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Saturday, March 21, 2020

The Mysterious Affair at Styles

From Wikipedia, the free encyclopedia
 
The Mysterious Affair at Styles
Mysterious affair at styles.jpg
Dustjacket illustration of the first edition in both the UK and the US
AuthorAgatha Christie
Cover artistAlfred James Dewey
CountryUnited Kingdom
LanguageEnglish
GenreCrime novel
PublisherJohn Lane
Publication date
October 1920
Media typePrint (hardback & paperback)
Pages296 (first edition, hardback)
Followed byThe Secret Adversary 
TextThe Mysterious Affair at Styles at Wikisource

The Mysterious Affair at Styles is a detective novel by British writer Agatha Christie. It was written in the middle of the First World War, in 1916, and first published by John Lane in the United States in October 1920 and in the United Kingdom by The Bodley Head (John Lane's UK company) on 21 January 1921.

Styles was Christie's first published novel. It introduced Hercule Poirot, Inspector (later, Chief Inspector) Japp, and Arthur Hastings. Poirot, a Belgian refugee of the Great War, is settling in England near the home of Emily Inglethorp, who helped him to his new life. His friend Hastings arrives as a guest at her home. When the woman is killed, Poirot uses his detective skills to solve the mystery.

The book includes maps of the house, the murder scene, and a drawing of a fragment of a will. The true first publication of the novel was as a weekly serial in The Times, including the maps of the house and other illustrations included in the book. This novel was one of the first ten books published by Penguin Books when it began in 1935.

This first mystery novel by Agatha Christie was well received by reviewers. An analysis in 1990 was positive about the plot, considered the novel one of the few by Christie that is well-anchored in time and place, a story that knows it describes the end of an era, and mentions that the plot is clever. Christie had not mastered cleverness in her first novel, as "too many clues tend to cancel each other out"; this was judged a difficulty "which Conan Doyle never satisfactorily overcame, but which Christie would."

Composition and original publication

Agatha Christie began working on The Mysterious Affair at Styles in 1916, writing most of it on Dartmoor. The character of Hercule Poirot was inspired by her experience working as a nurse, ministering to Belgian soldiers during the First World War, and by Belgian refugees who were living in Torquay.

The manuscript was rejected by Hodder and Stoughton and Methuen. Christie then submitted the manuscript to The Bodley Head. After keeping the submission for several months, The Bodley Head's founder, John Lane at The Bodley Head offered to accept it, provided that Christie make slight changes to the ending. She revised the next-to-last chapter, changing the scene of Poirot's grand revelation from a courtroom to the Styles library. Christie later stated that the contract she signed with Lane was exploitative.

The Mysterious Affair at Styles was published by John Lane in the United States in October 1920 and by The Bodley Head in the United Kingdom on 21 January 1921. The US edition retailed at $2.00[1] and the UK edition at seven shillings and sixpence (7/6).

Plot summary

One morning at Styles Court, an Essex country manor, its household wake to the discovery that the owner, elderly Emily Inglethorp, has died. She had been poisoned with strychnine. Arthur Hastings, a soldier from the Western Front staying there as a guest on his sick leave, ventures out to the nearby village of Styles St. Mary, to enlist help from his friend staying there - Hercule Poirot. Poirot learns that Emily was a woman of wealth - upon the death of her previous husband, Mr. Cavendish, she inherited from him both the manor and a large portion of his income. Her household includes: her husband Alfred Inglethorp, a younger man she recently married; her stepsons (from her first husband's previous marriage) John and Lawrence Cavendish; John's wife Mary Cavendish; Cynthia Murdoch, the daughter of a deceased friend of the family; and Evelyn Howard, Emily's companion.

Poirot learns that per Emily's will, John is the vested remainderman of the manor - he inherits the property from her, per his father's will. However, the money she inherited would be distributed according to her own will, which she changed at least once per year; her most recent will favours Alfred, who will inherit her fortune. On the day of the murder, Emily had been arguing with someone, suspected to be either Alfred or John. She had been quite distressed after this, and apparently made a new will - no one can find any evidence that it exists. Alfred left the manor early that evening, and stayed overnight in the village. Meanwhile, Emily ate little at dinner and retired early to her room, taking her document case with her; when her body was found, the case had been forced open and a document removed. Nobody can explain how or when the poison was administered to her. 

Inspector Japp, the investigating officer, considers Alfred to be the prime suspect, as he gains the most from his wife's death. The Cavendishes suspect him to be a fortune hunter, as he was much younger than Emily. Poirot notes his behaviour is suspicious during the investigation - he refuses to provide an alibi, and openly denies purchasing the strychnine in the village, despite evidence to the contrary. Although Japp is keen to arrest him, Poirot intervenes by proving he couldn't have purchased the poison; the signature for the purchase is not in his handwriting. Suspicion now falls on John - he is the next to gain from Emily's will, and has no alibi for the murder. Japp soon arrests him - the signature for the poison is in his handwriting; a phial that contained the poison is found in his room; a beard and a pair of pince-nez identical to Alfred's, are found within the manor.

Poirot soon exonerates John of the crime. He reveals that the murder was committed by Alfred Inglethorp, with aid from his cousin Evelyn Howard. The pair pretended to be enemies, but were romantically involved. They added bromide to Emily's regular evening medicine, obtained from her sleeping powder, which made the final dose lethal. The pair then left false evidence that would incriminate Alfred, which they knew would be refuted at his trial; once acquitted, he could not be tried for the crime again if genuine evidence against him was found, per the law of double jeopardy. John was framed by the pair as part of their plan; his handwriting was forged by Evelyn, and the evidence against him was fabricated.

Poirot reveals that when he realised that Alfred wanted to be arrested, he prevented Japp from doing so until he could discover why. He also reveals that he found a letter in Emily's room, thanks to a chance remark by Hastings, that detailed Alfred's intentions for his wife. Emily's distress on the afternoon of the murder, was because she had found it in his desk while searching for stamps. Her case was forced open by Alfred, as he had discovered she had taken it; he was forced to recover it from the case, and he hid it in the room, as he couldn't be found with it.

Characters

  • Hercule Poirot - Renowned Belgian private detective. He lives in England after being displaced by the war in Europe. Asked to investigate the case by his old friend Hastings.
  • Hastings - Poirot's friend, and the narrator of the case. He is a guest at Styles Court while on sick leave from the Western Front.
  • Inspector Japp - A Scotland Yard detective, and the investigating officer. He is an acquaintance of Poirot at the time of the novel's setting.
  • Emily Inglethorp - A wealthy old woman, and the wife of Alfred Inglethorp. Her fortune and home of Styles Court were inherited by her following the death of her first husband, Mr Cavendish. The victim of the case.
  • Alfred Inglethorp - Emily's second husband and a much younger man than her. Considered by her family to be a spoiled fortune-hunter. The killer of the case.
  • John Cavendish - Emily's elder stepson, from her first husband's previous marriage, and the brother of Lawrence. The chief suspect after suspicion on Alfred is swayed away at Poirot's insistence.
  • Mary Cavendish - John's wife, a friend of Dr Bauerstein.
  • Lawrence Cavendish - Emily's younger stepson, from her first husband's previous marriage, and the brother of John. Known to have studied medicine.
  • Evelyn Howard - Emily's companion, who is vocal about her negative views of Alfred Inglethorp.
  • Cynthia Murdoch - The daughter of a deceased friend of the family, an orphan. She performs war-time work at a nearby hospital's pharmacy.
  • Dr Bauerstein - A well-known toxicologist, living not far from Styles.
  • Dorcas - A maid at Styles.

Dedication

The book's dedication reads: "To my Mother".

Christie's mother, Clarissa ("Clara") Boehmer Miller (1854–1926), was a strong influence on her life and someone to whom Christie was extremely close, especially after the death of her father in 1901. It was while Christie was ill (circa 1908) that her mother suggested she write a story. The result was The House of Beauty, now a lost work which hesitantly started her writing career. Christie later revised this story as The House of Dreams, and it was published in issue 74 of The Sovereign Magazine in January 1926 and, many years later, in 1997, in book form in While the Light Lasts and Other Stories.

Christie also dedicated her debut novel as Mary Westmacott, Giant's Bread (1930), to her mother who, by that time, had died.

Literary significance and reception

The Times Literary Supplement (3 February 1921) gave the book an enthusiastic, if short, review, which stated: "The only fault this story has is that it is almost too ingenious." It went on to describe the basic set-up of the plot and concluded: "It is said to be the author's first book, and the result of a bet about the possibility of writing a detective story in which the reader would not be able to spot the criminal. Every reader must admit that the bet was won."

The New York Times Book Review (26 December 1920), was also impressed:
Though this may be the first published book of Miss Agatha Christie, she betrays the cunning of an old hand... You must wait for the last-but-one chapter in the book for the last link in the chain of evidence that enabled Mr. Poirot to unravel the whole complicated plot and lay the guilt where it really belonged. And you may safely make a wager with yourself that until you have heard M. Poirot's final word on the mysterious affair at Styles, you will be kept guessing at its solution and will most certainly never lay down this most entertaining book.
The novel's review in The Sunday Times of 20 February 1921, quoted the publisher's promotional blurb concerning Christie writing the book as the result of a bet that she would not be able to do so without the reader being able to guess the murderer, then said, "Personally we did not find the "spotting" so very difficult, but we are free to admit that the story is, especially for a first adventure in fiction, very well contrived, and that the solution of the mystery is the result of logical deduction. The story, moreover, has no lack of movement, and the several characters are well drawn."

The contributor who wrote his column under the pseudonym of "A Man of Kent" in the 10 February 1921 issue of the Christian newspaper The British Weekly praised the novel but was overly generous in giving away the identity of the murderers. To wit,
It will rejoice the heart of all who truly relish detective stories, from Mr. McKenna downwards. I have heard that this is Miss Christie's first book, and that she wrote it in response to a challenge. If so, the feat was amazing, for the book is put together so deftly that I can remember no recent book of the kind, which approaches it in merit. It is well written, well proportioned, and full of surprises. When does the reader first suspect the murderer? For my part, I made up my mind from the beginning that the middle-aged husband of the old lady was in every way qualified to murder her, and I refused to surrender this conviction when suspicion of him is scattered for a moment. But I was not in the least degree prepared to find that his accomplice was the woman who pretended to be a friend. I ought to say, however, that an expert in detective stories with whom I discussed it, said he was convinced from the beginning that the true culprit was the woman whom the victim in her lifetime believed to be her staunchest friend. I hope I have not revealed too much of the plot. Lovers of good detective stories will, without exception, rejoice in this book.
The Bodley Head quoted excerpts from this review in future books by Christie but, understandably, did not use those passages which gave away the identity of the culprits.

"Introducing Hercule Poirot, the brilliant – and eccentric – detective who, at a friend's request, steps out of retirement – and into the shadows of a classic mystery on the outskirts of Essex. The victim is the wealthy mistress of Styles Court, found in her locked bedroom with the name of her late husband on her dying lips. Poirot has a few questions for her fortune-hunting new spouse, her aimless stepsons, her private doctor, and her hired companion. The answers are positively poisonous. Who's responsible, and why, can only be revealed by the master detective himself." (Book jacket, Berkley Book edition April 1984)

In his book, A Talent to Deceive – An Appreciation of Agatha Christie, Robert Barnard wrote:
Christie's debut novel, from which she made £25 and John Lane made goodness knows how much. The Big House in wartime, with privations, war work and rumours of spies. Her hand was over-liberal with clues and red herrings, but it was a highly cunning hand, even at this stage
In general The Mysterious Affair at Styles is a considerable achievement for a first-off author. The country-house-party murder is a stereotype in the detective-story genre, which Christie makes no great use of. Not her sort of occasion, at least later in life, and perhaps not really her class. The family party is much more in her line, and this is what we have here. This is one of the few Christies anchored in time and space: we are in Essex, during the First World War. The family is kept together under one roof by the exigencies of war and of a matriarch demanding rather than tyrannical – not one of her later splendid monsters, but a sympathetic and lightly shaded characterisation. If the lifestyle of the family still seems to us lavish, even wasteful, nevertheless we have the half sense that we are witnessing the beginning of the end of the Edwardian summer, that the era of country-house living has entered its final phase. Christie takes advantage of this end-of-an-era feeling in several ways: while she uses the full range of servants and their testimony, a sense of decline, of break-up is evident; feudal attitudes exist, but they crack easily. The marriage of the matriarch with a mysterious nobody is the central out-of-joint event in an intricate web of subtle changes. The family is lightly but effectively characterised, and on the outskirts of the story are the villagers, the small businessmen, and the surrounding farmers – the nucleus of Mayhem Parva. It is, too, a very clever story, with clues and red herrings falling thick and fast. We are entering the age when plans of the house were an indispensable aid to the aspirant solver of detective stories, and when cleverness was more important than suspense. But here we come to a problem that Agatha Christie has not yet solved, for cleverness over the long length easily becomes exhausting, and too many clues tend to cancel each other out, as far as reader interest is concerned. These were problems which Conan Doyle never satisfactorily overcame, but which Christie would.".
In the "Binge!" article of Entertainment Weekly Issue #1343-44 (26 December 2014–3 January 2015), the writers picked The Mysterious Affair at Styles as an "EW favorite" on the list of the "Nine Great Christie Novels".

Golden Age of Detective Fiction

The story is told in the first person by Hastings, and features many of the elements that have become icons of the Golden Age of Detective Fiction, largely due to Christie's influence. It is set in a large, isolated country manor. There are a half-dozen suspects, most of whom are hiding facts about themselves. The plot includes a number of red herrings and surprise twists.

Impact on Christie's career

The Mysterious Affair at Styles launched Christie's writing career. Christie and her husband subsequently named their house "Styles".

Hercule Poirot, who first appeared in this novel, would go on to become one of the most famous characters in detective fiction. Decades later, when Christie told the story of Poirot's final case in Curtain, she set that novel at Styles.

Adaptations

Television

The Mysterious Affair at Styles was adapted as an episode for the series Agatha Christie's Poirot on 16 September 1990; the episode was specially made by ITV to celebrate the centenary of the author's birth. Filmed at Chavenage House, Gloucestershire, the adaptation was generally faithful to the novel. However, it omitted Dr Bauerstein and some minor characters, while it provided further elaboration on Hastings' first meeting with Poirot - the pair met during an investigation into a shooting, in which Hastings was a suspect.

Adaptor: Clive Exton

Director: Ross Devenish

Cast:

Radio

The novel was adapted as a five-part serial for BBC Radio 4 in 2005. John Moffatt reprised his role of Poirot. The serial was broadcast weekly from Monday, 5 September to Monday, 3 October, from 11.30 am to 12.00 noon. All five episodes were recorded on Monday, 4 April 2005, at Bush House. This version retained the first-person narration by the character of Hastings.

Adaptor: Michael Bakewell
Producer: Enyd Williams
Cast:
  • John Moffatt as Hercule Poirot
  • Simon Williams as Arthur Hastings
  • Philip Jackson as Inspector James Japp
  • Jill Balcon as Emily Inglethorp
  • Hugh Dickson as Alfred Inglethorp
  • Susan Jameson as Mary Cavendish
  • Nicholas Boulton as Lawrence Cavendish
  • Hilda Schroder as Dorcas
  • Annabelle Dowler as Cynthia Murdoch and Annie
  • Nichola McAuliffe as Evelyn Howard
  • Sean Arnold as John Cavendish
  • Richard Syms as Mr. Wells
  • Ioan Meredith as Mr. Phillips
  • Michael Mears as Sir Ernest Heavyweather
  • Harry Myers as Mr. Mace
  • Peter Howell as the Coroner
  • Robert Portal as Dr Bauerstein

Stage

On 14 February 2012, Great Lakes Theater in Cleveland, Ohio debuted a 65-minute stage adaptation as part of their educational programming. Adapted by David Hansen, this production is performed by a cast of five (3 men, 2 women) with most performers playing more than one role.

On 17 March 2016, the Hedgerow Theatre company in Media, Pennsylvania, premiered an adaptation by Jared Reed. While largely faithful to the novel, the character of Inspector Japp was omitted.

Publication history

  • 1920, John Lane (New York), October 1920, Hardcover, 296 pp
  • 1920, National Book Company, Hardcover, 296 pp
  • 1921, John Lane (The Bodley Head), 21 January 1921, Hardcover, 296 pp
  • 1926, John Lane (The Bodley Head), June 1926, Hardcover (Cheap edition – two shillings) 319 pp
  • 1931, John Lane (The Bodley Head), February 1931 (As part of the Agatha Christie Omnibus along with The Murder on the Links and Poirot Investigates), Hardcover, Priced at seven shillings and sixpence; a cheaper edition at five shillings was published in October 1932
  • 1932, John Lane (The Bodley Head), July 1932, Paperback (ninepence)
  • 1935, Penguin Books, 30 July 1935, Paperback (sixpence), 255 pp
  • 1945, Avon Books (New York), Avon number 75, Paperback, 226 pp
  • 1954, Pan Books, Paperback (Pan number 310), 189 pp
  • 1959, Pan Books, Paperback (Great Pan G112)
  • 1961, Bantam Books (New York), Paperback, 154 pp
  • 1965, Longman (London), Paperback, 181 pp
  • 1976, Dodd, Mead and Company, (Commemorative Edition following Christie's death), Hardback, 239 pp; ISBN 0-396-07224-0
  • 1984, Berkley Books (New York, Division of Penguin Putnam), Paperback, 198 pp; ISBN 0-425-12961-6
  • 1988, Fontana Books (Imprint of HarperCollins), Paperback, 208 pp; ISBN 0-00-617474-4
  • 1989, Ulverscroft Large Print Edition, Hardcover; ISBN 0-7089-1955-3
  • 2007, Facsimile of 1921 UK first edition (HarperCollins), 5 November 2007, Hardcover, 296 pp; ISBN 0-00-726513-1
  • 2018, Srishti Publishers & Distributors, Paperback, 186 pp; ISBN 978-93-87022-25-6
Additional editions are listed at Fantastic Fiction, including
  • 29 Hardcover editions from 1958 to September 2010 (ISBN 116928986X / 9781169289864 Publisher: Kessinger Publishing)
  • 107 Paperback editions from 1970 to September 2013 (ISBN 0007527497 / 9780007527496 (UK edition) Publisher: Harper)
  • 30 Audio editions from September 1994 to June 2013 (ISBN 1470887711 / 9781470887711 Publisher: Blackstone Audiobooks)
  • 96 Kindle editions from December 2001 to November 2013 (ISBN B008BIGEHG).
The novel received its first true publication as an eighteen-part serialisation in The Times newspaper's Colonial Edition (aka The Weekly Times) from 27 February (Issue 2252) to 26 June 1920 (Issue 2269). This version of the novel mirrored the published version with no textual differences and included the maps and illustrations of handwriting examples used in the novel. At the end of the serialisation an advertisement appeared in the newspaper, which announced, "This is a brilliant mystery novel, which has had the unique distinction for a first novel of being serialised in The Times Weekly Edition. Mr. John Lane is now preparing a large edition in volume form, which will be ready immediately." Although another line of the advertisement stated that the book would be ready in August, it was first published by John Lane in the United States in October 1920 and was not published in the UK by The Bodley Head until the following year.

The Mysterious Affair at Styles later made publishing history by being one of the first ten books to be published by Penguin Books when they were launched on 30 July 1935. The book was Penguin Number 6.

The blurb on the inside flap of the dustwrapper of the first edition reads:
This novel was originally written as the result of a bet, that the author, who had previously never written a book, could not compose a detective novel in which the reader would not be able to "spot" the murderer, although having access to the same clues as the detective. The author has certainly won her bet, and in addition to a most ingenious plot of the best detective type she has introduced a new type of detective in the shape of a Belgian. This novel has had the unique distinction for a first book of being accepted by the Times as a serial for its weekly edition.

Strychnine

From Wikipedia, the free encyclopedia
 
Strychnine
Strychnine.svg
Strychnine-from-xtal-3D-balls.png
Names
Other names
Strychnidin-10-one
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.000.290
KEGG
PubChem CID
RTECS number
  • WL2275000
UNII
UN number 1692
Properties
C21H22N2O2
Molar mass 334.419 g·mol−1
Appearance White or translucent crystal or crystalline powder; Bitter tasting
Odor Odorless
Density 1.36 g cm−3
Melting point 270 °C; 518 °F; 543 K
Boiling point 284 to 286 °C; 543 to 547 °F; 557 to 559 K
0.02% (20°C)[2]
Acidity (pKa) 8.25[3]
Hazards
Main hazards Very toxic
GHS piktogrami GHS06: ToxicGHS09: Environmental hazard
GHS Signal word Danger
H300, H310, H330, H410
P260, P264, P273, P280, P284, P301+310
NFPA 704 (fire diamond)
Flammability code 0: Will not burn. E.g. waterHealth code 4: Very short exposure could cause death or major residual injury. E.g. VX gasReactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no codeNFPA 704 four-colored diamond
0
4
0
Flash point Non flammable.
Non flammable.
Lethal dose or concentration (LD, LC):
LD50 (median dose)
0.5 mg/kg (dog, oral)
0.5 mg/kg (cat, oral)
2 mg/kg (mouse, oral)
16 mg/kg (rat, oral)
2.35 mg/kg (rat, oral)[4]
0.6 mg/kg (rabbit, oral)[4]
NIOSH (US health exposure limits):
PEL (Permissible)
TWA 0.15 mg/m3[2]
REL (Recommended)
TWA 0.15 mg/m3[2]
IDLH (Immediate danger)
3 mg/m3[2]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Strychnine (/ˈstrɪknn/ STRIK-neen or /-nɪn/ -⁠nin; US mainly /ˈstrɪknn/ STRIK-nyne) is a highly toxic, colorless, bitter, crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine, when inhaled, swallowed, or absorbed through the eyes or mouth, causes poisoning which results in muscular convulsions and eventually death through asphyxia. While it has no known medicinal effects, in the past the convulsant effect was believed to be beneficial in small doses. The most common source is from the seeds of the Strychnos nux-vomica tree.

Biosynthesis

strychnine biosynthesis

Strychnine is a terpene indole alkaloid belonging to the Strychnos family of Corynanthe alkaloids, and it is derived from tryptamine and secologanin. The enzyme, strictosidine synthase, catalyzes the condensation of tryptamine and secologanin, followed by a Pictet-Spengler reaction to form strictosidine. While the enzymes that catalyze the following steps have not been identified, the steps have been inferred by isolation of intermediates from Strychnos nux-vomica. The next step is hydrolysis of the acetal, which opens the ring by elimination of glucose (O-Glu) and provides a reactive aldehyde. The nascent aldehyde is then attacked by a secondary amine to afford geissoschizine, a common intermediate of many related compounds in the Strychnos family.

A reverse Pictet-Spengler reaction cleaves the C2–C3 bond, while a subsequent Mannich reaction forms the C3–C7 bond, and a Michael addition forms the C2–C16 bond to provide dehydropreakuammicine. Hydrolysis of the methyl ester and decarboxylation leads to norfluorocurarine. Stereospecific reduction of the endocyclic double bond by NADPH and hydroxylation provides the Wieland-Gumlich aldehyde, which was first isolated by Heimberger and Scott in 1973, although previously synthesized by Wieland and Gumlich in 1932. To elongate the appendage by 2 carbons, acetyl-CoA is added to the aldehyde in an aldol reaction to afford prestrychnine. Strychnine is then formed by a facile addition of the amine with the carboxylic acid or its activated CoA thioester, followed by ring-closure via displacement of an activated alcohol.

Chemical synthesis

As early researchers have noted, the strychnine molecular structure, with its specific array of rings, stereocenters, and nitrogen functional groups, is a complex synthetic target, and has stimulated interest for that reason and for interest in the structure-activity relationships underlying its pharmacologic activities. An early synthetic chemist targeting strychnine, R.B. Woodward, quoted the chemist who determined its structure through chemical decomposition and related physical studies as saying that "for its molecular size it is the most complex organic substance known" (attributed to Sir Robert Robinson).

Strychnine Star chemdraw.jpg

The first total synthesis of strychnine was reported by the research group of R. B. Woodward in 1954, and is considered a classic in this field. The Woodward account published in 1954 was very brief (3 pp.), but was followed by a 42-page report in 1963. The molecule has since received continuing wide attention in the years since for the challenges to synthetic organic strategy and tactics presented by its complexity; its synthesis has been targeted and its stereocontrolled preparation independently achieved by more than a dozen research groups since the first success (see main strychnine total synthesis article).

Mechanism of action

Strychnine is a neurotoxin which acts as an antagonist of glycine and acetylcholine receptors. It primarily affects the motor nerve fibers in the spinal cord which control muscle contraction. An impulse is triggered at one end of a nerve cell by the binding of neurotransmitters to the receptors. In the presence of an inhibitory neurotransmitter, such as glycine, a greater quantity of excitatory neurotransmitters must bind to receptors before there will be an action potential generated. Glycine acts primarily as an agonist of the glycine receptor, which is a ligand-gated chloride channel in neurons located in the spinal cord and in the brain. This chloride channel will allow the negatively charged chloride ions into the neuron, causing a hyperpolarization which pushes the membrane potential further from threshold. Strychnine is an antagonist of glycine; it binds noncovalently to the same receptor, preventing the inhibitory effects of glycine on the postsynaptic neuron. Therefore, action potentials are triggered with lower levels of excitatory neurotransmitters. When the inhibitory signals are prevented, the motor neurons are more easily activated and the victim will have spastic muscle contractions, resulting in death by asphyxiation. Strychnine binds the Aplysia californica acetylcholine binding protein (a homolog of nicotinic receptors) with high affinity but low specificity, and does so in multiple conformations.

Toxicity

In high doses, strychnine is very toxic to humans (minimum lethal oral dose in adults is 30–120 mg) and many other animals (oral LD50 = 16 mg/kg in rats, 2 mg/kg in mice), and poisoning by inhalation, swallowing, or absorption through eyes or mouth can be fatal. S. nux-vomica seeds are generally effective as a poison only when they are crushed or chewed before swallowing because the pericarp is quite hard and indigestible; poisoning symptoms may therefore not appear if the seeds are ingested whole.

Animal toxicity

Strychnine poisoning in animals usually occurs from ingestion of baits designed for use against gophers, moles, and coyotes. Strychnine is also used as a rodenticide, but is not specific to such unwanted pests and may kill other small animals. In the United States, most baits containing strychnine have been replaced with zinc phosphide baits since 1990. In the Netherlands, rodenticides with strychnine are forbidden. Some animals are immune to strychnine, usually these are species such as fruit bats that have evolved resistance to poisonous alkaloids in the fruit they eat. The drugstore beetle has a symbiotic gut yeast that allows it to digest pure strychnine.

Strychnine toxicity in rats is dependent on sex. It is more toxic to females than to males when administered via subcutaneous injection or intraperitoneal injection. Differences are due to higher rates of metabolism by male rat liver microsomes. Dogs and cats are more susceptible among domestic animals, pigs are believed to be as susceptible as dogs, and horses are able to tolerate relatively large amounts of strychnine. Birds affected by strychnine poisoning exhibit wing droop, salivation, tremors, muscle tenseness, and convulsions. Death occurs as a result of respiratory arrest. The clinical signs of strychnine poisoning relate to its effects on the central nervous system. The first clinical signs of poisoning include nervousness, restlessness, twitching of the muscles, and stiffness of the neck. As the poisoning progresses, the muscular twitching becomes more pronounced and convulsions suddenly appear in all the skeletal muscles. The limbs are extended and the neck is curved to opisthotonus. The pupils are widely dilated. As death approaches, the convulsions follow one another with increased rapidity, severity, and duration. Death results from asphyxia due to prolonged paralysis of the respiratory muscles. Following the ingestion of strychnine, symptoms of poisoning usually appear within 15 to 60 min. The LD50-values for strychnine in animals are listed below in table 1.

The LD50 values for strychnine in animals
Organism Route LD50 (mg/kg)
Bird-wild Oral 16
Cat Intravenous 0.33
Cat Oral 0.5
Dog Intravenous 0.8
Dog Subcutaneous 0.35
Dog Oral 0.5
Duck Oral 3.0
Mouse Intraperitoneal 0.98
Mouse Intravenous 0.41
Mouse Oral 2.0
Mouse Parenteral 1.06
Mouse Subcutaneous 0.47
Pigeon Oral 21.0
Quail Oral 23.0
Rabbit Intravenous 0.4
Rabbit Oral 0.6
Rat Oral 16.0
Rat Intravenous 2.35

Human toxicity

An 1809 painting depicting opisthotonus

The symptoms of poisoning in humans are generally similar to those as in other animals, because the mechanism of action is apparently similar across species. The toxicity of strychnine in humans is not ethically studied, so most information known comes from cases of strychnine poisoning, both unintentional and deliberate.

After injection, inhalation, or ingestion, the first symptoms to appear are generalized muscle spasms. They appear very quickly after inhalation or injection — within as few as five minutes — and take somewhat longer to manifest after ingestion, typically approximately 15 minutes. With a very high dose, the onset of respiratory failure and brain death can occur in 15 to 30 minutes. If a lower dose is ingested, other symptoms begin to develop, including seizures, cramping, stiffness, hypervigilance, and agitation. Seizures caused by strychnine poisoning can start as early as 15 minutes after exposure and last 12 – 24 hours. They are often triggered by sights, sounds, or touch and can cause other adverse symptoms, including hyperthermia, rhabdomyolysis, myoglobinuric kidney failure, metabolic acidosis, and respiratory acidosis. During seizures, mydriasis (abnormal dilation), exophthalmos (protrusion of the eyes), and nystagmus (involuntary eye movements) may occur.

As strychnine poisoning progresses, tachycardia (rapid heart beat), hypertension (high blood pressure), tachypnea (rapid breathing), cyanosis (blue discoloration), diaphoresis (sweating), water-electrolyte imbalance, leukocytosis (high number of white blood cells), trismus (lockjaw), risus sardonicus (spasm of the facial muscles), and opisthotonus (dramatic spasm of the back muscles, causing arching of the back and neck) can occur. In rare cases, the affected person may experience nausea or vomiting.

The proximate cause of death in strychnine poisoning can be cardiac arrest, respiratory failure, multiple organ failure, or brain damage.
The minimum lethal dose values estimated from different cases of strychnine poisoning are listed below in table 2. 

Minimum lethal dose estimates for strychnine in humans

Route Dose (mg)
Human Oral 100–120
Human Oral 30–60
Human (child) Oral 15
Human (adult) Oral 50–100
Human (adult) Oral 30–100
Human Intravenously 5–10 (approximate)

For occupational exposures to strychnine, the Occupational Safety and Health Administration and the National Institute for Occupational Safety and Health have set exposure limits at 0.15 mg/m3 over an 8-hour work day.

Because strychnine produces some of the most dramatic and painful symptoms of any known toxic reaction, strychnine poisoning is often portrayed in literature and film including authors Agatha Christie and Arthur Conan Doyle.

Pharmacokinetics

Absorption

Strychnine may be introduced into the body orally, by inhalation, or by injection. It is a potently bitter substance, and in humans has been shown to activate bitter taste receptors TAS2R10 and TAS2R46. Strychnine is rapidly absorbed from the gastrointestinal tract.

Distribution

Strychnine is transported by plasma and erythrocytes. Due to slight protein binding, strychnine leaves the bloodstream quickly and distributes to the tissues. Approximately 50% of the ingested dose can enter the tissues in 5 minutes. Also within a few minutes of ingestion, strychnine can be detected in the urine. Little difference was noted between oral and intramuscular administration of strychnine in a 4 mg dose. In persons killed by strychnine, the highest concentrations are found in the blood, liver, kidney and stomach wall. The usual fatal dose is 60–100 mg strychnine and is fatal after a period of 1–2 hours, though lethal doses vary depending on the individual.

Metabolism

Strychnine is rapidly metabolized by the liver microsomal enzyme system requiring NADPH and O2. Strychnine competes with the inhibitory neurotransmitter glycine resulting in an excitatory state. However, the toxicokinetics after overdose have not been well described. In most severe cases of strychnine poisoning, the patient dies before reaching the hospital. The biological half-life of strychnine is about 10 hours. This half-life suggests that normal hepatic function can efficiently degrade strychnine even when the quantity ingested is high enough to cause severe poisoning.

Excretion

A few minutes after ingestion, strychnine is excreted unchanged in the urine, and accounts for about 5 to 15% of a sublethal dose given over 6 hours. Approximately 10 to 20% of the dose will be excreted unchanged in the urine in the first 24 hours. The percentage excreted decreases with the increasing dose. Of the amount excreted by the kidneys, about 70% is excreted in the first 6 hours, and almost 90% in the first 24 hours. Excretion is virtually complete in 48 to 72 hours.

Treatment

There is no specific antidote for strychnine but recovery from exposure is possible with early supportive medical treatment. Strychnine poisoning demands aggressive management with early control of muscle spasms, intubation if loss of airway control, toxin removal (decontamination), intravenous hydration and potentially active cooling efforts in the context of hyperthermia as well as hemodialysis in kidney failure (to note, strychnine has not been shown to be removed by hemodialysis). Strychnine poisoning in today's age generally results from herbal remedies and strychnine-containing rodenticides. Moreover, management should be tailored to the patient's history of chief complaint and workup to rule out other causes. If a poisoned person is able to survive for 6 to 12 hours subsequent to initial dose, they have a good prognosis. The patient should be kept in a quiet and darkened room, because excessive manipulation and loud noises may cause convulsions. Because these convulsions are extremely painful, appropriate analgesics should be administered. Treatment of strychnine poisoning involves oral administration of activated charcoal which adsorbs strychnine within the digestive tract; unabsorbed strychnine is removed from the stomach by gastric lavage, along with tannic acid or potassium permanganate solutions to oxidize strychnine. Activated charcoal may be beneficial, but its benefit remains unproven, to note its use should be avoided in any patient with a tenuous airway or altered mental status. Seizures are controlled by anticonvulsants, such as phenobarbital or diazepam, along with muscle relaxants such as dantrolene to combat muscle rigidity. Historically chloroform or heavy doses of chloral, bromide, urethane or amyl nitrite were used to restrain the convulsions.[citation needed] Because medications such as diazepam are not effective to relieve convulsions in all cases, concurrent use of barbiturates and/or propofol can be utilized. 

The sine qua non of strychnine toxicity is the "awake" seizure, in which tonic-clonic activity occurs but the patient is alert and oriented throughout and afterwards. Accordingly, George Harley (1829–1896) showed in 1850 that curare (wourali) was effective for the treatment of tetanus and strychnine poisoning. It is important to note that if seizure activity is present, the use of muscle paralysis will only mask the signs of ongoing seizure activity despite otherwise ongoing present brain damage.

History

Strychnine was the first alkaloid to be identified in plants of the genus Strychnos, family Loganiaceae. Strychnos, named by Carl Linnaeus in 1753, is a genus of trees and climbing shrubs of the Gentianales order. The genus contains 196 various species and is distributed throughout the warm regions of Asia (58 species), America (64 species), and Africa (75 species). The seeds and bark of many plants in this genus contain strychnine.

The toxic and medicinal effects of Strychnos nux-vomica have been well known from the times of ancient India, although the chemical compound itself was not identified and characterized until the 19th century. The inhabitants of these countries had historical knowledge of the species Strychnos nux-vomica and Saint-Ignatius' bean (Strychnos ignatii). Strychnos nux-vomica is a tree native to the tropical forests on the Malabar Coast in Southern India, Sri Lanka and Indonesia, which attains a height of about 12 metres (39 ft). The tree has a crooked, short, thick trunk and the wood is close grained and very durable. The fruit has an orange color and is about the size of a large apple with a hard rind and contains five seeds, which are covered with a soft wool-like substance. The ripe seeds look like flattened disks, which are very hard. These seeds are the chief commercial source of strychnine and were first imported to and marketed in Europe as a poison to kill rodents and small predators. Strychnos ignatii is a woody climbing shrub of the Philippines. The fruit of the plant, known as Saint Ignatius' bean, contains as many as 25 seeds embedded in the pulp. The seeds contain more strychnine than other commercial alkaloids. The properties of S. nux-vomica and S. ignatii are substantially those of the alkaloid strychnine. 

Strychnine was first discovered by French chemists Joseph Bienaimé Caventou and Pierre-Joseph Pelletier in 1818 in the Saint-Ignatius' bean. In some Strychnos plants a 9,10-dimethoxy derivative of strychnine, the alkaloid brucine, is also present. Brucine is not as poisonous as strychnine. Historic records indicate that preparations containing strychnine (presumably) had been used to kill dogs, cats, and birds in Europe as far back as 1640. The structure of strychnine was first determined in 1946 by Sir Robert Robinson and in 1954 this alkaloid was synthesized in a laboratory by Robert B. Woodward. This is one of the most famous syntheses in the history of organic chemistry. Both chemists won the Nobel prize (Robinson in 1947 and Woodward in 1965).

Strychnine has been used as a plot device in the author Agatha Christie's murder mysteries.

Performance enhancer

Strychnine was popularly used as an athletic performance enhancer and recreational stimulant in the late 19th century and early 20th century, due to its convulsant effects. It was thought to be similar to coffee. Its effects are well-described in H. G. Wells' novella The Invisible Man: the title character states "Strychnine is a grand tonic ... to take the flabbiness out of a man." The protagonist replies: "It's the devil, ... It's the palaeolithic in a bottle."

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