leading autism researchers. But so what? All that means is that they don't have the same theory of mind as the researchers. I may not have the same theory of mind as you. And in fact, we may not even have a vocabulary sufficient to understand what the differences are between us, or the similarities.

 * All I know is this: if I burn you, I believe you will feel severe pain, so I won't burn you. If I do it, and you scream, I would regard myself as "knowing" that you feel pain, even though in fact I would know no such thing, because only you can know whether you're in pain (and some philosophers would argue even with that). But my sense of you as being in some important way quite like me would make your scream enough information to make me back off.

 * I won't cause you pain because (in part) I don't want you to do it to me. This is the basis of empathy and conscience. It all works without us needing to develop theories about who does or doesn't have a theory of mind, or who does or doesn't pass the mirror test. (And the mirror test tests what we regard as self-knowledge and knowledge of others. But who are we to define this for the entire world? I also have to add here that many philosophers and psychologists would dispute that knowing "you" comes after knowing "I", as you wrote. They would argue that it's the other way round: that we extrapolate from recognition of "other" (not-me) to recognition of "self".)

 * So the argument about animal rights isn't based on who has a theory of mind or who passes the mirror test. It's based largely on two ideas: first, that each human and non-human animal is what Tom Regan has called the "subject of a life". For each of us, our life is all that we have and all that we are (so far as we know), and we therefore have an inherent interest in protecting it, and a right to express that interest. And secondly, it's based on Jeremy Bentham's argument: "The question is not, Can they reason?, nor Can they talk? but, Can they suffer? Why should the law refuse its protection to any sensitive being?" (Introduction to the Principles of Morals and Legislation, 1781)

 * For me, the argument is very simple: animals in laboratories are in some important way quite like me. That's why they're being used in the first place. If we concentrate on the similarities between us, rather than on what divides us (theories of mind, mirror tests, language), it seems to me entirely reasonable to award them legal "personhood," because all that means is that we recognize them as beings, as subjects-of-a-life, and not things — not our property to inflict pain on because of some perceived long-term benefit to us, and sometimes for no reason at all. SlimVirgin (talk) 23:30, 7 October 2005 (UTC)

More long-windedness
Thanks for your post; all of your points are well-taken.

Before proceeding I thought I’d make a general clarification about persons in law versus persons as such. An infant is and should be a person in law though I wouldn’t actually consider them a person as such—just a loveable bundle of neurons. I’d make a similar argument for the severely disabled. Sorry if this is a bad example considering other issues, but I’d suggest Terri Schiavo essentially ceased to be a person as such when she entered a PVS (though again, she was and should have been a person in law). I don’t mean that to be callous—I mean it to be intellectually consistent.

In general, it is possible to hold pain and personhood distinct. I can acknowledge an animal feels pain without granting that they’re a person as such. If you want to take pain as your starting point for personhood, OK—"the answer could be pain," as a teacher once said to me—though I won’t agree.

If not, then what is the starting point? What is a person as such? And how can the GA project present a declaration on personhood in law without taking a stab at defining the term more generally? I’m sure individuals take a stab in the book but their declaration doesn’t. Similarly, in the statement of goals from GRASP we find: "Nonhuman apes meet the generally accepted criteria for personhood." And then they fail to define those criteria. Note, that I actually agree with all of the points in the declaration from GAP but my reasoning is this: apes are large-brained, intelligent mammals with a robust sentience and a relatively robust emotional sense; I don’t see we have the right to hold them and we sure as hell don’t have the right to torture them. But note I’m not asserting that they’re persons; if accepting the points as law makes apes de facto persons legally, fair enough, but in the ontological sense I'm not obliged to consider them such. And the "if this, why not that" point still holds. What about Lesser Apes, Gibbons? (Did you see my happy Gibbon picture on the ape page by the way :)?

"Theory of mind…is a dodgy concept in general." Far from it—it’s a valid point of scientific distinction and it’s discussed in philosophy. Robin Dunbar is one needs-to-be-destubified scientist who has worked on the issue recently. I haven’t pushed it on any page but I think it as valid a criterion as any. I will definitely admit the Theory of mind page needs work (as does intentionality). I’ve never, incidentally, bought the idea that an average autistic doesn’t have theory of mind (particularly after my sponsor’s autistic son took my by the hand and said "I love you Mr. Tim!" :)

"I may not have the same theory of mind as you." Yes, in the "I can’t disprove a solipsist" sense but not true in more practical ways. Here is a statement: "Marskell wants Slim to know that Tom’s brother Joe is aware that user:Mary has been lying about Tom’s edits on the Main Page." I think we can both follow that sentence and in more or less the same way; if we didn't follow it in more or less the same way we wouldn't be able to communicate. It’s five orders of intentionality, about as much as an adult human being can intake without getting confused. This IS something that’s tested and I see nothing dodgy about saying the fact that human beings can apprehend such information and no other animal can is one reason we differ in kind from other animals. OK to underscore similarities but we can’t ignore the differences.

Well now, this has become quite lengthy. Take care and of course respond as you please. Marskell 10:26, 8 October 2005 (UTC)

SlimVirgin3

 * Before proceeding I thought I’d make a general clarification about persons in law versus persons as such. An infant is and should be a person in law though I wouldn’t actually consider them a person as such—just a loveable bundle of neurons. I’d make a similar argument for the severely disabled.

 * But they're persons in law, and would be regarded as persons by some or most philosophers. SlimVirgin (talk) 22:38, 9 October 2005 (UTC)

 * What is a person as such?

 * One approach to the disabled-person problem, called the animal-attribute theory, proposed by David Wiggins, is that a person is any human or non-human animal that by its kind has the biological capacity to enjoy a certain list of psychological attributes. The "by its kind" means that someone of that kind who is either too young or too sick to enjoy the list of psychological attributes retains his or her personhood. As to the list of attributes, they usually include some or all of: language (of some kind), reason, moral agency, the ability to stand in relation to another (object relations), and that the person's behavior can be explained with reference to beliefs and desires.

 * It's anyone's guess how many of these attributes apes possess, but why would we doubt that they possess many of them to a significant degree? Occam's razor, for one thing, demands that we adopt the simplest explanation for their apparent close similarity to us — namely that they are closely similar to us. SlimVirgin (talk) 22:38, 9 October 2005 (UTC)

 * (Did you see my happy Gibbon picture on the ape page by the way :)?

 * Yes, it's lovely, thank you. ;-D SlimVirgin (talk) 22:38, 9 October 2005 (UTC)

 * "Theory of mind…is a dodgy concept in general." Far from it—it’s a valid point of scientific distinction and it’s discussed in philosophy.

 * It's a whole branch of philosophy. But I meant it's a dodgy way of judging the mental world of animals. SlimVirgin (talk) 22:38, 9 October 2005 (UTC)

 * Robin Dunbar is one needs-to-be-destubified scientist who has worked on the issue recently. I haven’t pushed it on any page but I think it as valid a criterion as any.

 * So what do you mean by it exactly? SlimVirgin (talk) 22:38, 9 October 2005 (UTC)

 * I’ve never, incidentally, bought the idea that an average autistic doesn’t have theory of mind (particularly after my sponsor’s autistic son took my by the hand and said "I love you Mr. Tim!" :)

 * What's meant by saying that severely autistic people don't have a theory of mind is that they can't see the world from the point of view of another person. See Simon Baron-Cohen (a cousin of Ali G). SlimVirgin (talk) 22:38, 9 October 2005 (UTC)

 * Here is a statement: "Marskell wants Slim to know that Tom’s brother Joe is aware that user:Mary has been lying about Tom’s edits on the Main Page." I think we can both follow that sentence and in more or less the same way; if we didn't follow it in more or less the same way we wouldn't be able to communicate. It’s five orders of intentionality, about as much as an adult human being can intake without getting confused. This IS something that’s tested and I see nothing dodgy about saying the fact that human beings can apprehend such information and no other animal can is one reason we differ in kind from other animals. OK to underscore similarities but we can’t ignore the differences.

 * But isn't that example just a generative-grammar thing? We shouldn't judge animals in terms of an ability for human languages, just as we shouldn't judge ourselves in terms of our inability to make meaningful whale noises. As to the differences, they have to be morally significant if you want to withhold rights and protections on the basis of those differences. So what are the morally significant differences, and why are they morally significant? What differences could be sufficiently morally significant as to allow us to say of any animal: you must live in a laboratory in great discomfort, loneliness, and pain for the entirety of your life in order (maybe) to benefit us medically, perhaps only so that we can buy Chanel No. 5, and possibly for no reason whatsoever?

 * Don't feel compelled to answer this, by the way. But perhaps you could watch this. SlimVirgin (talk) 22:38, 9 October 2005 (UTC)

Marskell 4
OK, I’m going to cherry-pick a couple of points and create an archive for it all.

First, your last point: “what differences could be sufficiently morally significant as to allow us to say of any animal: you must live in a laboratory in great discomfort, loneliness, and pain for the entirety of your life in order (maybe) to benefit us medically, perhaps only so that we can buy Chanel No. 5, and possibly for no reason whatsoever?” I stated that I actually agree, for instance, with the points in the GAP declaration. I just do not believe I have to consider an animal a person to accept they shouldn’t be tortured or kept in awful conditions.

“Occam's razor, for one thing, demands that we adopt the simplest explanation for their apparent close similarity to us — namely that they are closely similar to us.” Hmm, well, this is a tautology and it can also be inverted: “Occam's razor, for one thing, demands that we adopt the simplest explanation for their apparent differences to us — namely that they are different from us.”

“It's a whole branch of philosophy. But I meant it's a dodgy way of judging the mental world of animals.” But it’s almost always brought up in reference to the mental world of animals (or autistics) and that’s why I brought it up here. If you’re not a fan of it, OK. (Philosophy of mind, rather than theory of mind, is a branch of philosophy, incidentally).

Indeed it is assumed autistics “can't see the world from the point of view of another person” but in the simple words of a colleague who works with them “no two autistics are the same.” Obviously this is true of many cognitive disorders but I think especially so with autism which is what I meant by “I have never bought” that we can make a blanket statement that they don’t have TOM.

“But isn't that example just a generative-grammar thing?” I don’t think so: if I am capable of five-orders of intentionality I can incorporate five individual viewpoints and/or multiple viewpoints from two or three individuals at once. I believe animals can’t do this not merely can’t express it generatively. We don’t waste metabolic resources on our 1300g brains for no reason :).

title: User talk:Marskell/Archive 3


text:
Emory Peak

Emory Peak, located in Big Bend National Park, is the highest peak in the Chisos Mountains and the highest in Brewster County. The peak is named for William H. Emory, the chief surveyor of the U.S. Boundary Survey team of 1852. From the Chisos Basin the peak appears to be a minor ridge, while the summit of Casa Grande, one mile closer, seems to be much taller. From the west, Emory Peak is clearly visible as a point slightly higher than most of the mountain range.

The peak can be reached by a moderate hike on a well-marked path across steep rocky terrain with an elevation gain of approximately 2500 ft. The Emory Peak Trail is about 1.5 mi long. The trail is reached by climbing the Pinnacles Trail 3.5 mi from the Chisos Basin trailhead. Once at the base there is a semi-technical rock scramble to navigate before reaching the summit. No gear is needed for this climb although hikers should take great care. High-desert flora and fauna including alligator juniper (Juniperus deppeana), pinyon pine (Pinus cembroides), mule deer (Odocoileus hemionus), prickly pear cacti (Opuntia spp.), Mexican jay (Aphelocoma wollweberi), sotol (Dasylirion leiophyllum), and Texas madrone (Arbutus xalapensis) may be seen along the trail. There are signs warning of mountain lions and bears.

The view from the top takes in most of the northern section of the park and a good portion of the Chisos range to the south. One surprise at the top, during the right season, is the population of lady bugs on the summit. There are solar panels, radio transmission equipment, and antennae at the top.

title: Emory Peak


text:
Hangnyeoul station

Hangnyeoul Station is a station on the Seoul Subway Line 3 in Gangnam-gu, Seoul. The only exit of this station is connected to SETEC (Seoul Trade Exhibition & Convention Center). This station has the least ridership of all Line 3 stations in Seoul.

It is located in Daechi-dong, Gangnam-gu, Seoul.

Vicinity

 * Exit 1 : Seoul Trade Exhibition Center

title: Hangnyeoul station


text:
Talk:Emory Peak

Untitled
not sure if wikipedia wants to become a hiking guide, sure would be nice though... ffangs 12:07, 10 October 2005 (UTC)ffangs

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title: Talk:Emory Peak


text: User talk:81.173.142.201

title: User talk:81.173.142.201


text:
Gupabal station

Gupabal Station is a station on the Seoul Subway Line 3. Some Line 3 trains only offer service up to this station, although it is not the technical end of Line 3 (Seoul Metro controlled section, Jichuk is the actual end). The name comes from 'Pabal', a Joseon-era post station that existed in the area. Nearby attractions include Jingwan Neighborhood Park, Gupabal Falls, Bukhansan National Park and Seooreung, a cluster of royal tombs. Lotte Mall, Eunpyeong NewTown and Eunpyeong Hanok village is near the station.

title: Gupabal station


text:
Alligator Alley (disambiguation)

Alligator Alley may refer to:

 * Alligator Alley, a designation for Interstate 75 in Florida between Naples and Fort Lauderdale
 * Alligator Alley, a grade 2/3 band piece by Michael Daugherty
 * Alligator Alley, a novel by K. W. Jeter (as "Dr. Adder") and Tim MacNamara (as "Mink Mole")
 * "Alligator Alley" a song by the musician Keller Williams
 * "Alligator Alley" or "Gator Alley", nickname of Florida Gymnasium on the University of Florida campus

title: Alligator Alley (disambiguation)


text:
Lent Bumps

The Lent Bumps (also Lent Races, Lents) are a set of rowing races held annually on the River Cam in Cambridge. They began in 1887, after separating from the May Bumps, which are bumping races held in mid-June. Prior to the separation there had been a single set of annual bumps dating from its inception in 1827. The races are open to all college boat clubs from the University of Cambridge, the University Medical and Veterinary Schools and Anglia Ruskin Boat Club. The Lent Bumps take place over five days (Tuesday to Saturday) at the end of February / start of March and are run as bumps races.

The most recent in the series was the Lent Bumps 2024, held from 27 February to 2 March 2024.

Structure

The races are run in divisions, each containing 17 crews. The number of crews in each bottom division varies yearly depending on new entrants. Each crew consists of eight rowers and one coxswain. Unlike the May Bumps, rowers trialling for places in university crews are not allowed to take part in the Lents. A total of 120 crews took part in 2020, totalling around 1080 participants. There are currently four divisions for men's crews (referred to as M1, M2 ... M4) and four divisions for women's crews (similarly W1 to W4). Both M4 and W4 are "short" divisions which marshall together; W4 goes off 5 minutes separated from M4 whereas other divisions are separated by 40 minutes. The divisions represent an overall race order, with Division 1 at the top. The ultimate aim is to try to finish Head of the River (also said as gaining the 'Headship'), i.e. first position in Division 1.

At the start, signalled by a cannon, each crew is separated by a distance of about 1½ boat lengths (approximately 30 m or 90 ft). Once the race has begun, a crew must attempt to catch up with the crew ahead of it and bump (physically touch or overtake it) before the crew behind does the same to them. A crew which bumps or is bumped must pull to the side of the river to allow other crews to continue racing. A crew which neither bumps the crew ahead nor is bumped by the crew behind before crossing the finishing post is said to have rowed over. Any crew which bumps then swaps places with the crew that it bumped in the following day's racing. A crew which rows over stays in the same position. Crews finishing at the top of a division, the sandwich boat, row at the bottom of the next division to try to move up a division. The process is repeated over four effective days, allowing crews to move up or down in the overall order of boats. The finish order of one year's Lent Bumps is then used as the starting order of the following year's races. Due to the shortness of reliable daylight, the races are actually currently run over five days, with one division level dropped out each day except Saturday: on Tuesday M/W 1, on Wednesday 2, Thursday 3 and Friday 4.

Between 2010 and 2019, the leading men's and women's crews of the Lent Bumps went on to race the leading Oxford Torpids men's and women's crews at the Henley Boat Races around Easter. However, following the move of The Lightweight Boat Races to the Championship Course, this competition ceased to be held.

Men's Lent Bumps (1887–2023)
Lent Bumps were cancelled from 1915 to 1918 due to war, and in 1895 and 1963 due to ice; in 2018 two days were lost to the towpath being too icy for bank parties and umpires; in 2023, the Friday day was lost due to high rainfall and resulting high stream. The Lents in 1888 were not completed due to the death of an oarsman. When the races ceased, were in 1st position. The Lent Bumps 2001 were not completed due to an outbreak of Foot and Mouth disease in the UK. The outbreak closed the towpath along the river, where all of the umpiring for the bumps takes place. When the races were abandoned on Friday 2 March 2001, were in 1st position. The Lents were also cancelled in 2021 due to the COVID-19 pandemic.

In 1919, college 1st VIIIs did not race as it was the first race after World War I. The start order for the 1920 races was the finish order for the 1914 races. Prior to 1946 were two separate rowing clubs: 1st Trinity and 3rd Trinity, hence both separate and combined titles.

Women's Lent Bumps (1976–2023)
NB. The Lent Bumps were not completed in 2001 due to an outbreak of Foot and Mouth disease in the UK. When the races were abandoned on Friday 2 March 2001, were in 1st position. The Lents were also cancelled in 2021 due to the COVID-19 pandemic.

Table of Winning Boats (1887–2024)
Nineteen boats have been head of the river.

* The head of the river in 1919 was, unusually, 1st Trinity’s second boat. It was the first race after World War I and 1st eights did not race. The start order for the 1920 races was the finish order for the 1914 races.

Prior to 1946 were two separate rowing clubs: 1st Trinity and 3rd Trinity, hence both separate and combined titles.

Anglia Ruskin, Clare Hall, Darwin, Homerton, Hughes Hall, King's, Lucy Cavendish, Magdalene, Robinson, St. Catharine's, Selwyn, Sidney Sussex, St Edmund's, Wolfson, Addenbrooke's and the Veterinary School are the regular entrants never to have finished Head of the River in either the men's or women's events.

title: Lent Bumps


text:
Category:Nice

Nice is a city in southern France located on the Mediterranean coast, between Marseille and Genoa, with about a million inhabitants. The city is a major tourist center and a leading resort on the French Riviera.

title: Category:Nice


text:
Daecheong station

Daecheong Station is a station on the Seoul Subway Line 3. It is located in Irwon-dong, Gangnam-gu, Seoul, South Korea.

Around the station

 * Milal Museum of Art

title: Daecheong station


text:
Cladribine

Cladribine, sold under the brand name Leustatin, among others, is a medication used to treat hairy cell leukemia (leukemic reticuloendotheliosis) and B-cell chronic lymphocytic leukemia. Cladribine, sold under the brand name Mavenclad, is used for the treatment of adults with highly active forms of relapsing-remitting multiple sclerosis.

Cladribine is a purine analogue that selectively targets and suppresses lymphocytes implicated in the underlying pathogenesis of multiple sclerosis and B-cell leukaemia. Chemically, it mimics the nucleoside deoxyadenosine. However, unlike deoxyadenosine, it is relatively resistant to breakdown by the enzyme adenosine deaminase, which causes it to accumulate in targeted cells and interfere with the cell's ability to process DNA. Cladribine is taken up by cells via transporter proteins. Once inside a cell, cladribine undergoes phosphorylation by the enzyme deoxycytidine kinase (DCK) to produce mononucleotide 2-chlorodeoxyadenosine 5’monophosphate (2-CdAMP), which is subsequently phosphorylated to the triphosphorylated active compound 2-chlorodeoxyadenosine 5’triphosphate (2-CdATP). Activated cladribine is incorporated into cellular DNA, which triggers apoptosis. Accumulation of cladribine into cells is dependent on the ratio of DCK and 5'-nucleotidase (5’-NT), which breaks down and inactivates the compound. This ratio differs between cell types, with high levels in T and B lymphocytes, resulting in selective targeting of these cells. In contrast, DCK:5'NT is relatively low in other cell types, thus sparing numerous non-haematological cells.

It is on the World Health Organization's List of Essential Medicines.

Medical uses
Cladribine is used as a first- and second-line treatment for symptomatic hairy cell leukemia and for B-cell chronic lymphocytic leukaemia, and is administered by intravenous or subcutaneous infusion. Some investigators have used the parenteral formulation orally to treat patients with hairy cell leukemia. About 37–51% of oral cladribine is bioavailable orally. It is used, often in combination with other cytotoxic agents, to treat various kinds of histiocytosis, including Erdheim–Chester disease and Langerhans cell histiocytosis.

Following EMA approval of cladribine tablets for the treatment of adult patients with highly active relapsing-remitting multiple sclerosis in 2017, as of July 2020, cladribine tablets have gained marketing authorisation in over 75 countries. In 2019, cladribine tablets were approved by the FDA for the treatment of relapsing forms of multiple sclerosis, to include relapsing-remitting disease and active secondary progressive disease, in adult patients who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of multiple sclerosis.

Cladribine may cause foetal harm when administered to a pregnant woman and is listed by the FDA as pregnancy category D; safety and efficacy in children has not been established.

Mechanism of action
As a purine analogue, cladribine is taken up into rapidly proliferating cells, including B and T lymphocytes, to be incorporated into DNA synthesis. Chemically, it mimics nucleoside adenosine; however, unlike adenosine, cladribine has a chlorine molecule at position 2, which renders it partially resistant to breakdown by adenosine deaminase. This causes it to accumulate in cells and interfere with the targeted cell's ability to process DNA.

Cladribine is taken up by specific nucleoside transporter proteins. Once inside a cell, cladribine undergoes phosphorylation by the enzyme deoxycytidine kinase (DCK) to produce mononucleotide 2-chlorodeoxyadenosine 5’monophosphate (2-CdAMP), which is subsequently phosphorylated to the triphosphorylated active compound, 2-chlorodeoxyadenosine 5’triphosphate (2-CdATP).

Activated cladribine is incorporated into the DNA synthesis pathway, where it disrupts DNA repair and synthesis, resulting in an accumulation of DNA strand breaks This is followed by the activation of transcription factor p53, the release of cytochrome c from mitochondria and eventual programmed cell death (apoptosis). This process occurs over approximately 2 months, with a peak level of cell depletion 4–8 weeks after treatment.

Another family of enzymes, the 5'-nucleotidase (5'-NT) family, is also capable of dephosphorylating cladribine, making it inactive. The most important subtypes of this group appear to be cytosolic 5'-NT, c-5NCT1A and c-NT1B, which are cytosolically active and specific for purine analogues.

Accumulation of cladribine into cells is dependent on the ratio of DCK and 5'-NT. This ratio differs between cell types, with high levels in T and B lymphocytes, making them particularly susceptible to cell death. The cells with the highest ratios are B cells, especially germinal centre and naïve B cells. This helps to explain which B cells are more vulnerable to cladribine-mediated apoptosis. DCK is the rate-limiting enzyme for conversion of the cladribine prodrug into its active triphosphate form, leading to the selective depletion of dividing and non-dividing T and B lymphocytes. In contrast, the DCK:5'-NT ratio is relatively low in other cell types, thus sparing numerous non-hematologic cells.

In multiple sclerosis, cladribine's effectiveness may be due to depletion of B cells, in particular memory B cells. In the pivotal phase 3 clinical trial of oral cladribine in multiple sclerosis, CLARITY, cladribine selectively depleted 80% of peripheral B cells, compared to only 40–45% of CD4+ T cells and 15‒30% CD8+ T cells. More recently, cladribine has been shown to induce long term, selective suppression of certain subtypes of B cells, especially memory B cells.

Although cladribine is selective for B cells, the long-term suppression of memory B cells, which may contribute to its effect in multiple sclerosis, is not explained by gene or protein expression. Instead, cladribine appears to deplete the entire B cell department, but while naïve B cells rapidly move from lymphoid organs, the memory B cell pool repopulates slowly from the bone marrow. Both hairy cell leukemia and B-cell chronic lymphocytic leukaemia are types of B cell blood cancers.

History in hairy cell leukemia
Ernest Beutler and Dennis A. Carson had studied adenosine deaminase deficiency and recognised that because the lack of adenosine deaminase led to the destruction of B cell lymphocytes, a drug designed to inhibit adenosine deaminase might be useful in lymphomas. Carson then synthesised cladribine, and through clinical research at Scripps starting in the 1980s, Beutler tested it as intravenous infusion and found it was especially useful to treat hairy cell leukemia. No pharmaceutical companies were interested in selling the drug because hairy cell leukemia was an orphan disease, so Beutler's lab synthesised and packaged it and supplied it to the hospital pharmacy; the laboratory also developed a test to monitor blood levels. This was the first treatment that led to prolonged remission of hairy cell leukemia, which was previously untreatable.

In February 1991, Scripps began a collaboration with Johnson & Johnson to bring intravenous cladribine to market, and by December of that year, Johnson & Johnson had filed a new drug application; cladribine was approved by the FDA in 1993 for hairy cell leukemia as an orphan drug, and was approved in Europe later that year.

The subcutaneous formulation was developed in Switzerland in the early 1990s and it was commercialised by Lipomed GmbH in the 2000s.

Safety profile of cladribine in hairy cell leukemia
Injectable cladribine suppresses the body's ability to make new lymphocytes, natural killer cells, and neutrophils (called myelosuppression); data from hairy cell leukemia studies showed that about 70% of people taking the drug developed dangerously low levels of white blood cells and about 30% developed infections and some of those progressed to septic shock; about 40% of people taking the drug had fewer red blood cells and became severely anaemic; and about 10% of people had too few platelets. At the dosage used to treat hairy cell leukemia in two clinical trials, 16% of people had rashes and 22% had nausea, the nausea generally did not lead to vomiting.

History in multiple sclerosis
In the mid-1990s, Beutler, in collaboration with Jack Sipe, a neurologist at Scripps Institute, ran several clinical trials exploring the utility of cladribine in multiple sclerosis, based on the drug's immunosuppressive effects. Sipe's insight into multiple sclerosis, and Beutler's interest in multiple sclerosis due to his sister having the disease, initiated a very productive collaboration. Ortho-Clinical, a subsidiary of Johnson & Johnson, filed a new drug application for cladribine for multiple sclerosis in 1997 but withdrew it in the late 1990s after discussion with the FDA proved that more clinical data would be needed.

Ivax acquired the rights for oral administration of cladribine to treat multiple sclerosis from Scripps in 2000, and partnered with Serono in 2002. Ivax was acquired by Teva in 2006, and Merck KGaA acquired control of Serono's drug business in 2006.

An oral formulation of the drug with cyclodextrin was developed by Ivax and Serono, and then Merck KGaA conducted clinical trials. Merck KGaA submitted an application to the European Medicines Agency in 2009, which was rejected in 2010, and an appeal was denied in 2011. Likewise Merck KGaA's new drug application with the FDA rejected in 2011.

The ratio of benefit to harm was not clear to regulators, and further studies were requested to address concerns related to severe lymphopenia and cancer cases observed during pivotal trials. Clinical studies of multiple sclerosis were still ongoing at the time of the rejections, and Merck KGaA committed to completing them. A meta-analysis of data from clinical trials comparing the risk of cancer and other disease-modifying therapies showed that cladribine tablets did not increase the risk of cancer at the doses used in the initial clinical trials. Based on the supporting data from the completed clinical trials that confirmed no increased risk of cancer, Merck announced it would again seek regulatory approval. In 2016, the EMA accepted its application for review. On June 22, 2017, the EMA's Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the treatment of relapsing forms of multiple sclerosis.

Cladribine tablets were later approved in Europe, in August 2017, for highly active relapsing-remitting multiple sclerosis, and has since been approved by the FDA for the treatment of relapsing-remitting and secondary progressive multiple sclerosis in the US.

Use in multiple sclerosis
As per the EU label, cladribine tablets are indicated for the treatment of adult patients with highly active relapsing multiple sclerosis as defined by clinical or imaging features: (i) patients with a relapse in the previous year and at least one T1 Gd+ lesion or 9 or more T2 lesions, while on another disease-modifying therapies or (ii) patients with two or more relapses in the previous year, whether on disease-modifying treatment or not.

Two main approaches to multiple sclerosis treatment maintenance therapy are used – immunomodulation and immunosuppression and alternatively, immune reconstitution therapy. Classified as the latter, cladribine tablets are administered intermittently as a short treatment course without continuous immunosuppression. In contrast to maintenance therapies, clinical efficacy extends beyond the dosing period.

Cladribine tablets are administered as 2 courses separated by 1 year (a maximum of 20 days of treatment). The recommended cumulative dose is 3.5 mg/kg weight over 2 years, administered as 1 treatment course of 1.75 mg/kg per year. Each treatment course consists of 2 treatment weeks, one at the beginning of the first month and one at the beginning of the second month of the respective treatment year. Each treatment week consists of 4 or 5 days on which a patient receives 10 mg or 20 mg (1 or 2 tablets) as a single daily dose based on body weight.

Before initiating treatment with cladribine tablets, blood tests, MRI and infection screening must be performed. Due to an increased risk of herpes zoster with cladribine tablets, patients who are antibody-negative for varicella zoster virus are recommended to be vaccinated before starting treatment. Treatment should not be initiated within 4 to 6 weeks of receiving a live or attenuated live vaccine because of a risk of active infection. Vaccination with live or attenuated live vaccines should also be avoided during and after treatment, but can be considered when lymphocyte counts have recovered to ≥1000 cells/mm3.

Following completion of the two treatment courses, no further treatment or additional monitoring is required.

The use of cladribine tablets is contraindicated in pregnant women, and women of childbearing potential must use effective contraception to prevent pregnancy during treatment and 6 months after receiving the last dose.

Efficacy of cladribine tablets in multiple sclerosis
Clinical trial results have shown that cladribine tablets can be an effective treatment for highly active, relapsing forms of multiple sclerosis, with significant clinical benefits in relapse rate, disability progression, and radiological measures. Compared with placebo, patients who received cladribine tablets (3.5 mg/kg) in the CLARITY study had a 58% reduction in annualized relapse rate and 47% of patients showed no evidence of disease activity at 2 years. Clinical improvements can be observed at Week 24 of treatment, and benefits may be sustained up to 4 years, beyond the 2-year dosing period and recovery of total lymphocytes. Post-hoc analyses of clinical trial data showed that 89% of patients remained free from disability progression two years after treatment.

Further analyses of a subgroup of patients in the CLARITY study who had very active multiple sclerosis showed a 67% reduction in relapse rates and an 82% reduction in disability progression in those treated with cladribine tablets. Similarly, clinical improvements were seen in lesion burden on MRI scans in this population.

Studies evaluating the treatment effects of cladribine tablets across a spectrum of baseline demographics and disease characteristics showed that the relative risk of relapse was significantly reduced compared with placebo, irrespective of previous treatment experience.

Furthermore, treatment with cladribine tablets has been shown to significantly reduce the rate of brain atrophy in patients with highly active relapsing-remitting multiple sclerosis. This reduction correlated with a reduced risk in disability progression in a retrospective analysis.

In clinical trials, higher cumulative doses of cladribine tablets did not result in further improvement in efficacy nor did additional courses after the 2-year treatment period, but was associated with a higher incidence of Grade 3 and Grade 4 lymphopenia.

Safety profile of cladribine tablets in multiple sclerosis
Cladribine tablets target the cells of the adaptive immune system with minimal impact on innate immune cells. Although the exact mechanism by which cladribine exerts its therapeutic effect is not fully elucidated, it is proposed to have a transient effect on B and T lymphocyte depletion, interrupting the cascade of immune events central to multiple sclerosis. As a result, a reduction in lymphocyte count (lymphopenia) may be reported following treatment. In clinical trials, lymphocyte levels above Grade 0 (≥1000 cells/mm3) and Grade 1 (<1000–800 cells/mm3) were maintained in most patients, with levels continuing to improve after the 2-year dosing period. Less than 1% of patients developed Grade 4 lymphopenia (<200 cells/mm3). It is important that patients with lymphocyte counts below 500 cells/mm3 should be actively monitored for signs suggestive of infection and that anti-infective treatments are given to at-risk patients.

Despite the initial reduction in lymphocyte counts following treatment, studies showed the overall risk of infection in patients receiving cladribine tablets was comparable to those who received placebo, except for herpes zoster infection. Due to this increased risk, it is recommended that patients are screened for varicella zoster virus and antibody-negative patients are vaccinated prior to receiving treatment. In an analysis of post-approval data, as of 2020, no new infection safety signals were observed in over 18,000 patients.

Progressive multifocal leukoencephalopathy has been reported in patients with hairy cell leukemia treated with parenteral cladribine. However, in up to 10 years of follow-up of patients receiving cladribine tablets for multiple sclerosis, no cases of progressive multifocal leukoencephalopathy have been observed; baseline MRI must be performed prior to initiating treatment.

In clinical trials, malignancies were observed more frequently in patients treated with cladribine tablets compared with patients who received placebo. Compared with a matched reference population from the Global Cancer Observatory database, cladribine tablets had no increased risk of malignancy in long-term real-world evidence data.

Research
Cladribine has been studied as part of a multidrug chemotherapy regimen for drug-resistant T-cell prolymphocytic leukaemia.

title: Cladribine


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Muakjae station

Muakjae Station is a station on Seoul Subway Line 3 in Seodaemun-gu, Seoul. The area was named Muakjae after Muhak, a Buddhist monk who played a vital role in moving the Korean capital to Seoul in the 14th century.

title: Muakjae station