User:Fvasconcellos/Fvasconcellos

Tecovirimat

Tecovirimat (INN, codenamed ST-246) is an antiviral drug being investigated for the prevention and treatment of orthopoxvirus infections, including smallpox. It is in Phase II clinical trials, and has been granted orphan drug and fast-track development status by the U.S. Food and Drug Administration. There are no approved treatments for smallpox as of 2009.

Tecovirimat is an egress inhibitor: it prevents the virus from exiting infected cells and spreading to healthy ones. Based on data from Phase I trials, it is safe (and likely effective) for use in humans.

History

Since the eradication of smallpox was declared in 1980, the main concern surrounding the disease has been its possible use as a biological warfare agent. Extensive research into new prevention and treatment agents for smallpox has been conducted in recent years, and tecovirimat is the result of one such program. After high-throughput screening of over 350,000 chemical compounds, a "hit compound" with potent activity against orthopoxviruses was identified. Based on structure-activity relationship studies, around 200 analogues of this compound were developed and analyzed further, and tecovirimat was found to be the most potent and stable.

In studies with mice, tecovirimat was found to protect against infection when animals were inoculated with lethal doses of vaccinia and mousepox viruses. Animals that did become infected (and survived) acquired immunity. Thirteen-lined ground squirrels given tecovirimat after inoculation with monkeypox virus always survived when treated within three days of infection, and 67% survived when given the drug on the fourth day after inoculation, whereas no animals survived with placebo.

Adverse effects

The only common adverse effect of tecovirimat identified in clinical trials thus far was neutropenia, although it was reported as being unrelated to treatment.

Pharmacokinetics

Tecovirimat is more rapidly and completely absorbed when given with food, perhaps because it is lipophilic (logP, 2.94).

AEDs in pregnancy

http://www.medscape.com/viewarticle/410736 PMID 19087117 (review) PMID 18062721 (review) PMID 15266543 (Cochrane) PMID 11934528 (CBZ) PMID 11468320 (CBZ) PMID 18336060 (VPA) PMID 19369666 (NEJM, cognitive function)

Did you know...

/ˈɒksəzɵˌlɪdɨnoʊn/

• ...that oxazolidinone antibiotics, now considered drugs of last resort against "superbugs" such as MRSA, were first used to treat diseased tomato plants?
• ...that retigabine is the first anticonvulsant to work by activating the K_v7 family of voltage-gated potassium channels?
• ...that the platinum-based antineoplastics are some of the most effective chemotherapeutic agents available, and are used in the treatment of over half of all cancers?
• ...that, if approved, tecovirimat would become the first specific treatment for smallpox, a disease that has been known for at least 1500 years?
• ...that romidepsin, a new treatment for T-cell lymphomas, was discovered in a culture of bacteria obtained from a soil sample collected in Yamagata Prefecture? ✓
• ...that the two drugs available in the United States for treatment of acute hereditary angioedema attacks, ecallantide and Berinert, were approved by the FDA within one month of each other?

For Penicillin

Penicillin

Natural

Penicillin G (benzylpenicillin, "crystalline penicillin") procaine benzylpenicillin benzathine benzylpenicillin

Penicillin V (phenoxymethylpenicillin) benzathine phenoxymethylpenicillin

Semisynthetic

The semisynthetic penicillins are prepared starting from the penicillin nucleus 6-APA.

Narrow-spectrum

• Beta-lactamase sensitive
  • benzathine penicillin
  • benzylpenicillin (penicillin G)
  • phenoxymethylpenicillin (penicillin V)
  • procaine penicillin

• Penicillinase-resistant penicillins
  • methicillin
  • oxacillin
  • nafcillin
  • cloxacillin
  • dicloxacillin
  • flucloxacillin

Moderate- and extended-spectrum

The aminopenicillins, amoxicillin and ampicillin,

The carboxypenicillins, carbenicillin, ticarcillin, and temocillin,

The ureidopenicillins, azlocillin, mezlocillin, and piperacillin

http://books.google.com/books?id=91altE1evAsC&pg=PA181

http://www.cdc.gov/std/treatment/misc/penicillinG.htm

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• User:Fvasconcellos/Oscar Freire
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FACs supported

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Metformin: sources for expansion

History

Goal: expand
Gottlieb, B.; Auld, W. H. (1962). "Metformin in treatment of diabetes mellitus". British medical journal. 1 (5279): 680–682. doi:10.1136/bmj.1.5279.680. PMC 1958151. PMID 13900753. (1962 trial, secondary source for synthesis etc.) PMID 16402501
doi:10.1177/14746514070070051001
doi:10.1002/pdi.606 excellent history by C.J. Bailey

Clinical use

Goal: expand and improve sourcing
PMID 16034881: monotherapy (Cochrane Review, 2005, should be in article already)
PMID 17655510: failure of monotherapy, metformin vs. TZDs vs. sulfonylureas (retrospective study, 2007)
PMID 19366942: pre-diabetes (meta-analysis, Can Fam Physician, 2009)

Off-label use

PMID 19634921: in PCOS (review, 2009)
PMID 19405411: in PCOS (review, 2009)
PMID 19160294: in T1DM (Cochrane Review, 2009)

Gestational diabetes

Goal: reduce reliance on low-quality evidence
PMID 19640341 (review, August 2009)
PMID 19621846 (review, Am Fam Physician)
PMID 19401478

Investigational findings

Goal: expand
PMID 19721204: metformin and bone disease (review, September 2009)
PMID 19476423: antipsychotic-induced weight gain (review, June 2009)

Mechanism of action

PMID 19754381: in PCOS (review, 2009)

Comments

Is it OK to comment here? I looked through the history references except for doi:10.1002/pdi.606 excellent history by C.J. Bailey, which is unavailable to me. It seems that the first mention of metformin was in 1923 not 1957. While galegin is chemically and, perhaps, pharmacodinamically related to metformin, it appears to be not related to it historically: "Jean Sterne first gave metformin to type 2 diabetic patients 50 years ago, in Paris after the serendipitous discovery of effects on blood glucose during attempts to treat influenza and other conditions with metformin". In this light, do galegin and related history deserve to be mentioned in any detail?

On another note, I would not hit the reader with a chemical name "biguanides" in the first sentence of the lead. Are biguanides really a "class" of antidiabetic agents if metformin is the only representative still used in clinic? What was the first trade name Aron Labs marketed it under in 1958? It deserves to be mentioned along with Glucophage, but all other trade names are disctracting and better be removed. The Sceptical Chymist (talk) 11:50, 30 November 2009 (UTC)

Yes, please do comment. Metformin was first synthesized in 1922 but was mostly forgotten untill Sterne's interest was piqued by reports of hypoglycemic effects, as you mention (the discovery of antihyperglycemia as a side effect of proguanil was also important). Galegine is important because it was the first guanidine derivative used as an antidiabetic, and it led to the development of the synthalins (the first diguanides to enter clinical use), which were used despite toxicity and limited efficacy in the 20s and 30s; apparently, people have short-term memories when it comes to drugs that are superseded by more effective treatments. Glucophage was the first trade name, coined by Sterne himself; Aron was sold to Lipha, which was bought by Merck, and metformin was licensed by BMS in the U.S. (as you can see, the history section needs not only expansion but updating). The biguanides are a chemical class of therapeutic interest, and phenformin and buformin are actually still available in some countries (very few, not sure which ones; phenformin could still be found in Brazil until a few years ago). Fvasconcellos (t·c) 12:10, 30 November 2009 (UTC)

Right. All this could be mentioned in the history of biguanides. But we are not writing about the class of biguanides. The references clearly state that metformin's sugar-lowering effect was re-discovered serendipitously when it was tried for infuenza, and not because sinthalins were used before.The Sceptical Chymist (talk) 02:13, 1 December 2009 (UTC)

...but Sterne's studies began with galegine (for the treatment of diabetes, not influenza). Prompted by those anecdotal reports of hypoglycemia, he moved to biguanides, chose metformin for clinical study (officially, with no clue of the '29 studies) and the rest is history. Do you have e-mail enabled? I can send you a copy of the Bailey article. Fvasconcellos (t·c) 11:43, 1 December 2009 (UTC)

I enabled the e-mail and would appreciate you sending me the full reference. I hope the full article resolves the contradiction with Howlett's presentation abstracted here [1], which states "In the 1940s and

early 1950s interest in biguanides (including metformin) was boosted by their use for the treatment of influenza and the serendipitous observation of hypoglycaemic activity. Jean Sterne, a physician working with Jan Aron at his Laboratoires Aron in Paris reviewed these data and singled out metformin for further attention. A careful and systematic series of preclinical studies led to the first administration of metformin to diabetic humans by Sterne in 1957." The Sceptical Chymist (talk) 02:49, 2 December 2009 (UTC)

Will do. Meanwhile, you may want to have a look at section 4 of this article (free full text). There are a few minor inaccuracies but it gives a good account (although it doesn't mention Sterne's work with galegine). Fvasconcellos (t·c) 03:23, 2 December 2009 (UTC)

A carefult review of the literature is also in order to establish (1) the year in which metformin was first marketed (not mentioned), and (2) the year in which it made it past the French market. Would also be nice to determine when the name "metformin" was actually coined. Contemporary primary sources may be more useful than secondary ones for this... Fvasconcellos (t·c) 03:26, 2 December 2009 (UTC)

RE: "section 4 of that article". First, it seem to suggest that Sterne's work comes from tying to treat influenza. Second, I cannot consider the FASEB article reliable. For example, it makes five errors in two adjacent paragraphs:

"One of the first drugs shown to do both is a chemical cousin of the active compound in a diabetes folk remedy, the plant goat's rue or French lilac. This plant had been used since medieval times to treat diabetes and is rich in a compound known as guanidine.

But as is true for many folk remedies, guanidines had side effects that were too dangerous to warrant their use to routinely treat diabetes. A number of researchers tried to synthesize less toxic versions of guanidine that still lowered blood sugar levels. One of those versions, called a biguanide because it was comprised of two molecules of guanidine linked together, was first synthesized in 1922 by two English chemists" The Sceptical Chymist (talk) 04:06, 2 December 2009 (UTC)

I did mention some minor inaccuracies :) By the way, I like keeping alternate trade names in the lead. This is useful information from which readers may be redirected to the article. Fvasconcellos (t·c) 04:36, 2 December 2009 (UTC)

E-mail sent, although this is probably easier: Google Docs. Best, Fvasconcellos (t·c) 11:33, 2 December 2009 (UTC)

Thanks a lot. How did you search it through the Googledocs? The document seemed to me not be open access.

RE: trade names. I am not so sure. There may be 20-30 of different trade names for metformin. Where do we stop? Is the convenience for querying a sufficient reason to override MEDMOS recommendations? Why does not the convenience for querying overrides MEDMOS recommendations for any other drug? In addition, any reader who is not a complete idiot can query the INN name which is usually listed on the drug package right after the trade name in parenthesis. There are also redirects to handle the problem of queries. The Sceptical Chymist (talk) 11:36, 2 December 2009 (UTC)

I could access the free full text with no problems directly from the journal website. As for the trade names, see Wikipedia:Lead section#Abbreviations and synonyms for my rationale; the availability of redirects is one of the reasons for mentioning alternate names in the lead. I agree we need to reach a consensus re. MEDMOS. Fvasconcellos (t·c) 23:53, 2 December 2009 (UTC)

Well, I wanted to help you but it seems we got stuck on the issue of names, and galega with Greenwood obstructing any changes to those items. I would like to repeat that including many names is absurd and no good pharmacology article does it. I do not think we can move further without following the MEDMOS and if the article goes to FAC I will bring that up. The Sceptical Chymist (talk) 02:19, 3 December 2009 (UTC)

I'm sure we can reach an agreement on names (I wouldn't call this "absurd" at all; note WP:LEAD). Linezolid (FA) mentions all trade names in the lead (only four, but still). In that case, this is key information, as linezolid trade names vary by region. and no opposition has ever been noted (not during FAC either). I still don't understand your objection to Galega. I cannot see how it is not pertinent, and it is probably no coincidence that it is an essential mention in any history of metformin in the literature. Have you had a chance to read the Bailey article? Fvasconcellos (t·c) 02:24, 3 December 2009 (UTC)

• I would not mind if there were 2-4 main trade names for metformin. Which ones do you suggest? The Sceptical Chymist (talk) 03:02, 3 December 2009 (UTC)

• • Will see about popularity etc. Fvasconcellos (t·c) 16:00, 3 December 2009 (UTC)

• • • Moving the other names down into a separate section is a useful solution, though I'm still not completely happy with it. Fvasconcellos (t·c) 13:08, 4 December 2009 (UTC)
• Despite some inaccuracies, (for example, galega contains guanidines but no guanidine) Bailey looks reasonable overall. To find out when metformin was introduced in France and elsewhere, I am going to try to order some of the books cited by Bailey. But it may take more than a month, so for know we can use Bailey. I am going to look through the following chapters. The Sceptical Chymist (talk) 04:37, 3 December 2009 (UTC)
  • I hope you'll order them through your library! I dare you to find a scientific article free of inaccuracies :) Seriously. Fvasconcellos (t·c) 16:00, 3 December 2009 (UTC)
    • ...Scientific article free of inaccuracies - my articles, of course ;)) Seriously, see my later comments and suggestions. The Sceptical Chymist (talk) 12:29, 4 December 2009 (UTC)

RE: Galega problem.

• The current version of the article: "the biguanide class of anti-diabetic drugs... originates from the French lilac (Galega officinalis), a plant known for several centuries to reduce the symptoms of diabetes mellitus.[7]"
  • Could easily replace with "a plant used in folk medicine for hundreds of years" or something along those lines. Or simply follow the sources and note what you note below—believed to have been used... though I hate this sort of statement. Fvasconcellos (t·c) 23:26, 3 December 2009 (UTC)
    • How about this outline? -- Galega was used in folk medicine for centuries - in XXX year it was found to contain galegin which had sugar-lowering properties, Sterne studied galegine and then when he saw a report about using metformin in Fillipines, tried it -- etc.
      • Yes, that's good. Fvasconcellos (t·c) 13:09, 4 December 2009 (UTC)
• Bailey lists other uses and mentions the diabetes connection as very tentative: "Aerial parts of the plant were used medicinally in medieval Europe to treat plague, worms, snake bites, miasma, dysuria and St Vitus dance, and the plant was fed to livestock

to increase milk yield." ---- No mention of diabetes so far.

• • Yes, the genus name is believed to have been a reference to its use as a galactogogue (not sure how accurate that is, thoughnot that it's germane to this discussion :). Fvasconcellos (t·c) 23:29, 3 December 2009 (UTC)

• Then Bailey goes: "it is believed that G. officinalis was also used in folklore medicine to treat symptoms now ascribed to type 2 diabetes" -- Please note how tentative it is. Do not you think that type 2 diabetes in medieval times was very rare? Consider that most of the population ate very little, and that they did not live long - and you know that diabetes 2 is a disease of middle age and overeating.
  • Well, diabetes mellitus has been known as a distinct entity since antiquity, although the (key) distinction between T1 and T2 is of course recent. I can't speak to how rare it would have been in the middle ages, although I can presume. Fvasconcellos (t·c) 23:29, 3 December 2009 (UTC)

• Other evidence Bailey cites is also equivocal: "some versions of Culpeper’s herbal suggest it has antidiabetic properties". However, that could be an artifact of one of the translations since as far as I understand later editions do not mention "diabetes": "discrepancies in later editions may be due to differences in translation and interpretation." The Sceptical Chymist (talk) 03:01, 3 December 2009 (UTC)

• • There's quite a bit more on galegine, the synthalins and metformin in http://media.wiley.com/product_data/excerpt/19/04707254/0470725419.pdf. It's a chapter from a Merck book, though, so take it with a grain of COI salt. And do try to look past the minor inaccuracies, such as "guanidine-like" for "guanidine-containing" and one instance in which the synthalins are described as biguanides and not diguanides :) The book is ISBN 0470725419, if you're interested. I can't get it here, not unless I buy it, of course. Fvasconcellos (t·c) 16:05, 3 December 2009 (UTC)

I did read that ref (ref A). To prove the use of Galega for diabetes it refers to this article (ref B)[2]. Ref B states: "In medieval times, a prescription of Galega officinalis was said to relieve the intense urination accompanying the disease that came to have the name of diabetes mellitus." and refers to ... nothing. Seriously, it is hearsay based on a hearsay based on a hearsay etc ad infinitum.

As an aside, I find this to be an unfortunate common problem with the articles on the history of medicine written by MDs (unlike with articles written by real historians). A secondary source refers to a tertiary source, which refers to a secondary source, which refers to a secondary source, which refers to a a secondary source published in 1920s, which the author of the n-1 secondary source, probably, did not read or quoted from the memory. Nobody is intellectually curious enough to check what actually was said in the primary source.

For example, everybody knows that Hippocrates recommended tea of willows bark containing salicylates for pain, including pain of childbirth. However, if you go to the full Hippocratic Corpus, the only mention of the willow for pain is that a woman should sit over a smoke made from willow. Imagine how ineffective that was (my guess is placebo effect), and what was the dose of salicylates she received through this vaginal smoke delivery method (my guess is 0). The Sceptical Chymist (talk) 12:26, 4 December 2009 (UTC)

You forgot to mention inaccurate and "embellished" translations. What about the chemical inaccuracies in articles written by MDs, and the lack of clinical awareness (sometimes to the point of ignorance) in those written by lab folks? Seriously, historical information is inherently of dubious reliability. If we dwell too long on this we will come to the conclusion that it is simply best to forgo its inclusion altogether—but that would make us think about the reliability of published research findings in an industry-dominated world, and by the end of the day we'd be editing pop culture articles instead. Fvasconcellos (t·c) 13:14, 4 December 2009 (UTC)

Here we disagree -- only the best will do for me. History of science is less subjective than general history. Much of it consists of journal articles, hence it is much better documented and it is much easier to access all the sources. One just has to be intellectually curious. Besides, to dig out all this fascinating stuff is fun. The Sceptical Chymist (talk) 06:20, 5 December 2009 (UTC)

That it is. Fvasconcellos (t·c) 11:18, 5 December 2009 (UTC)

That is it, - in a good sense ;) or a bad sense :(( ? The Sceptical Chymist (talk) 14:54, 5 December 2009 (UTC)

No, that it is, it is indeed fun :) Fvasconcellos (t·c) 15:22, 5 December 2009 (UTC)

Clinical use and Chemistry

RE: Clinical use. I looked at the three references you suggested on clinical use. Only one (Cochrane) deals with its main use - diabetes. The abstract of Cochrane meta-analysis reads like a mishmash of data - with no underlying idea. Maybe full version is better but I do not have the access to it. Are there recent good reviews (not meta-analyses) in the literature? Should I maybe look in my textbooks (but they are not very recent)?

Plenty, but sorting through them to find the good ones will take a while. Which meta-analysis are you talking about? What the article actually needs is more information on the off-label uses, namely PCOS, gestational diabetes (where it is moving toward becoming an established treatment) and augmentation of therapy in T1DM (which is not mentioned at all). The main use has not changed in 50 years; this particular section should be expanded with things such as efficacy, comparison with other anti-diabetics (*plenty* of high-quality studies in this area), etc. Fvasconcellos (t·c) 12:13, 8 December 2009 (UTC)

I am talking about PMID 16034881. IMHO the main clinical section is cursory, and would be logical to start with it. The Sceptical Chymist (talk) 00:28, 9 December 2009 (UTC)

Sure. By the way, I think we should include some more context on UKPDS (what it is, why it matters). Fvasconcellos (t·c) 12:18, 23 December 2009 (UTC)

RE: chemistry. As a "chymist" I can tell you that Shalmashi ref is not a green method. Heating in a microwave on a glass plate to obtain miligrams of metformin ... The journal in which it was published is not even third rate. I never heard about it before. Its impact factor is probably lower than 0.2 if it has an IF at all. It is not edited by a reputable publisher. Molecular Diversity Preservation International (MDPI) is an outfit with a goal "to preserve permanently historically significant research chemical samples in the chemical museum in Basel, Switzerland"

Go ahead and remove it. Fvasconcellos (t·c) 12:13, 8 December 2009 (UTC)

In addition, the preparation method by Shapiro is the same as the original 1922 method, and is similar to the Boots (1948) method. It, probably, does not deserve mentioning.The Sceptical Chymist (talk) 11:53, 8 December 2009 (UTC)

I suspected as much. I always like to include a little synthesis information, though; can you reword it for historical accuracy? Fvasconcellos (t·c) 12:13, 8 December 2009 (UTC)

I've dropped the Shapiro line. How's that? Fvasconcellos (t·c) 12:17, 23 December 2009 (UTC)