This is not a Wikipedia article: This is a workpage, a collection of material and work in progress that may or may not be incorporated into an article. It should not necessarily be considered factual or authoritative. |
Tecovirimat ( INN, [1] 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. [2] There are no approved treatments for smallpox as of 2009 [update].
Tecovirimat is an egress inhibitor: it prevents the virus from exiting infected cells and spreading to healthy ones. [2] Based on data from Phase I trials, it is safe (and likely effective) for use in humans. [3]
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. [2] [3] 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. [2] 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. [3] [4]
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. [5] 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. [6]
The only common adverse effect of tecovirimat identified in clinical trials thus far was neutropenia, although it was reported as being unrelated to treatment. [3]
Tecovirimat is more rapidly and completely absorbed when given with food, perhaps because it is lipophilic ( logP, 2.94). [3]
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)
Penicillin G (benzylpenicillin, "crystalline penicillin") procaine benzylpenicillin benzathine benzylpenicillin
Penicillin V (phenoxymethylpenicillin) benzathine phenoxymethylpenicillin
The semisynthetic penicillins are prepared starting from the penicillin nucleus 6-APA.
The aminopenicillins, amoxicillin and ampicillin,
The carboxypenicillins, carbenicillin, ticarcillin, and temocillin,
The ureidopenicillins, azlocillin, mezlocillin, and piperacillin
|
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
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)
PMID
19634921: in PCOS (review, 2009)
PMID
19405411: in PCOS (review, 2009)
PMID
19160294: in T1DM (Cochrane Review, 2009)
Goal: reduce reliance on low-quality evidence
PMID
19640341 (review, August 2009)
PMID
19621846 (review, Am Fam Physician)
PMID
19401478
Goal: expand
PMID
19721204: metformin and bone disease (review, September 2009)
PMID
19476423: antipsychotic-induced weight gain (review, June 2009)
PMID 19754381: in PCOS (review, 2009)
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)
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)
"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)
to increase milk yield." ---- No mention of diabetes so far.
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)?
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"
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)
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This is not a Wikipedia article: This is a workpage, a collection of material and work in progress that may or may not be incorporated into an article. It should not necessarily be considered factual or authoritative. |
Tecovirimat ( INN, [1] 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. [2] There are no approved treatments for smallpox as of 2009 [update].
Tecovirimat is an egress inhibitor: it prevents the virus from exiting infected cells and spreading to healthy ones. [2] Based on data from Phase I trials, it is safe (and likely effective) for use in humans. [3]
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. [2] [3] 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. [2] 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. [3] [4]
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. [5] 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. [6]
The only common adverse effect of tecovirimat identified in clinical trials thus far was neutropenia, although it was reported as being unrelated to treatment. [3]
Tecovirimat is more rapidly and completely absorbed when given with food, perhaps because it is lipophilic ( logP, 2.94). [3]
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)
Penicillin G (benzylpenicillin, "crystalline penicillin") procaine benzylpenicillin benzathine benzylpenicillin
Penicillin V (phenoxymethylpenicillin) benzathine phenoxymethylpenicillin
The semisynthetic penicillins are prepared starting from the penicillin nucleus 6-APA.
The aminopenicillins, amoxicillin and ampicillin,
The carboxypenicillins, carbenicillin, ticarcillin, and temocillin,
The ureidopenicillins, azlocillin, mezlocillin, and piperacillin
|
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
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)
PMID
19634921: in PCOS (review, 2009)
PMID
19405411: in PCOS (review, 2009)
PMID
19160294: in T1DM (Cochrane Review, 2009)
Goal: reduce reliance on low-quality evidence
PMID
19640341 (review, August 2009)
PMID
19621846 (review, Am Fam Physician)
PMID
19401478
Goal: expand
PMID
19721204: metformin and bone disease (review, September 2009)
PMID
19476423: antipsychotic-induced weight gain (review, June 2009)
PMID 19754381: in PCOS (review, 2009)
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)
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)
"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)
to increase milk yield." ---- No mention of diabetes so far.
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)?
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"
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)
{{
cite journal}}
: Explicit use of et al. in: |author=
(
help); Unknown parameter |month=
ignored (
help)CS1 maint: multiple names: authors list (
link)
{{
cite journal}}
: Explicit use of et al. in: |author=
(
help); Unknown parameter |month=
ignored (
help)CS1 maint: multiple names: authors list (
link)
{{
cite journal}}
: Explicit use of et al. in: |author=
(
help); Unknown parameter |month=
ignored (
help)CS1 maint: multiple names: authors list (
link)
{{
cite journal}}
: Explicit use of et al. in: |author=
(
help); Unknown parameter |month=
ignored (
help)CS1 maint: multiple names: authors list (
link)