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Migraine 偏头痛: II Treatment of Pain

发表于 12-4-2017 13:42:32 | 显示全部楼层 |阅读模式
本帖最后由 choi 于 12-5-2017 16:17 编辑

(1) migraine (n; etymology)

(2) Migraine is a mystery to medical professionals. Its cause remains unclear: whether it lies in -- or originates from -- brain or vessels (in or around the brain) is unknown.
(a) Please read
(paragraph 1 of introduction)
for symptoms.
(i) One characteristic of migraine is headache of "pulsating" (or throbbing) in nature, as if blood vessels dilate and contract rhythmically.
(ii) Another characteristic is aura (also occurring in epilepsy). In medicine, both aura and hallucination are subjective, but, in contrast to a hallucination, an aura is not elaborate (never seeing a monster or hearing a voice). See aura (symptom)
(section 2 Example)

The mere fact that both epilepsy and migraine MIGHT both be preceded by aura hints the real problem may lie with brain, not blood vessels there.
(b) "Migraine is a recurrent headache disorder affecting ∼15% of the population during the formative and most productive periods of their lives, between the ages of 22 and 55 years. It frequently starts in childhood, particularly around puberty, and affects women more than men (3:1 female-to-male ratio). It tends to run in families and, as such, is considered a genetic disorder."
Burstein R, Noseda R and Borsook D, Migraine: Multiple Processes, Complex Pathophysiology. Journal of Neuroscience, 35: 6619–6629 (2015; citations omitted).

(3) The long road to migraine treatment.
(a) https://en.wikipedia.org/wiki/Migraine
(i) section 9 History: "While many treatments for migraines have been attempted, it was not until 1868 that use of a substance which eventually turned out to be effective began.[132] This substance was the fungus ergot from which ergotamine was isolated in 1918.[137] Methysergide was developed in 1959 and the first triptan, sumatriptan, was developed in 1988.[137] During the 20th century with better study design effective preventative measures were found and confirmed."  last paragraph.
(ii) Footnote 132 is
David Borsook, Anne May, Peter J Goadsby, and Richard Hargreaves (eds), The Migraine Brain; imaging, structure, and function. Oxford University Press, pp 3–11 (2012). As I note, currently we still do not know the cause or mechanism of migraine, it is not surprising that the history reads like voodoo. For example: "Sigmund Freud put forward a psychidynamic interpretation of the origin of the disorder (Karwautz, Wober-Bingol & Wober, 1996)."  Id, at page 13.
(A) Footnote 132 supplies a link to the book, which unfortunately leads to blank pages of the book (in Google Books).
(B) The book is not written for laypersons. A reader should at least have some knowledge of biology.
(b) Here is the link to the book The Migraine Brain, with real pages:
https://books.google.com/books?i ... e&q&f=false


"Over the preceding centuries an enormous array of substances were used therapeutically in attempts to relieve migraine. None proved consistently useful. Then, in August 1868, Edward Woakes (1837-1912), a medical practitioner from Luton in England, reported the use of liquid extract of ergot of rye in seven patients (four with scieta). The extract proved effective in two young women with probable migraine (though diagnosed by Woakes as having tic douloureux) and in a 35-year-old man with hemicrania. Woakes's account marks the beginning of the use of ergot derivatives in migraine, a story that belongs to the 20th century. * * * The Swiss chemist [Arthur] Stoll [of Sandoz(1918) isolated pure ergotamine from the mix of alkaloids in ergot. The pure substance, given parenterally and later by mouth, proved efficacious in relieving migraine attacks in small numbers of sufferers (Maier, 1926; Rothlin, 1955). and came into increasing therapeutic use despite growing awareness of the long record of ergot's toxicity"  Id, at page 12.

"Several lines of evidence from human clinical physiology and pharmacology (eg, Curran, Hinterberger & Lance, 19765; Sicuteri, 1976; Sicuteri, Testi & Anselmi, 1961) suggested a role played for serotonin in migraine pathogenesis 病因学 and therapy (Humphrey, 2007). In the 1980s and 1990s, molecules with serotoninlike structures but selectivity for intracranial and trigeminal 5-HT receptors were synthesized in the hope that they would relieve migraine symptoms. On the whole this hope was realized, and a series of triptan derivatives (Humphrey, 2007) became available for treating the attacks. Also, the old migraine specific age nt ergotamine was shown to be a very potent serotonin agonist. The role of serotonin agonism in migraine pathogenesis as compared to treatment remains poorly understood, and emphasis has shifted from its vascular role to its role in brainstem pain modulation."  Id, at page 13.

* There is no need to read the rest.
(i) Through the history, the treatment was through trial and error.
(ii) Novartis
("Before the 1996 merger with Ciba-Geigy to form Novartis, Sandoz Pharmaceuticals (Sandoz AG) was a pharmaceutical company headquartered in Basel, Switzerland (as was Ciba-Geigy)" )

Geigy and Sandoz were founders' surnames. CIBA or Ciba is the acronym for "Gesellschaft für Chemische Industrie Basel" (Company for Chemical Industry Basel)."
(A) Gesellschaft (noun feminine; [noun masculine] Geselle [craftman] +‎ [suffix] -schaft [-ship, -hood]): "1. society, community; 2. (business) company"
(B) FAQ. Novartis Canada, undated
('"What does the name Novartis mean?  Novartis comes from the Latin term 'novae artes,' which means 'new arts' or 'new skills.' In essence, Novartis means utilizing scientific research, imagination, and new technologies to provide ever-greater benefits for humankind")
(A) Edward Woakes, MD. British Medical Journal, 2(2702): 1001 (1912; in the Obituary section)
(photo; "born at Luton in Bedfordshire in 1837 * * * He graduated M.B.Lond [occasionally abbreviated as M.B.-Lond; medical bachelor degree from University of London] in 1860, proceeding to doctor's degree in 1863. He served the office of house-surgeon at St Thomas's [Hospital, in London; established in 12th century; named after Thomas Becket (Archbishop of Canterbury, 1162-1170)], and might have looked forward to a position on the staff when he was recalled to joined his father [also a medical practitioner] in general practice at Luton in 1859")
(B) Luton is "30 miles (50 km) northwest of London."  en.wikipedia.org for Luton
(C) English dictionary:
* parenteral (adj; International Scientific Vocabulary para- 非 + enteral 肠的形容词)

(4) ergot
(a) Ideally treatment is based on cause of a disease. Oftentimes, cause is unknown, but accidental observations lead to treatments, without knowledge of underlying cause of a disease.
(b) Observation about ergot  (a fungal disease of grains, including rye (principally) and wheat, and rice occasionally) and poisoning caused by oral ingestion of ergot (ergotism).
(A) ergot
(B) ergot 麦角(症)
(C) The English noun ergot may mean either a diseased grain or the disease -- hence the Chinese translation.
(A) I googled with 麦角 and 中国 or 历史 (in traditional Chinese also) and found nothing. Of course, the term 麦角 might appear after Western civilization, especially ergot, was introduced to China. Still it is surprising that few Chinese historical reports mentioned symptoms and signs of the diseas.
(B) Further search shows:
Virgil A Johnson and Halsey L Beemer Jr (eds), Wheat in the People's Republic of China; A trip report of the American Wheat Studies Delegation. Committee on Scholarly Communication with People's Republic of China (CSCPRC), National Academy of Sciences, 1977 (the report was CSCPRC No 6), at page 57
https://books.google.com/books?i ... 20ergot&f=false
("Ergot, caused by Claviceps purpurea (Fr.) Tul., probably has never been a serious disease of wheat in China. It has occurred in northeast China on winter rye. With advances in agriculture, rye has generally been replaced with spring wheat in the northeast, and thus, no ergot occurs. In triticale breeding, which is done mainly at Peking, they reportedly have not had much ergot. We looked at a commercial triticale seed production field near Peking and saw no ergot, even though some floral sterility existed. In the Peking area the normal spring seasons are probably too dry for floral infection by ergot")
(iii) When a grain is infected with fungus Claviceps purpurea, the grain turns black and bigger. See Ergot of Rye - I: Introduction and History. Botany Department, University of Hawaii, undated (for Botany 135 lectures)
(View first pair of photos)
(A) The problem was people in Dark Ages did not know these ergot grains were diseased. They ground them and ate the flour, and got ergotism: convulsions and/or gangrene of ends of the limbs. The gangrene looked as if the ends were burned off, hence the name St Anthony's fire.
(B) So named, because in Catholicism St Anthony the Great [c 251 – 356; Egypt] was patron saint of ergotism sufferers and because monks in Order of St Anthony specialized in treating these sufferers. See  Hospital Brothers of St Anthony
(also known as Order of St Anthony; a Roman Catholic congregation founded in c 1095 [in present-day France], with the purpose of caring for those suffering from the common medieval disease of St Anthony's fire)
(c) It is absolutely certain that ergotamine caused systemic (which means the entire body) blood constriction in all blood vessels (arterial and venous) -- thereby decreased blood supply and resulting in gangrene.
(i) Because ergot-infected grains contains many alkaloids, it is not conclusively decided which one(s) caused convulsion.
(ii) Convulsion is not the focus of this posting. Suffice it to note that epilepsy (a disease) may be divided medically into grand mal and petit mal (French for big illness and small illness, respectively). Grand mal is marked by convulsion. "The term 'seizure' is often used interchangeably with 'convulsion.' "
(A) As a symptom (disease is epilepsy), convulsion is a medical term and seizure is used by laymen.
(B) Compare
epileptic seizure
(section 1 Signs and Symptoms: "The signs and symptoms of seizures vary depending on the type. The most common type of seizure is convulsive (60%) [occurring in grand mal]. Two-thirds of these begin as focal seizures and become generalized while one third begin as generalized seizures.[9] The remaining 40% of seizures are non-convulsive, an example of which is absence seizure [whose medical term is petit mal]")

In petit mal, patient suddenly stop what they are doing and stare for seconds. Laymen may not call the attacks seizures, but they are seizures all right.
(e) "Ergot does not contain lysergic acid diethylamide (LSD) but instead contains lysergic acid as well as its precursor, ergotamine. Lysergic acid is a precursor for the synthesis of LSD."  en.wikipedia.org for ergot.

(5) The first triptan drug.
(a) serotonin
(i) Maurice M Rapport (1919 – 2011; as a small child immigrated to US from Russia with parents whose surname was spelled Rapoport in Russia; BS in chemistry, City College of New York, 1940; PhD in organic chemistry, 1946); that same year started working in research arm of Cleveland Clinic. He, Irvine H Page (first Chair (ie, head) of Research, Clinic Clinic),  and Arda A Green, a female physical biochemist in 1948 discovered and named serotonin)  en.wikipedia.org for him
(ii) "Rapport identified it as a vasoconstrictor substance in the blood serum, and because it is a serum agent that affected vascular tone [by acting on smooth muscle of blood vessels] he called it serotonin."
Serotonin. Encyclopedia.org, undated.
http://www.encyclopedia.com/scie ... chemistry/serotonin
(b) Patrick Paul Anthony Humphrey (in short: Patrick P or PA Humphrey; born in South Africa in 1946; B.Pharm from then (independent) School of Pharmacy, University of London, 1868 (the School has been nicknamed The Square, as it was located at a square; annexed in 2012 as School of Pharmacy, University College London -- UCL is a constituent of University of London); PhD in pharmacology, St Mary's Hospital Medical School, London (year can not be found in the Web); entered Allen and Hanburys at Ware in 1972; his wife suffered from migraine triggered by menstruation, according to Humphrey himself
(i) Allen & Hanburys
(founded in 1715 in London; William Allen joined in 1792, whose second wife was a member of the Hanbury family; absorbed by Glaxo Laboratories in 1958)
(ii) Ware, Hertfordshire

is 25-mile air distance north of London.  Allen & Hanburys had a plant/factory here, which GlaxoSmithKline continues to operate.
(c) triptan
(section 6 History: serotonin (5-hydroxytryptamine, 5-HT) was discovered in late 1940s [actually 1948]; in the 1960s, studies showed that vasoconstriction caused by 5-HT, noradrenaline and ergotamine could reduce migraine attacks)
(i) But 5-HT, acting on many receptors, has many side effects. Patrick PA Humphrey identified the first triptan (sumatriptan) that acts on "5-HT1B and 5-HT1D receptors at blood vessels and nerve endings in the brain."  The triptan drugs are now used to treat headache once it starts.
(ii) I fail to find out the origin and meaning of "suma" but the "triptan" part is derived from 5-hydroxyTRYPTAmine.
(iii) Triptan drugs cause angina-like chest pain with abnormality in EKG; some have died who took the medication. So Patients who have heart disease or stroke may not take it.
(d) Humphrey PP. The Discovery of a New Drug Class for the Acute Treatment of Migraine. Headache, 47 (Suppl 1), S10-S19)
http://onlinelibrary.wiley.com/d ... 0.2007.00672.x/full


"This manuscript is an edited version of a transcript of a lecture given to the New England Center for Headache in Greenwich, CT, November 2004.

"ergotamine ([at the dosage of] 30 μg/kg) * * * was found to increase vascular resistance in all the vascular beds, as would be expected of a nonselective vasoconstrictor. In marked contrast sumatriptan only constricted the arteriovenous anastomoses * * * Excitingly for us, sumatriptan, unlike ergotamine, had no effect on vascular beds supplying the kidneys, adrenals, the heart, or the brain." (citation omitted)

"We still do not know why sumatriptan, when given subcutaneously or even intravenously, is much more effective than any triptan orally. It would seem to be something to do with the rate of rise in plasma concentration.

"What we do know about the mechanism of action of triptans is that:
1 They cause selective extracerebral intracranial vasoconstriction.
2 They inhibit trigeminal nerve terminals innervating extracerebral vessels.

(e) Jenny Bryan, How Sumatriptan Transformed the Lives of Millions of Migraine Sufferers. Pharmaceutical Journal, Mar 19, 2010
http://www.pharmaceutical-journa ... rs/11002417.article

two consecutive paragraphs:

"Humphrey and his colleagues identified a new serotonin receptor, now called 5-HT1B, which was found mainly in cranial rather than peripheral blood vessels.

"Hundreds of 5-HT analogues were synthesised and screened for activity against the new receptor, and preclinical studies eventually confirmed the vasoconstrictor effects of GR43175 (sumatriptan) within the carotid circulation. This selective activity at 5-HT1B and, as it turned out, 5-HT1D receptors gave sumatriptan the antimigraine efficacy that was needed, seemingly without the potential for the more generalised effects of less selective compounds.

* There is no need to read the rest.

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