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SOME HISTORY AND EFFECTS OF CONIUM MACULATUM L.

S OME HISTORY AND EFFECTS OF MACULATUM L. by Thomas Larsson, a literature work in Pharmacognosy

by Thomas Larsson, a literature work in Pharmacognosy C, Department of Medicinal chemistry, Uppsala University, 2004.

Supervisor: Lars Bohlin.

Larsson | Some history and effects of Conium maculatum L.

Cover: The Death of Socrates by Jacques-Louis David, 1787, Metropolitan Museum of Art, New York. Source: http://www.ibiblio.org/wm/paint/auth/david/socrates.jpg

1. Abbreviations

BBB C(integer), e.g. C(5)

C-integer, e.g. C-5

14 C

blood brain barrier the number of carbon atoms in an organic compound a specific carbon atom in an organic compound carbon-14, a radioactive isomer to the common

carbon-12

CNS

central nervous system

and if high priority groups through a number of

E

from German Entegen, which means “opposite”.

Through the Cahn-Ingold-Prelog-rules the functional groups around a double bond are valued,

sequences are on opposite sides, the compound are

et al.

named E-

If they are on the same side it is called

... Z, which means Zuzammen, meaning “together”. et alii, and others

IM

intramuscular injection

SARs

structure-activity relationships

2. Wordlist

The word in question will not be included in the list, if it is written only once and described in the text. If it can be visualized, e.g. hypersalivation (hyper: over, exaggerated plus salivation), it will not be included either. If the word is underlined in the text it means that one can find it in this list.

agonal

describing or relating to the phenomena that are

amniotic fluid

associated with the moment of death the fluid contained within the amniotic cavity. It

anodyne

surrounds the growing fetus, protecting it from external pressure. pain-relieving, analgesic agent

arthrogryposis

contracture of soft tissues that causes fixed deformities

asphyctic

of the joints if untreated. condition of asphyxia; suffocation, a life-threatening state in which oxygen is prevented from reaching the tissues by damage to any part of the respiratory system. ataxia the shaky movements and unsteady gait that result from the brain’s failure to regulate the body’s posture and the strength and direction of limb movements. It may be due to disease of the sensory nerves or the cerebellum.

Larsson | Some history and effects of Conium maculatum L.

biopsy

the removal of a small piece of living tissue from an

biotransformation

organ or part of the body for microscopic examination. the changes of chemical compounds that occur in the

carpal

body relating to the wrist

chorea

jerky involuntary movement particularly affecting the

cleft palate

head, face or limbs. Each movement is sudden, but the resulting posture may be prolonged for a few seconds. cleft palate fissure in the midline of the palate due to failure of the two sides to fuse in embryonic development. Only part of the palate may be affected, or the cleft may extend the full length with bilateral clefts at the front of the upper jaw. a fissure in the midline of the palate due to failure of the two sides to fuse in embryonic development.

clonic

relating to, or resembling clonus. The

term is

most

commonly used to describe the rythmical limb movements seen as a part of a convulsive epileptic seizure.

clonus

rythmical contraction of a muscle

in

response to a

congenital

suddenly applied and then sustained stretch stimulus. It is caused by an exaggeration of the stretch reflexes and is usually a sign of disease in the brain or spinal cord. describing a condition that is recognized at birth or that

cyanosis

is believed to have been present since birth. Congenital malformations include all disorders present at birth whether they are inherited or caused by an environmental factor. a bluish discoloration of the skin and mucous

cyanotic

membranes resulting from an inadequate amount of oxygen in the blood. the condition of cyanosis.

depressor

here; a nerve that lowers blood pressure.

diurnal

daily

encephalopathy

any of various diseases that affect the functioning of the

etiology

brain. 1. the study or science of the causes of a disease. 2. the

extensor

cause of a specific disease. any muscle that causes the straightening of a limb or

fasciculation

other part. brief spontaneous contraction of a few muscle fibers,

gestation

which is seen as a flicker of movement under the skin. pregnancy among animals and humans.

gout

a disease in which a defect in uric acid metabolism

histological

causes an excess of the acid and its salts (urates) to accumulate in the blood-stream and in the joints. referring to histology

Larsson | Some history and effects of Conium maculatum L.

histology

the study of the structure of tissues by means of special

hypermetria

staining techniques combined with light and electron microscopy. a condition in which voluntarily muscular movement

in utero

overreaches the intended goal inside the uterus

joint

the point at which two or more bones are connected.

lateral

The opposing surfaces of the bones are lined with cartilaginous, fibrous or soft tissue knee-jerk see patellar reflex here: situated at or related to the side of an organ or

lead compound

organism. the starting compound in the development of a novel

lethargy

drug. Often the lead compound can have serious side effects, be expensive to synthetize etc., but it always have some sort of desired effect worth studying. mental and physical sluggishness: a degree of inactivity

mandibular

and an unresponsiveness approaching. The condition results from disease or hypnosis. reffering to mandible

mandible

the lower jawbone. It consists of a horseshoe-shaped

mericarp

body, the upper surface of which bears the lower teeth, and two vertical parts (rami). a part of the fruit

metacarpophalangic

the area where the part of the hand with its five

joints

cylindrical bones and wrist meet

myoglobinuria

or myohemoglobinuria; the presence of the pigment

nictitating

myohemoglobin in the urine.

membranes

blink membranes

palate

the roof of the mouth, which separates the mouth from

patellar reflex

the nasal cavity the knee jerk, in which stretching the muscle at the

phrenic nerve

front of the thigh by tapping its tendon below the knee cap causes a reflex contraction of the muscle, so that the leg kicks. the nerve that supplies the muscles of the diaphragm.

placentation

On each side it arises in the neck from the third, fourth and fifth cervical spinal roots and passes downward between the lungs and the heart to reach the diaphragm. Impulses through the nerves from the brain bring about the regular contractions of the diaphragm during breathing. the manner of ovule attachment within the ovary; the

polyphagous

process of placenta formation. describing an animal that consumes a wide selection of

postnatal

food after birth

postpartum

relating to the period of a few days immediately after birth

Larsson | Some history and effects of Conium maculatum L.

prenatal

before birth

pressor effect

an agent that raises blood pressure.

recumbency

lying down

rhabdomyolysis

disintegration or dissolution of muscle, associated with

scoliosis

excretion of myoglobin in the urine lateral (sideway) deviation of the backbone, caused by

sequela

congenital or acquired abnormalities of the vertebrae, mucles and nerves.Treatment is with spinal braces, and in cases of severe deformity, surgical correction by fusion or osteotomy is done. any disorder or pathological condition that results from

sequelae

a preceeding disease or accident. plural form of sequela

teratogenic

adjective of teratogen, any substance, agent or process

tonic

that induces the formation of developmental abnormalities in a fetus. here: marked by continuous tension (contraction).

torticollis

wryneck; an irresistable turning movement of the head

vasoconstriction

that becomes more persistent, so that eventually the head is held continually to one side. a decrease in the diameter of the blood vessels,

especially arteries. This results from activation of the vasomotor center in the brain, which brings about contraction of the muscular walls of the arteries and hence an increase in blood pressure. vasomotor center a collection of nerve cells in the medulla oblongata that receives information from sensory receptors in the circulatory system, and brings about reflex changes in the rate of heartbeat and in the diameter of blood vessels, so that blood pressure can be adjusted. The vasomotor center also receives impulses from elsewhere in the brain, so that emotion (such as fear) may also influence the heart rate and blood pressure. The center works through vasomotor nerves of the sympathetic and parasympathetic systems.

Sources: The Bantam Medical Dictionary, 2000; Biology of Plants, Raven et al., 1992; International Dictionary of Medicine and Biology Vol 1 and 3, 1986; Dorland’s Illustrated Medical Dictionary, 2000.

3. Introduction

Conium maculatum (hemlock, poison hemlock) is a very common and worldwide plant species. It is one of the most toxic plants known [Vetter, 2004]. Poison hemlock is native to Europe and western Asia and has been brought in America and Oceania as an ornamental plant [López et al., 1999 (1)], although in other countries, for example Norway the plant have been introduced through the transport of grain [Vetter, 2004 (2)].

Larsson | Some history and effects of Conium maculatum L.

The old Roman name of C. maculatum was Cicuta, but this name was later occupied to another near related umbelliferous plant, Cicuta virosa L., (water hemlock) by Gesner, 1541. Then Linnaeus gave its classical Greek name Conium maculatum. Its generic name was derived fr om the Greek word Konas, which means to whirl about, since consumption of the plant causes ataxia, tremor and convulsions. The specific name (maculatum) is a Latin word, which means spotted and refers to its very characteristic browninsh-reddish spots of the stem [Vetter, 2004]. The English name hemlock can be little confusing since there are several different “hemlocks”, see chapter 4, “Botanical characterization”. therefore the Latin name Conium maculatum will be used mostly throughout this article. However, water hemlock, Cicuta virosa, is also toxic to animals and humans and a brief description of this plant and its active substances will be given later in this text. As with many other toxic plants which cause episodic poisoning incidents, they biosynthesize and accumulate compounds that provide a protective function against predation or a competitive advantage relative to other plants and microorganisms. These bioactive compounds have such serious effects on animals when consumed; they are also a threat to the livestock producers. This threat has decreased much the last few decades because of better equipment and techniques to isolate and identify these compounds. By changing the dose of the bioactive compound, the effect may be changed and could be manipulated to yield maybe even beneficial results [James et. al, 2004]. There are many plant genera which contain piperidine alkaloids that fulfill the teratogenic structural requirements, for example Conium, Nicotiana, Lupinus, Lobelia, Pinus, Punica, Dubosia, Sedum, Withania, Carica, Hydrangea, Dichroa, Cassia, Prosopis, Genista, Ammondendron, Liparia, Collidium, and others. Many of them show structural similarity to known piperidine teratogens, this suggests that some of the piperidine alkaloids in these plants may be teratogenic [Bunch et al., 1992 (13)].

4. Botanical characterization

4.1. Physical description, habitats etc.

Conium maculatum L., a member of Apiaceae (formerly Umbelliferae) of ryzomal plants, the carrot family [Vetter, 2004], is an annual, biennial or in favourable conditions perennial plant, usually 120-180 cm. high. During the first year of growth C. maculatum reaches 45 cm height forming dense stands around the parent plants. The second year new plants grow from rosettes, with larger leaves which are dark green, bisected, triangular and glabrous [López et al., 1999 (3)]. The root is long, forked, tuberous, pale yellow and reminds about a carrot. The stem is mottled with irregular purple spots, is erect, bright green and slightly ridged, much branched above and hollow. The leaves are fern-like [James et al., 2004], numerous, alternate, long-stalked and tripinnate (which means that they are divided along the midrib into opposite pairs of leaflets which in turn are divided and subdivided) [Vetter, 2004]. Its flowers are white, grouped in umbels, which are small and numerous and have a terminal position, with 12-16 rays per umbel. It produces a large number of green fruits, 2 to 3 mm long and about 2 mm wide,

Larsson | Some history and effects of Conium maculatum L.

grayish at maturity and formed by two closed mericarps [López et al., 1999 (4- 6)]. The fruit is a broadly ovoid and is composed of two greyish-brown seeds with five wavy, longitudinal ridges. The petals of the small flowers are white and the stamens of the flowers are longer than the petals and have white anthers. The inflorescence is produced mainly from June to September. At germination the cotyledons are narrow and lanceolate, the first true leaves have two or more leaflets along an axis and are hairless. The plant has a bitter taste and the odour reminds about a mouse. Where plants are numerous, the odour can be very pervasive. The seeds or fruits do not a have very marked odour, but if crushed or mixed with an alkali as potassium hydroxide solution, the same characteristic, odour of mouse urine is produced.

Larsson | Some history and effects of Conium maculatum L. grayish at maturity and formed by

Figure 1. Various parts of Conium maculatum L., poison hemlock.

C. maculatum grows in ground, hedgerows, roadsides and woodland, pastures, banks of streams and rivers, meadows and waste grounds modified soils, along

Larsson | Some history and effects of Conium maculatum L.

fences, roadsides and ditches, around windmills, abandoned constructions and around woods, under which it can vegetate during the winter [López et al., 1999 (7,8)]. The plant is very common weed in Europe, North and South America, North Africa, Australia and New Zealand [Vetter, 1999]. C. maculatum is a nitrophile plant which means that it prefers moist soils with high nitrogen level. Since it belongs to a group of very common, wide spreaded weed species, its germination is an important target of investigations. It acts as a pioneer species which quickly colonize disturbed areas. Poison hemlock can be a persistent weed species particularly in moist habitats. A single plant may produce 35,000-40,000 seeds, which usually fall near the parent plant, but can be spread by water and animals [Vetter, 2004 (9)].

Table 1. Non-quantitative comparisons of alkaloid contents in different plant organs of Conium maculatum. Source: López et al., 1999.

Organs

Fully formed fruit, still green > young leaves > roots

Half-ripe fruits > ripe fruits >> roots

Green fruits > ripe fruits

Stems > leaves > fruits > roots

Stems > leaves >> fruits > roots

Because of the large seed production, it may dominate small areas with a high density of plants and encroach on alfalfa fields, grass pastures and meadows (probably because of the rich nitrogen level in these plants). The seeds are non- dormant [López et al., 1999 (7,8,10)].

4.2. Other hemlocks and Apiaceaces

It should be noted that water hemlock (Cicuta virosa) is a different yet related toxic plant that may be more lethal than poison hemlock (C. maculatum). Water hemlock produces a C(17) polyacetylene neurotoxin termed cicutotoxin which produces direct brain-neural injury through the induction of convulsions. Since this group also is poisonous I will touch them briefly here.

Larsson | Some history and effects of Conium maculatum L.

Larsson | Some history and effects of Conium maculatum L. Figure 2. Cicuta virosa L., water

Figure 2. Cicuta virosa L., water hemlock, a near related plant to C. maculatum Compare with fig. 1.

Eastern hemlock, Tsuga canadensis (L.) Carr, and mountain hemlock, Tsuga heterophylla, belong to the family Pinaceae, are thereof very distant relatives to C. maculatum. Clapham et al. stated that there are some 43 genera of Apiaceae throughout Europe and that these can be grouped into various tribes or subtribes, depending on their taxonomic similarities. Apiaceae consists of annual or perennial herbs, rarely shrubs, many of which are strong smelling [Dodds et al., 1999 (11)]. In an experiment made by Dodds et al., extracts from 33 species representing 32 genera of Apiaceae were screened for antifeedant activity against the field slug, Deroceras reticulatum, of those 22 triggered nervous activity in the slug ofactory nerve preparation. Intensity of response differed with plant species, but extracts of Conium maculatum, Coriandrum sativum (coriander) and Petroselinum crispum (parsley), seemed to be both the most neuroactive and antifeedant, when incorporated in a standard food [Dodds et al., 1999]. For a more detailed list of the 33 species examined, the reader is recommended to see the article of Dodds et

Larsson | Some history and effects of Conium maculatum L.

al., see the reference list. Conium is a close relative to the genus Physospermum, but the latter was unable to to trigger any activity in the electrophysiological preparation. A possible explanation for this divergence could be that they are found in completely different habitats. Conium is living in damp areas such as open woods or river verges, whereas Physospermum generally grows in grass verges [Dodds et al., 1999 (11)]. Since mollusks need moist conditions to prevent desiccation, it seems likely that Conium is more exposed for the slug, which therefore need some form of defence, in this case antifeedant chemicals released through the leaves. This study shows, as well as Garraway has stated, that the most neuroactive extracts were also evidently antifeedants. Electrophysiological techniques can then give a valuable indication of the antifeedant potential of naturally occuring substances [Dodds et al., 1999 (12)].

5. The effect in livestock production and other animals

5.1. General

One of the most prevalent economic factors in livestock production is reproductive efficiency. The most significant are 1) dietary factors essential for normal reproduction 2) infectious diseases, 3) heredity, 4) management, 5) environment, and 6) toxic dietary factors. Of those factors mentioned, toxic dietary factors and natural toxins are these which are least understood and got least attention, this despite they could be the most important. This picture is further complicated by the fact that there are many different plants which contains a range of toxins able to affect reproduction, by that there are many different mechanisms involved (although only the mechanism of C. maculatum will be touched here). The quanities of toxins in the plant varies to a wide degree with environmental conditions, location and stage of growth. There is a huge variation among the plants containing these toxins, as well as the plant’s acceptability as feedstuff for livestock. Each plant requires in the most cases a special management strategy to prevent intoxication. Natural toxins are able to affect almost every reproductive processes.

It have shown through studies the past 40 years that many plants are responsible for death, abortion or teratogenesis when exposed to livestock. Many of these malformations have neither been reported nor diagnosed since they have been ascribed as genetic factors and reduce the importance of environmental causes. It is now obvious that much of the livestock losses dependent on embryonic death, abortion and teratogenesis are caused by poisonous plants [Bunch et al., 1992].

Generally one can say that

any plant toxin that

causes

injury

to

the

dam,

particularly in the latter part of the gestation, can cause a small and weak

offspring. By ultrasound imaging methods Panter et al. have demonstrated some of the fetotoxic effects of poisonous plants on fetal physiology, growth and development [James et al., 1992 (14)]. Ingestion of Conium maculatum, Nicotiana glauca and Lupinus formosus, which contains piperidines, during specific periods of gestation induced fetal abnormalities (i.e., cleft palate and limb, spine and neck

Larsson | Some history and effects of Conium maculatum L.

contractures). Since the fetus is very dependent on movement in specific periods during the pregnancy, these plants alkaloids have a severe effect on fetal movement during critical gestational periods. When feeding of these plants they are supposed to be responsible for plant-induced cleft palate and skeletal contractures [James et al., 1992 (15)].

  • 5.2. Sensitivity among the different species

Monogastric animals and ruminants show similar symptoms but different susceptibilities caused by the ingestion of fresh C. maculatum. There are cases where domestic animals have ingested C. maculatum despite a good forage availability [López et al., 1999 (3)]. An apparent willingness to ingest more hemlock (even if the animal in question have been suffering from intoxication) has also been recorded for different animal species: cows [López et al., 1999 (7,8,16), pigs (1,17), goats (18), elk (19) and chickens (20)].

Table 2. The susceptibility among different livestock species of fresh Conium maculatum. Source: Lopes et al., 1999.

Toxicity

Susceptibility, from highest to lowest

Acute

Cattle > sheep = goats > pigs

Chronic

Cows > sows > sheep

Insects which have been reported to attack C. maculatum are Agonopterix alstroemeriana (Oecophoridae) [Vetter, 2004 (21)]. Polyphagous lepidopterans, Eupitheca miserulata, Spilosoma virginica, and others have been notified to eat the plant. On one polyphagous insect species, Heliothis zea, bioassay for toxicity, growth inhibition and feeding rejection was done for coniine, but the compound did not appear to have any biological activity against the insect species at the concentrations tested [Vetter, 2004 (22)].

6. The substances in hemlock

  • 6.1. General

The majority of the family Apiaceae produce volatile oils in defined tissues named vittae of the fruits. These tissues also seem to be the sites of synthesis and/or storage of biologically-active secondary products such as flavonoids and coumarins [Corsi and Biasci, 1998 (23,24)]. Although Conium maculatum produces alkaloids, linear furano-coumarins have been isolated from the plant [Corsi and Biasci, 1998, (25)], and synthesis and/or accumulation sites have not yet been clearly identified [Corsi and Biasci, 1998 (26,27)]. In a study made by Corsi and Biasci it was found that all tissues of C. maculatum were very rich in alkaloids [Corsi and Biasci, 1998]. Cromwell stated that alkaloid synthesis in Conium maculatum took place more readily in tissues of the shoot than the root [Corsi and Biasci, 1998, (26)].

Larsson | Some history and effects of Conium maculatum L.

6.2. The alkaloids in Conium maculatum.

There are eight known piperidinic alkaloids in poisonous hemlock [López et al., 1999, (28, Panter et al., 1988b)]. Two of them, coniine and γ-coniceine (figure 7 resp. 8) are frequently found in largets amounts. Coniine is reported to be eight times more toxic than γ-coniceine [López et al., 1999, (29, The Merck Index,

1996)].

N
N

Figure 3. Coniine

(2-propylpiperidine)

N
N

Figure 5. N-methylconiine

.

(1-methyl-2-propylpiperidine) HO N
(1-methyl-2-propylpiperidine)
HO
N

Figure 7. Pseudoconhydrine

((5-hydroxypropyl)-piperidine) HO N
((5-hydroxypropyl)-piperidine)
HO
N

Figure 9. N-methylpseudoconhydrine

((5-hydroxy-1-methyl-2-propyl)-piperidine)

N
N

Figure 4. Coniceine

(2n-propyl-1∆-piperidine) N
(2n-propyl-1∆-piperidine)
N

OH

Figure 6. Conhydrine

(2-(1-hydroxypropyl)-piperidine)

N
N

O

Figure 8. Conhydrinone

((1-oxo-propyl)-piperidine)

N
N

Figure 10. 2-methylpiperidine

O O HOOC O
O
O
HOOC
O

Figure 11. Poly-β-keto acid (2,5,7-tri-oxo-octanoic acid)

A large width in the outcome regarding the alkaloid content, both qualitatively and quantitatively have been found, depending on different researchers have not used exactly the same method, which stage one study and which organ. Other

Larsson | Some history and effects of Conium maculatum L.

parameters which had an effect on the alkaloid concentration was rain (give an increase of γ-coniceine level in fruits and flowers) and temperature [López et al., 1999 (27,30)]; even the diurnal concentration varied in the alkaloids [López et al., 1999 (17)]. The quantity of alkaloid were the twice during the sunny seasons compared to cloudy seasons. As the fruits ripen, the alkaloid content increase, and this also depends upon the soil moisture and its exposure to the sun. Since green fruits contains more alkaloids than mature fruits and seeds, the level of alkaloids in fruits reaches its peak while ripening, but reduces near maturity. The concentrations of coniine and coniceine are found in similar degrees in cloudy summers, while coniine is most prevalent during dry summers (27). López et al. have detected a significant increase in the alkaloid concentration of C. maculatum on nitrogen fertilized soils [López et al., 1999].

Experiments made by Leete has demonstrated that coniine is derived from acetic acid [López et al., 1999 (31)] by labelling the 1-C atom with the 14 C isotope. This result indicated that coniine is formed from an eight-carbon poly-β-keto acid (see Fig. 11), produced by the combination of four acetate units. Obviously is γ- coniceine a precursor of coniine and the other hemlock substances, but the knowledge of the eight-carbon compound which is converted to the former alkaloid is still like a black box [Vetter, 2004].

6.3. The polyacetylenes of Cicuta virosa

Larsson | Some history and effects of Conium maculatum L. parameters which had an effect on

OH

OH

Figure 12. Cicutoxin, the main substance in Cicuta virosa (water hemlock) ( 8,10,12-Heptadec-triene-4,6-diyne-1,14-diol).

The major toxic substance of water hemlock (Cicuta virosa L.), is cicutoxin, which belongs to a class of conjugated polyacetlylenes. It is assumed to be produced from oleic acid in the biotransformation pathway which involves oxidation and decarboxylation reactions [Uwai et al., 2000 (32)]. The citutoxin contains the following functional groups: (i) a hydroxyl group and an allylic hydroxyl group at C-1 and C-14, respectively, (ii) a diacetylene group, and (iii) an all-E-triene group conjugated with the diacetylene. Cicutoxin is known to act directly on the CNS, and is responsible for tonic and clonic convulsions and respiratory paralysis [Uwai et al., 2000 (33)]. Despite cicutoxin is a severe convulsant compound, its mechanism and structure-activity relationships (SARs) is little known because of its chemical instability. To be able to comprehend the features of these type of substances, it is necessary to study the principal structural properties for the toxicity of polyacetylenes. Additionally, these studies can very well lead to better understanding of the reaction mechanisms and give information when developing new anticonvulsant drugs.

Larsson | Some history and effects of Conium maculatum L.

7. Biological activity

  • 7.1. General

The piperidine toxins from the Conium (and also Lupinus and Nicotioana) species induce cleft palate and contracture skeletal malformations in livestock, as was mentioned above [James et al., 1992 (14)]. Different chemical structures of the piperidine toxins from each plant lead to different toxic potencies [James et al., 2004 (34)]. These differences are important in the mechanisms of action, such as reduction of fetal movement and fetal malpositioning [James et al., 2004 (15)].

The induced cleft palates by toxic plants in goats look closely like the cleft palates induced in humans [James et al., 2004 (35,36)]. The similarity between goats and humans in this case is also useful as a model for histological comparisons of the prenatal- and postnatal-repaired cleft palate and comparison of craniofacial growth and development. This is a very good congenital model to study the etiology of cleft palate in humans and develop fetal surgical techniques in utero. The most of the discovered biomedical applications from these plants today derives from their relationship with similar conditions in humans [James et al.,

  • 2004 (15,35-38). Conium alkaloids may also cross the placenta and produce a

similar sedative and anesthetic effect on the fetus as on the dam [Bunch et al.,

1992].

  • 7.2. Symptoms of poisoning of Conium

When this group of piperidine alkaloid-containing plants is involved the symptoms of poisoning are similar in all livestock production. The initial symptoms includes nervousness, depression, grinding of the teeth, frothing around the mouth, relaxation of the nictitating membrane of the eye, frequent urination and defecation and lethargy. Then eventually follows muscular weakness, tremors and fasciculations, ataxia, collapse, respiratory failure and death [James, 2004]. Signs of toxicosis may appear as early as 1 h after ingestion and get worse the next 24-48 h even if further ingestion does not occur. However, if the animal does not die within this time frame it generally recovers completely. Coniine and γ-coniceine from Conium and anabasine from N. tabacum used identical birth defects in cattle, pigs, sheep, and goats [James et al., 2004 (15,39-

44)].

  • 7.3. Pharmacological actions

Hemlock alkaloids have been found to have an action on spinal cord reflexes and depress autonomic activity and in large quantities cause neuromuscular blockade. This action may lead to respiratory depression and anoxic brain injury, with eventual death following within 24 hr of ingestion. Despite rhabdomyolysis and assosiated acute renal failure have been recorded regarding hemlock poisoning, no direct toxic effects have been described concerning the liver or kidneys.

Larsson | Some history and effects of Conium maculatum L.

The action of poison hemlock of the central nervous system seems to play a minor role, as the senses seemingly remains intact in humans and in animals. Since stimulation of the sensory cells does not result in muscle contraction, there is an increased resistance in the sensory cells [de Boer, 1950 (45)]. The influence the hemlock alkaloids have on the heart is of minor importance. After preliminary stimulation the sympathetic and parasympathetic ganglia become paralysed, the same reaction takes place with the respiratory medullary center, which result in an respiratory arrest and asphyctic agonal convulsions. de Boer has studied the peripheral vasoconstriction effect of hemlock, and recorded varying results in frogs and a pressor effect in mammals. When coniine and opium were combined, the summarised result was that opium caused an emphasized effect of the paralysing action of coniine, when coniine decreased the anesthetic effect of opium. The character of the paralysis was more like the ascending type [de Boer,

1950].

Since the piperidines behaves in a specific way and are teratogenic they also fulfill specific criteria for teratogenesis [James et al., 2004 (39)]. The structural characteristics of these piperidines need to be determined and their main differences outlined to be able to find out their mechanism of action, as fetal movement and malpositioning. The birth defects caused by Conium, Lupinus and Nicotiana spp., are the same and their biological activities occur by a similar mechanism of action [James et al., 2004 (15)]. As usual with biological active compounds one use to characterise the toxicity into acute and chronic forms.

Sollman postulated that the peripheral actions of coniine are similar to those of nicotine, but it produces more prounounced paralysis of the central nervous system and of the skeletal muscle nerve endings [de Boer, 1950 (46)]. de Boer confirmed 1950 that coniine had similar activity as strychnine [de Boer, 1950]. One of the reasons why C. maculatum could not be used as a medicine was that different preparations varied too much in their potency. Fairbairn and Challen have found one possible explanation to the differing potency; alkaloidal content and composition from extracts differed widely dependent on the climatic conditions and even which time of the day the plants were collected [Bowman and Sanghvi, 1962 (27)]. Therefore the study of the individual alkaloids intensified. The four main alkaloids are coniine, γ-coniceine, N-methylconiine and conhydrine. Conhydrine occurs in the smallest proportions and has the weakest pharmacological action [Bowman and Sanghvi, 1962 (47)]. The most distinctive action of the three other hemlock alkaloids plus nicotine is their ability, provided the dose is small, to inhibit the crossed extensor reflex and the so called knee-jerk by an action potential in the spinal cord. The influence of nicotine on the knee-jerk was first demonstrated by Schweitzer and Wright 1938 [Bowman and Sanghvi, 1962 (75)]. Since these effects also occured with small doses, de Boer’s conclusion that the action of coniine was similar to that of strychnine could not be confirmed. In fact, it was to the contrary: the actions of the hemlock alkaloids and of strychnine were shown to be mutually antagonistic. Since neurons in the spinal cord may both be inhibited and activated by the action of hemlock, the mechanisms involved are a bit complicated. Both mephenesin and strychnine are able to antagonise the depressant action of the alkaloids on the patellar reflex. If the alkaloids initially stimulate inhibitory neurons rather than blocking excitatory ones, the antagonistic relationship of the two substances may

Larsson | Some history and effects of Conium maculatum L.

be explained. There is evidence that its central synapse is controlled by polysynaptic inhibitory pathways, although the patellar reflex is monosynaptic. Mephenesin acts in the first case on spinal interneurons [Bowman and Sanghvi, 1962 (48), and by that may have an antagonistic effect of the alkaloids by blocking the interneurons of the inhibitory pathways. Strychnine also antagonise the actions of inhibitory transmitters in the spinal cord [Bowman and Sanghvi, 1962 (49,50)].

  • 7.4. Acute poisoning

When exposed to non-toxic doses, a sedative or depressive effect of the central nervous system, CNS arose, which produced deep sleep. These anesthetic effects were observed in several piperidinic substances by Hunt and Fosbinder 1940 [López et al., 1999 (56)]. Animals who survive acute poisoning from C. maculatum usually recover without future injuries, but abortions may result [López et al., 1999 (54,57)]. The necropsy examinations are consistent with what is expected from animals suffocated of respiratory arrest: dark and dense blood, dark congested liver, the right side of the heart is found full of blood while the left is empty, the lungs are congestive and dark colored, showing clear bands where the ribs have been in contact with the lungs [López et al., 1999 (53,54)]. The acute toxic activity of the compounds coniine, γ-coniceine and N-methylconiine is supposed to block the spinal reflexes through the action of the medulla: they an initial stimulus is followed by a depression of the autonomic ganglia.

High doses of the compound produce a stimulus of the skeletal muscles and a neuromuscular blockage through the action on nicotinic receptors. When the phrenic nerves are affected and the respiratory muscles become paralysed death occurs [Bowman and Sanghvi, 1963; López et al., 1999 (44,55)].

7.5. Cronic poisoning

The related malformations caused by C. maculatum have been described in calves, piglets and lambs: at birth they show arthrogryposis, scoliosis, torticollis, cleft palate and excessive flexure of the carpal joints. These injuries were reproduced experimentally to cows during the 55-75 days of pregnancy [López et al., 1999 (40,58-60). If fresh hemlock was to dry under the sun during 7 days an important loss of biological activity occurred.

  • 7.6. Treatment

There are no known antidotes and treatment of poisoned victims consists of supportive care including sedation, intubation and ventilation [Foster et al., 2003]. Respiratory support and gastric decontamination should be administered directly. Anti-cunvulsants should be given when needed. Forced diuresis can be applied to prevent renal failure from rhabdomyolysis and myoglobinuria [Frank et al.,

Larsson | Some history and effects of Conium maculatum L.

1995]. The use of stimulants and large volumes of water have been suggested as treatments against poisoned livestock. Among human beings treatment with alcoholic beverages, tea and coffee has been suggested and also the induction of vomit with a tablespoon of salt dissolved in warm waters, repeating this treatment until the vomit is empty, keeping the victim laying down, resting, covered and under medical control [López et al., 1999 (54,57)]. The reasons to why not poison by hemlock are more frequent are the plant’s “mousy” odor, bitter taste and burning sensation of the mouth, throat and abdomen on ingestion [Frank et al., 1995 (61)]. A poisoned victim from hemlock stated that the plant tasted like “carrot tops” [Frank et al., 1995]. Survivors of poisoning have in the most cases not shown permanent sequelae and have neither shown any long-term damage of the liver nor kidneys. For nonsurvivors brain death often occurs, without serious extraneural losses, thereby making them possible multiorgan donors (read more about this at next chapter, “Hemlock victims as organ donators”.

  • 8. Hemlock victims as organ donators

Today more patients are dying while waiting for their organ transplantation, despite the improving results of transplantations. Therefore one have investigated the so-called “mariginal donors” (i.e. donors not previously thought to be usable). Mariginal donors may be victims of poisoning, including those involving carbon monoxide, tricyclic antidepressants, methanol, cyanide and poisonous plants. Foster et al. have reported a case of successful transplantation of the liver, kidney and pancreas from a 14-year old girl who accidentally had ingested fresh hemlock on a nature hike. The cause of death was assigned anoxic encephalopathy. The liver and kidney biopsy results showed normal values. All the three recipients had immediate function of their organs, and no of them seemed to have any clinical evidence of transmitted toxin. Still 6 months after transplantation, all recipients were well, with functioning transplants. Foster et al. made the conclusion in their report that intoxication of poison hemlock does not have to contradict organ donation [Foster et al., 2003].

  • 9. Structure activity relationships

The molecular structure of C. maculatum alkaloids determines its teratogenic effect. The side chain of the molecule must be at least a propyl group to have any effect. 2-ethylpiperidine has for instance been shown to be non-teratogenic [López et. al, 1999]. The piperidine ring must also be alpha-substituted [Bunch et al., 1992]. According to experiments [Vetter, 2004 (60)] coniine, γ-coniceine and N-methyl- coniine were teratogenic, the other five homologous substances described in chapter 6, “The alkaloids in poisonous hemlock” were not. No information has been found considering the acute toxicity and the structure of the alkaloids [Vetter, 2004]. If one superimposes the active alkaloids of C. maculatum and nicotine one can see the similarities of the molecular structures and that will give

Larsson | Some history and effects of Conium maculatum L.

some clues which type of bondings there are between the alkaloids and the nicotinic receptor. It is obvious that the nitrogen atom play a major role (since it is apparent in all of the molecules), and the similarity between C. maculatum’s alkaloids (piperidine ring and a propyl side chain in 2-position), indicates that this is of importance.

Keeler and Balls, fed pregnant cows with structural analogues of coniine to compare structural relationships to their teratogenic effects. The results indicated that the piperidine alkaloids must fulfil certain chemical structural criteria to be regarded as teratogenic. These data suggested that the piperidine alkaloids with either a saturated ring or a single double bond in the ring with a side chain of at least three carbon atoms in length adjacent to the nitrogen atom, were potential teratogens [James et al., 2004 (60)]. Those alkaloids with a double bond adjacent to the nitrogen atom are more toxic than either the fully saturated or N-methyl derivatives [James et al., 2004 (34)].

10. History

10.1. The trial and execution of Socrates

A “cocktail” of extract from Conium maculatum, the poison hemlock, mixed with opium have been reported to be the lethal poison which the Greek philosopher Socrates was condemned to drink in the year 399 B.C. [de Boer, 1950]. Socrates’ symptoms from he drank the cup to he passed away was described by Plato, who also was a pupil to Socrates. The trial and execution of Socrates is by many estimated to be the next most famous execution in the world’s history, next after the crucifixion of Jesus. Jesus life, trial and execution have been documented very well, and is world wide known, but what do we know about Socrates and his theology and philosophy (since I bring the trial and execution of Socrates up here, it may be interesting to know why he was sentenced to death)?

Larsson | Some history and effects of Conium maculatum L.

Larsson | Some history and effects of Conium maculatum L. Figure 13 . Bust of Socrates.

Figure 13. Bust of Socrates. http://www.molloy.edu/ academic/philosophy/sophia/plato/socrates.htm.

The trial of Socrates in 399 B.C. confronted an old desire for restful social life and a new idea of human dignity, in a legal system where trial by jury was in its infancy in a primitive, experimental stage. Socrates postulated to his defense, that his claim on free inquiry would make him to an official benefactor and not any criminal. He failed to convince the jury of 501 delegates and was found guilty and sentenced to death [Brumbaugh, 1989].

Socrates was prosecuted by a younger man named Meletus. His charge against Socrates was impiety. The more specified arguments that Socrates was supposed to be impious were

  • 1. Socrates did not recognise the gods of the city.

  • 2. He invented new divine things.

  • 3. He was charged to corrupt the youth.

There are different reports about the defence Socrates gave about the charges against him. Some sources have said him to be silent during the trial, but Xenophon’s and Plato’s statements are to the contrary. Xenophon was a famous soldier at that time and a friend of Socrates and have published a report named Memorabilia. [Brumbaugh, 1989]. Socrates speech was perceived by many to have been quite haughty and proud. Xenophon characterise it as megalegoria, which can be translated as “big talk” [Brickhouse and Smith, 2002].

Xenophon interpreted Socrates behaviour at the trial as he did not want to die in old ages and pain and decided to end his life as a martyr. He also concluded that Socrates had religious scruples about suicide and thereof he provoked the court [Brumbaugh, 1989]. This Xenophon explains as Socrates “big talk” at his trial. In Plato’s version, Socrates claims that it is his duty as a defendant to instruct and persuade the jury. The “big talk” in Socrates defense is by many scholars only the

Larsson | Some history and effects of Conium maculatum L.

natural result of a mission given to him by the god of Delphi (Apollo) [Brickhouse and Smith, 2002]

Larsson | Some history and effects of Conium maculatum L. natural result of a mission given

Figure 14. Xenophon. http://www.philosophypages.com/dy/x.htm#xenp.

To be able to get a picture of why Socrates was accused for not recognise their gods, one need to understand a little of the situation in Greece at that time and Socrates’ philosophy. Since this is neither any history nor philosophy thesis, it will only be touched very briefly here.

The Athenian expansion during the fifth century B.C. collided to some degree with Sparta and its allies, and for thirty years hot and cold warfaring occured alternately, which ended with the total defeat of Athens in 404 B.C. Then Sparta supported an interim council of representatives of the conservative group of a party named The Thirty Tyrants took over the government [de Boer, 1950]. The more active democratic leaders fled from the city, and Critias, the leader of The Thirty Tyrants, instituted a reign of terror. Since they were short of public revenues, they took advantage by a law that the property of traitors could be confiscated by the state. Wealthy foreign residents (and some others) could be arrested and executed for treason after secret cross-examinations, and by that they managed to keep the treasury solvent. Critisism of the reign was almost the same as being quieted by assassination [Brumbaugh, 1989].

The most fundamental dogma of the Socratic theology is that the gods are truly wise. Socrates reasoned, that wisdom guaranteed virtue, which followed that the gods are completely virtuous. Socrates claims that humans get nothing good that does not come from the gods. This line of reasoning explains why Socrates found the ancient Greek myths who were fighting with one another hard to believe, because disagreements would by that logic reasoning not exist, and hence they should never fight. Moreover, the gods would never, in Socrates’s view, do anything evil or harmful. This reasoning was by many at this time seen like he questionized the ancient Greek mythology, which seemed to be very fatal [Brickhouse and Smith, 2002].

Larsson | Some history and effects of Conium maculatum L.

10.2. The death of Socrates

The first noteworthy thing in the description of Socrates’ execution is that his legs could not carry the weight of his body, so he had to lay down. At the same time Socrates felt a cold sensation in his feet. Both the strong vasoconstriction, the cyanosis and the curare-like action played a part to the total effect of coniine. The sensibility of the skin is strongly impaired, or maybe paralysed, this symptom is not a special feature of coniine poisoning. The peripheral paralysis in Socrates’ case could not have proceeded far, since he was still able to talk and to move away his blanket. It is evident from records that Conium poisoning affects swallowing and speech, particularly at the end of the process. None of these symptoms is described in Phaedo, where Plato describes how Socrates dies by poisoning from hemlock, after agonal convulsions death arrived. Plato would unlikely miss such symptoms as ataxia, convulsions, tremors and spastic rigidity, as normally occurs in Conium poisoning [de Boer, 1950]. However, as Plato describes the scene and the effects of the hemlock on Socrates there are certain curious features. In the Phaedo, hemlock just produces first heaviness and then numbness in the body. The numbness starts in the feet and then proceeds gradually upwards, to the groin and when the heart is affected, he dies [Gill, 1973]. His mind remainied clear until the end, and his death arrived calmly and peacefully. It is remarkable account, rich in emotive power and in clinical detail [Brickhouse and Smith, 2002 (63)].

Larsson | Some history and effects of Conium maculatum L. 10.2. The death of Socrates The

Figure 15. Plato. http://www.philosophypages.com/ph/plat.htm

The only other symptom he mention in Phaedo is a single movement prior to death. The symptom of numbness in the lower legs have also been registered in other ancient documents. Modern medical authorities recount more effects of this kind, as salivation, nausea, vomiting, dryness and choking in the lower throat, dilated pupils, blurred vision and hearing and thick speech. Arms and legs becomes paralysed, which often is accompanied by spasms and convulsions. Thus

Larsson | Some history and effects of Conium maculatum L.

Plato’s only describe two of the symptoms of hemlock-poisoning, and his description of the death scene in the Phaedo gives a quite different impression of the effects compared with the medical accounts. In Plato’s point of view is the hemlock’s penetration into the body a calm, almost rythmic process. This is contrast to how the second century writer Nicander describes it. There are many theories why Plato gave such very short description of Socrates symptoms. One theory is that Socrates covered his face with clothes or hands and then Plato could not see his heavy salivation, eye rolling, dilated pupils etc. One another is that he may have made his selection of symptoms: As so often, especially in ancient times, big heroes were described almost as half-gods. Even if it was unconciously, Plato may have wished to show Socrates’s physical toughness and stoicism, that his mind totally was able to control his body. His description of Socrate’s death may be the purification of the psyche from the body, which begins in the lower part of the body and goes upwards [Gill, 1973]. The fact that Socrates was still able to speak until a few minutes before he deseased, does not mean that his cerebral function was unaffected, because he was laying down without speaking for some time, or moving and reacted only when he was spoken to. This is comparable with a study made by de Boer, where rats could be awaked very easily after administered a mix of coniine and opium. The sudden death of Socrates which occured one or two minutes after his last words is similar to the death of Britannicus. Plato’s description of Socrates’s death seems to be a rather short process. As death must be sure in executions, the dose of the poison must have been a large one. As mentioned above in this article, an insufficient quantity of C. maculatum gives the opportunity to recover completely. For a such quick and sudden death by Conium juice alone, the quantity of poison had to be so overwhelming that it would be impracticable. Based on this reasoning, de Boer estimates the death of Socrates to be the outcome of the administration of Conium maculatum juice mixed with opium [de Boer, 1950]. But is Plato’s records about Socrates’ death true then? When putting all the pieces of information of old and new records we know together, many scholars still think he did tell the truth, despite all the doubts mentioned above [Brickhouse and Smith, 2002 (63)].

Larsson | Some history and effects of Conium maculatum L.

Larsson | Some history and effects of Conium maculatum L. Figure 16 . Totenmahl relief known

Figure 16. Totenmahl relief known formerly as the "Death of Socrates" From Svoronos 1903-12, pl. 83. http://www.perseus.tufts.edu/cgi- bin/image? lookup=Perseus:image:1998.01.0083.

Tacitus described the execution of Britannicus, who was poisoned by a mixture of C. maculatum and opium by the Roman emperor Nero [de Boer, 1950 (62)].

The plant have been used in ancient Anglo-Saxon medicine, and its English name – hemlock – is derived from the Anglo-Saxon words hemlic or hymelic. Through the centuries its name has taken many forms, like hymlice, hymlic, hemeluc, hemlake, hemlocke and finally hemlock [Vetter, 2004]. It was William Shakespeare who first used the modern spelling hemlock in his “Life of Henry the Fifth” [Vetter, 2004 (64)]. Conium maculatum was used as a remedy to treat herpes, erysipelas (a form of superficial cellulites) and breast tumours. Dried, stored and unripe Conium seeds have also been used as an antispasmodic, a sedative or an analgesic. The dried leaf and juice of the plant were listed in pharmacopeias of London and Edinburgh from 1864 to 1898 and the last official medicinal recognition appeared in the British Pharmaceutical Codex of 1934 in Great Britain [Bowman and Sanghvi, 1963]. As mentioned above, the direct medicinal usage of hemlock is difficult since the small limit between the therapeutic and poisonous levels [Vetter, 2004 (65)]. Greek and Arabian physicians have used the plant to treat indolent tumours, swellings and pains of the joints. The bitter juice of the plant was used together with betony (Stachys officinalis) and fennel (Foeniculum vulgare) seeds as a remedy against the bite of a mad dog. Later in history, this plant extract have been administered as an antidote against strychnine and other strongly poisonous compounds, when nothing else was supposed to help [Vetter, 2004 (66)]. During the 15 th and 16 th centuries religious sects used roasted roots from C. maculatum for relieving the

Larsson | Some history and effects of Conium maculatum L.

pains of gout. However, in the 1760s, it began to be used to treat cancerous ulcers. Only USA imported about 14,000 kg of seeds and 7,000 kg of dried leaves from the drug. The tinctures and extracts were used because of their sedative, anodyne and antispasmodic properties (in the case of asthma, epilepsy, whooping cough, angina, chorea and stomach pains). The drug has to be given with meticulous care; narcotic poisoning may result from internal use which can produce paralysis. The use of C. maculatum in the medicine have been disputed. However, it remains as a classic homeopathic agent with various uses [Vetter, 2004 (67)]. It is known to be a long-acting remedy, it is especially of use against elderly people, when the vital powers of the body are declining. It has also been used in the treatment against a serious type of malignant tumour [Vetter, 2004].

During the 1800s and early 1900s the livestock industries developed rapidly in western United States, and then the poisonous plants were soon discovered as a source to economic loss for it. Much because of these losses, the U.S. Department of Agriculture initiated research on the effects the poisonous plants caused on the livestock. So far they had mostly concentrated their research to identify the specific poisonous plants, with only limited efforts to identify plants toxins. After the World War II more advanced and sophisticated scientific equipment were developed and facilitated the identification of plant toxicants and the mechanisms of their actions [James et al., 2004 (51,68)]. At this time, members of the ranching communities asked that research be initiated on a number of problems causing great economic loss to producers.

  • 11. Management and control of the plant

Conium maculatum is an opportunist weed species, and has wide adaptations ability. Poisonous hemlock is infected by virus strains like the alfalfa mosaic virus (AMV), celery mosaic virus (CeMV), ringspot virus and carrot thin leaf virus [Vetter, 2004 (69)]. There are methods of viral infection or phytophagous insects to control and remove the plant, but those need more research. Mechanical control like hand pulling or grubbing works of course, but can be very time consuming. Hand pulling is most effective in wet soils and small infestations. The best thing is to pull or grub out the plant prior its flowering [Vetter, 2004 (70)]. Chemical control of hemlock is simpler if extensive areas are covered by the plant. One can for example use a synthetic auxin-like compound, like as 2,4-D (2,4-dichloro- phenoxy-acetic acid), which spare the grasses, except a few species. Since hemlock produce so numerous seeds, a repeated treatment the following year may be needed to eliminate the weed. Hexazone can be used to control the poison hemlock in alfalfa [Vetter, 2004 (71)]. To avoid or minimalize the chance to plant toxicosis one should not let pregnant animals grazing on fields when developmental problems may occurs. One have set 70 days as a critical gestation time for cows and 60 for pigs [Vetter, 2004].

Larsson | Some history and effects of Conium maculatum L.

Pharmacologic information about the Conium alkaloids adds further biochemical evidence upon which a mechanism of action may be hypothesized. It has been suggested that coniine and -coniceine possess some curare-like effects [James et al., 2004 (72)]. However, curare does not cause the initial stimulation that Conium alkaloids do, but induces a highly selective paralysis of motor end-plates in skeletal muscle and also paralyzes autonomic ganglion cells. The clinical effects of curare are very similar to the depressing effect of the Conium alkaloids, coniine and -coniceine, but less so for N-methylconiine. Could the teratogenicity of Conium be attributed to a mechanism similar to that of curare, or is it the side effects which are responsible for the teratogenicity? It is a matter of hypothese whether the teratogenic effects, which are believed to be due to reduced fetal movement during critical stages of gestation, might be attributed to the same mechanism of action, namely, the blockade of effector cells innervated by preganglionic cholinergic nerves in the fetus. If this is the case, then curare should cause arthrogrypotic-type malformations in livestock similar to those induced by Conium, assuming there were no metabolic, pharmacokinetic, or excretionary differences. Interestingly, curare and D-tubocurarine are reported to cause arthrogryposis in chicks when administered in eggs and cleft palate in rats [James et al., 2004 (73)]. Furthermore, it has been demonstrated in preliminary studies with goats that curare infused into the embryonic vesicle during early gestation caused severe contracture skeletal defects and cleft palate similar to that induced by Conium, Nicotiana, and Lupinus.

Larsson | Some history and effects of Conium maculatum L. Pharmacologic information about the Conium alkaloids

According to experiments made by Bowman and Sanghvi, seems the alkaloids of C. maculatum to have a peripheral blocking action in both parasympathetic and sympathetic ganglia in larger doses. The blocking action predominated with N- methylconiine, but with γ-coniceine the stimulant phase dominated while the blocking action was relatively difficult to demonstrate. Coniine produced in most experiments stimulant effects, but in others, the stimulant phase was absent and only the blocking action could be demonstrated; the summation of its action can be described to be somewhere between γ-coniceine and N-methylconiine. The neuromuscular block which the alkaloids differ in many respects from that produced by the mere depolarising blocking drugs, decamethonium and suxamethonium, although the alkaloids indicate a depolarising action. Generally, the drug affinity for the acetylcholine receptors must continually be high for persistent depolarisation. However, it appears like that the hemlock alkaloids have a low affinity for the receptors. The alkaloids are secondary and tertiary amines which are well absorbed after oral or subcutaneous administration, and penetrate the blood brain barrier, BBB, where they exert central actions. Thence, the hemlock alkaloids can penetrate cell membranes readily and indicates that their blocking action at the motor end-plates may thereof be a consequence of an intracellular action causes the end-plates to be inexcitable by acetylcholine [Bowman and Sanghvi, 1962]. The acetylcholine receptors are located only on the external surface of the motor end-plates and reaction with these receptors would might be the initial contraction produced by large doses of the alkaloids. The relatively slow following inhibition may be explained by that the alkaloids need time to penetrate the cell membrane [Bowman and Sanghvi, 1962 (74)]. Experiments with cats and hens by Bowman and Shanghvi, indicate that the failure in neuromuscular transmission exerted by the alkaloids is only partly

Larsson | Some history and effects of Conium maculatum L.

responsible on reducing the release of acetylcholine through the nerve ending. Through Bowman and Sanghvi’s experiment, N-methylconiine was quickest among the three alkaloids in onset after close arterial injection. It was also the least readily absorbed alkaloid after oral administration. These results plus that when injected into the carotid artery, N-methylconiine was without effect on respiration, suggests that its inhibiting action has also a large extra-cellular component in it. This conclusion may be correct since at body pH, the tertiary amine has the strongest positive charge. The mechanism of action of the C. macualtum’s alkaloids on neuromuscular transmission is complex and may involve more than one site of action. This is common with substances of this type which combine with acetylcholine receptors, but whose action is not limited to extra-cellular receptors (unlike the quaternary ammonium compounds, which cannot pass the cell membranes because their ion charge). The central depressant action occured was much longer lasting and occured with smaller doses than the peripheral neuromuscular blocking action, and the alkaloids might then seve as a lead compound for the synthesis of more specific and less toxic spinal relaxants [Bowman and Sanghvi, 1962].

The term “ascending paralysis” is used more to illustrate the poisoning process; it is someway difficult to represent a physiological substrate for it. There are no evidence that the myoneural junction of the muscle of the legs should be paralysed more rapidly than those of the arms, thorax and head. Following that line of reasoning, there should be one or more factors which induce this phenomenon. One explanation to it have been proposed by de Boer:

The relationship with vasoconstriction and distance are invertedly related; the resistence for the circulation will increase with the distance from the heart. Since coniine indeed causes a strong vasoconstriction and depressor effect, the blood circulation in the outmost periphery is affected very strongly, if there is any circulation at all. The results of both of these actions is that less blood is reaching the muscles. The muscles’ ability to do work diminishes strongly when they do not recieve sufficiently oxygenated blood. Since coniine causes cyanosis by central depression of the respiration, anoxemia occurs. Thus, the state called “ascending paralysis” is a summarized effect of partially the curare-like muscle relaxing action and partially by the vasoconstriction, lowered blood flow and central respiratory depression, which causes anoxemia. Since this state is not any pure paralysis it would may be better using another term than “ascending paralysis” for this phenomenon [de Boer, 1950].

The reason for the variation in susceptibility among a range of species to teratogenicity against coniine is unknown. Different theories have been proposed, like divergencies in receptor affinity, number or subtypes or coniine biotransformation [Forsyth et al., 1996].

13. Summary and conclusion

Some of the information given in the reports seems to be ambiguous and even in a few cases contradictory. But one should have in mind that the reaction mechanims

Larsson | Some history and effects of Conium maculatum L.

appear to be very complicated, and the alkaloids of Conium maculatum have only been known for a few decades.

There are four drug and medicinal related questions which raises when one studying Conium maculatum:

  • 1. Has coniine etc. a sufficiently potent curarizing action to justify its use in human surgery (there are of course other interesting biological activities to study, like the potency for skeletal deformities, but this seems too difficult to see at this stage how it can be used in drug development)?

  • 2. If the side effects of the crude compounds (coniine, γ-coniceine, etc.) are too serious, can they serve as lead comounds for research of muscle relaxing drugs?

  • 3. When the reaction mechanisms are known, is it possible to develop some form of antidote or prophylaxis against poisoning of C. maculatum?

  • 4. Why does the susceptibility among the species vary so much in teratogenicity against poison hemlock?

Or put it in another way: Is there any possibility to separate the unwanted side effects from the desired effects? One good starting point could be to study those animals which have developed resistance against C. maculatum, and see if they have any special enzymes, or biotransformation systems or sequestering the compounds for example. One another could be to look at the structure-activity relationship, SAR, between the different species’ bioactive compounds which are responsible for e.g. teratogenic skeletal malformation, and see what they have in common. As mentioned above in the text, if the victim can survive the first critical period of poisoning, the chance to recover without any further injuries is relatively big, so more research in this area is needed to unravel the connection between cause and effect.

14. Acknowledgements

I want to thank my supervisor Lars Bohlin.

15. References

When the reference is enclosed in square brackets, it means that it can be found in this list. If it is followed by a number within parantheses, it can be found in next chapter, “Further readings”.

The Bantam Medical Dictionary; 3 rd revised ed., The Editors of Market House Books Ltd, Bantam Books, 2000. Boer, J. de; Arch. Int. Pharmacodyn., 83: 473-490, 1950. Bowman W. C. and Sanghvi I. S.; Pharmacological actions of hemlock (Conium maculatum) alkaloids; J. Pharm. Pharmacol., 15, 1-25, 1962.

Larsson | Some history and effects of Conium maculatum L.

Brickhouse, Thomas C. and Smith, Nicholas D; The Trial and Execution of Socrates; Oxford University Press, Oxford, New York, 2002. Brumbaugh, Robert S.; Platonic Studies of Greek Philosophy; State University of

New York Press, Albany, 1989. Bunch T.D., Panter K.E. and James L.F.; Ultrasound Studies of the Effects of Certain Poisonous Plants on Uterine Function and Fetal Development in Livestock, J. Anim. Sci., 70: 1639-1643, 1992. Corsi, Gabriella and Biasci, David; Secretory Structures and Localization of Alkaloids in Conium maculatum L. (Apiaceae); Annals of Botany 81: 157-162,

1998.

Dodds, Catherine J.; Henderson, Ian F.; Watson, Peter and Leake, Lucy D.;

Action of extracts of Apiaceae on feeding behavior and neurophysiology of the field slug Deroceras reticulatum; Journal of Chemical Ecology, Vol 25, No. 9, 1999. Dorland’s Illustrated Medical Dictionary, W.B. Saunders and Company,

Philadelphia, 2000. Fortsyth, Carol S.; Speth, Robert C.; Wecker, Lynn; Galey, Francis D. and Frank, Anthony A.; Comparison of nicotinic receptor binding and biotransformation of coniine in the rat and chick; Toxicology Letters 89: 175-183, 1996. Foster, Preston F.; McFadden, Raul Trevino; Galliardt, Scott; Kopczewski, Lea Ann; Gugliuzza, Kristene; Gonzalez, Zulma and Wright, Francis; Successful Transplantation of Donor Organs From a Hemlock Poisoning Victim, Vol 76, No. 5, p. 874, Received 24 January 2003, Revision Requested 21 February. Accepted 10 april 2003. Frank B.S, Michelson W.B., Panter K.E., Gardner D.R.; Ingestion of Poison Hemlock (Conium maculatum); West J. Med., 163:573-574, 1995. Gill, Christopher; “The Death of Soocrates”, Classical Qarterly NS 23; 25-58,

1973.

International Dictionary of Medicine and Biology, Vol 1 and 3, John Wiley &

Sons Inc., 1986. James, Lynn F.; Panter, Kip E.; Gaffield, William and Molyneux Russell J. ; Biomedical Applications of Poisonous Plant Research; Poisonous Plant Research Laboratory, Agricultural Research Service, U.S. Department of Agriculture, 1150 East 1400 North, Logan, Utah 84341, and Western Regional Research Center, Agricultural Research Service, U.S. Department of Agriculture, 800 Buchanan Street, Albany, California 94710 Received for review December 16, 2003. Revised manuscript received March 5, 2004. Accepted March 5, 2004. López A., Cid S., and Bianchini L.; Biochemistry of hemlock (Conium maculatum L.) alkaloids and their acute and chronic toxicity in livestock. A review. Toxicon, 37: 841–865, 1999. Vetter; J.; Poison hemlock (Conium maculatum L.); Faculty of Veterinary Science, Department of Botany, Szent István University, 1400 Budapest, Pf. 2., Hungary. Received 18 January 2004; accepted 16 April 2004. Available online 15 June 2004.

The chemical structures have been drawn by ISIS Draw 2.3.

Larsson | Some history and effects of Conium maculatum L.

  • 16. Further readings

For the interested reader who want to know more about this plant here are a number of articles related to it.

  • 1. Holm L., Doll J., Holm E., Pancho J. and Herberger L.; Conium maculatum.In: World Weeds. Natural History and Distribution; J. Wiley and Sons, New York, pp. 221–225, 1997.

  • 2. Kielland J. and Anders O.; Conium maculatum in Hedmark county, Eastern Norway. Blyttia 56: 92–93, 1998.

  • 3. Panter K.E. and Keeler R.F.; The hemlocks: poison-hemlock (Conium maculatum) and water hemlock (Cicuta spp). In: James, L., Ralphs, M., Nielsen, D. (Eds.), The Ecology and Economic Impact of Poisonous Plants on Livestock Production. Westview Press, London, pp. 207–235, 1988.

  • 4. Cabrera A.; Conium maculatum. In: Flora de la Provincia de Buenos Aires, Part IV.; Colección Científica del INTA, Buenos Aires, pp. 389–390, 1965.

  • 5. Ragonese A. and Milano V.; Vegetales y Sustancias Tóxicas de la Flora Argentina, 2nd ed. Editorial ACME, Buenos Aires, pp. 229–231, 1984.

  • 6. Marzocca A., Mársico O. and Del Puerto O.; Conium maculatum. In: Manual de Malezas, 4th ed. Editorial Hemisferio Sur, Buenos Aires, pp. 357–359,
    1993.

  • 7. Panter, K.E., James, L.F., Keeler, R.F., Bunch, T.D.,. Radioultrasound of poisonous plants-induced fetotoxicity in livestock. In: James, L.F., Keeler, R.F., Bailey, E., Jr., Cheeke, P., Hegarty, M. (Eds.), Poisonous Plants. Proceedings of the Third International Symposium. Iowa University Press, Iowa, pp. 481–488, 1992a.

  • 8. Panter, K.E., Keeler, R.F., James, L.F. and Bunch, T.; Impact of plant toxins on fetal and neonatal development: a review. J. Range Manage. 45:52–57, 1992b.

  • 9. Mitich W.; Poison-hemlock (Conium maculatum L.); Weed Technology; 12:

194–197, 1998.

  • 10. Baskin C. and Baskin J.; Germination ecophysiology of herbaceous plant species in a temperate region; Am. J. Bot. 75, pp. 286–305, 1998.

  • 11. Clapham A.R., Tutin T.G. and Warbung E.F.; Flora of the British Isles. Cambridge University Press, Cambridge, 1962.

12 Garraway R.; The action of semiochemicals of olfactory nerve activity and behavior of Deroceras reticulatum (Müll.), J. Mollusc. Stud. 45: 167-171,

1992.

  • 13. Keeler R.F. and Crowe M.W.; Anabasine, a teratogen from the Nicotiana genus. In: A.A. Seawright, M.P. Hegarthy, L.F. James and R.F. Keeler (Ed.) Plant Toxicology p. 324, 1985. Queensland Poisonous Plants Committee, Queensland, Australia.

  • 14. Panter K.E., Keeler R.F., Bunch T.D. and Callan R.J.; Congenital skeletal malformations and cleft palate induced in goats by ingestion of Lupinus, Coium and Nicotiana species. Toxicon 28:1377, 1990a.

  • 15. Panter K.E., Keeler R.F., Bunch T.D. Sisson D.V. and Callan R.J.; Multiple

congenital contractures (MCC) and cleft palate induced in goats by ingestion of piperidine alkaloid-containing plants. Reduction in fetal movement as the probable cause. Clin. Toxicol. 28:69, 1990b.

Larsson | Some history and effects of Conium maculatum L.

  • 17. Panter K.E., Keeler R.F., Buck W. and Shupe J.L.; Toxicity and teratogenicity of in swine. Toxicon 20 (Suppl. 3): 333–336, 1983.

  • 18. Capithorne B.; Suspected poisoning of goats by hemlock (Conium maculatum); Vet. Rec. 49: 1018–1019, 1937.

  • 19. Jessup D., Boermans H. and Kock N; Toxicosis in tule elk caused by ingestion of poison hemlock. J. Am. Vet. Med. Assoc. 9: 1173–1175, 1986.

  • 20. Frank A. and Reed W.; Comparative toxicity of coniine, an alkaloid of Conium maculatum (poison hemlock), in chickens, quails, and turkeys; Avian Dis. 34: 433–437, 1990.

  • 21. Berenbaum R. and Harrison L.; Agonopterix alstroemeriana (Oecophoridae) and other lepidopteran associates of poison hemlock (Conium maculatum) in east central Illinois; Great Lakes Entomologist 27:1-5, 1994.

  • 22. Nitao, J.K.; Tests for toxicity of coniine to a polyphagous herbivore, Heliothis zea (Lepidoptera: Noctuidae). Environmental Entomology 16: 656–663, 1987.

  • 23. Crowden R.K., Harborne J.B.and Heywood V.H.; Chemosystematics of the Umbelliferae – a general survey, Phytochemistry 8: 1963-1984, 1969.

  • 24. Hegnauer R.; Chemical patterns and relationships of Umbelliferae. In: Heywood V.H., ed. The biology and chemistry of the Umbelliferae. London: Academic Press, 267-277, 1971.

  • 25. Nielsen B.E.; Coumarin patterns in the Umbelliferae. In: Heywood V.H., ed. The biology and chemistry of the Umbelliferae. London: Academic Press, 325- 336, 1971.

  • 26. Cromwell B.T.; the separation, micro-estimation and distribution of the alkaloids of hemlock (Conium maculatum L.). Biochemical Journal 64: 259- 266, 1956.

  • 27. Fairbairn J.W. and Challen S.B.; The alkaloids of hemlock (Conium maculatum L.). Distribution in relation to the development of the fruit. Biochemical Journal, 72: 556-561, 1959.

  • 28. Panter K.E., Keeler R.F. and Baker D.; Toxicoses in livestock from the hemlocks (Conium and Cicuta spp.). J. Anim. Sci. 66, pp. 2407–2413, 1988b.

  • 29. The Merck Index, Merck and Co., Whitehouse Station, pp. 423–424, 1996.

  • 30. Leete E. and Adityachaudhury N.; Ibid., 6, 219, 1967.

  • 31. Leete E.; J. Amer. Chem. Soc., 86, 2509, 1964.

  • 32. Anet E.F.L.J., Silk M.H. and Trippett S.; Oenanthotoxin and Cicutoxin. Isolation and Structures; J. Chem. Soc., 309-322, 1953.

  • 33. Starreveld E. and Hope E.; Cicutoxin Poisoning. Neurology, 25: 730-734,
    1975.

  • 34. Panter K. E., Gardner D. R., Shea R. E., Molyneux R. J. and James L. F.; Toxic and teratogenic piperidine alkaloids from Lupinus, Conium and Nicotiana species. In Toxic Plants and Other Natural Toxicants; Garland, T., Barr, A. C., Eds.; CAB International: New York, pp 345-350, 1998.

  • 35. Weinzweig J., Panter K. E., Pantaloni M., Spangenberger A., Harper J. S., Edstrom L.E., Gardner D. R. and Wierenga T.; The fetal cleft palate: I. Characterization of a congenital model. Plastic Reconstr. Surg., 103: 419-428, 1999a.

  • 36. Weinzweig J., Panter K. E., Pantaloni M., Spangenberger A., Harper J. S., Lui F., James L.F. and Edstrom L. E.; The fetal cleft palate: II. Scarless healing after in utero repair of a congenital model. Plastic Reconstr. Surg., 104: 1356- 1364, 1999b.

  • 37. Panter, K. E. and Keeler, R. F.; Induction of cleft palate in goats by Nicotiana

Larsson | Some history and effects of Conium maculatum L.

glauca during a narrow gestational period and the relation to reduction in fetal movement. J. Nat.Toxins, 1: 25-32, 1992.

  • 38. Panter K. E., Weinzweig J., Gardner D. R., Stegelmeier B. L. and James L. F.; Comparison of cleft palate induction by Nicotiana glauca in goats and sheep. Teratology, 61, 203-210, 2000.

  • 39. Keeler R. F., Balls L. D. and Panter K. E.; Teratogenic effects of Nicotianaglauca and concentration of anabasine, the suspect teratogen in plants; Cornell Vet., 71, 47-53, 1981.

  • 40. Keeler, R. F.; Coniine, a teratogenic principle from Conium maculatum producing congenital malformations in calves; Clin. Toxicol., 7: 195-206,
    1974.

  • 41. Keeler, R. F. and Crowe, M. W. Teratogenicity and toxictiy of wild tree tobacco, Nicotiana glauca in sheep. Cornell Vet., 74, 50-59, 1984.

  • 42. Panter K.E., Keeler R.F. and Buck, W.; Congenital skeletal malformations induced by maternal ingestion of Conium maculatum (poison hemlock) in newborn pigs. Am. Vet. Res. 46: 2064–2066, 1985a.

  • 43. Panter K. E., Keeler R. F. and Buck W. B.; Induction of cleft palate in newborn pigs by maternal ingestion of poison-hemlock (Conium maculatum). Am. J. Vet. Res., 46: 1368-1371, 1985b.

  • 44. Panter K. E., Bunch T. D., Keeler R. F. and Sisson D. V.; Radio ultrasound observations of the fetotoxic effects in sheep from ingestion of Conium maculatum (poison-hemlock). Clin .Toxicol., 26: 175-187, 1988a.

  • 45. Dixon W.E.; in Heffter’s Handbuch der Experimentellen Pharmakologie, Vol II, Part 2, p. 701, 1924.

  • 46. Sollman, 1975 Sollman T.; A Manual of Pharmacology; 8 th ed., p. 467, 1957, Philadelphia, Saunders.

  • 47. von Oettingen W.F.; The Therapeutic Agents of the Pyrrole and Pyridine Group, p. 85, Ann Arbor. Michigan: Edwards Brothers Inc., 1936.

  • 48. Taverner D.; Brit. J. Pharmacol. 7, 655-664, 1952.

  • 49. Bradley K., Easton W.M. and Eccles J.C.; Ibid., 122, 474-488, 1953.

  • 50. Eccles J.C., Fatt P. and Koketzu K.; J. Physiol. (Lond.); 126: 524-562, 1954.

  • 51. James L. F, Keeler R. F., Johnson A. E., Williams M. C., Cronin E. H. and Olsen J.D.; Plants Poisonous to Livestock in the Western States; AgricultureInformation Bulletin 415; U.S. Department of Agriculture: Washington, DC, pp. 90, 1980.

  • 52. Hulbert L. and Oehme F.W.; Conium maculatum (poison hemlock) In: Plants Poisonous to Livestock, 3rd ed. Kansas State University Press, Kansas, 1981.

  • 53. Everist S.; Umbelliferae. In: Poisonous Plants of Australia, 2nd ed. Angus and Robertson Publishers, Sidney, pp. 717–720, 1981.

  • 54. Forsyth A.A.; Conium maculatum. In: British Poisonous Plants. Her Majesty's Stationary Office, London, pp. 68–69, 1968.

  • 55. Galey F.D., Holstege D.M. and Fisher E.G.;. Toxicosis in dairy cattle exposed to poison hemlock (Conium maculatum) in hay: isolation of Conium alkaloids in plants, hay and urine; J. Vet. Diagn. Invest. 4, pp. 60–64, 1992.

  • 56. Hunt W. and Fosbinder R.; The anesthetic potency of some new piperidinederivatives; Anesthesiology 1: 305–311, 1940.

  • 57. Agricultural Research Service; 22 Plants Poisonous to Livestock in the Western States. Agriculture Information Bulletin No. 327. US Department of Agriculture, Washington, pp. 41–43, 1968.

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  • 58. Keeler R.F., Dell Balls, L., Shupe, J.L. and Ward Crowe, M.; Teratogenicity and toxicity of coniine in cows, ewes, and mares. Cornell Vet. 70: 19–26,

1980.

  • 59. Keeler R.F.; Toxins an teratogens of higher plants. Lloydia, 38: 56–86, 1975.

  • 60. Keeler, R.F. and Balls, Dell L.; Teratogenic effects in cattle of Conium maculatum and Conium alkaloids and analogues. Clin. Toxicol. 12: 49–64,

1978.

  • 61. Ober W.B.; Did Socrates die of hemlock poisoning? N. Y. State J. Med.,

 

77:254-258, 1977.

  • 62. Lewin L.; Die Gifte in der Weltgeschichte.

  • 63. Block, Enid; Hemlock Poisoning and the Death of Socrates. In: Thomas C. Brickhouse and Nicholas D. Smith; The Trial and Execution of Socrates; Oxford University Press, Oxford, New York, 2002.

  • 64. Simpson A. and Weiner C.; The Oxford English Dictionary, vol. 7. (second ed.), Clarendon Press, Oxford, 1989.

  • 65. Holm L.; World Weeds, Natural Histories and Distribution, Wiley, New York p. 1129, 1997.

  • 66. le Stragne R.; A History of Herbal Plants; Angus and Robertson, London,

1977.

  • 67. Zdanevich V. and Belodubrovskaya A.; Conum maculatum chemical

composition, useful and harmful properties. Rastitelnye Resursy 33, 108-113,

1997.

  • 68. James L. F.; History of USDA poisonous plant research; J. Nat. Toxins, 8: 3-

26, 1999.

  • 69. Howell E. and Mink I.; Viruses isolated from wild carrot and poison hemlock; Plant Diseases 65: 277–279, 1981.

  • 70. Parsons T.; Hemlock poisoning in cattle; Veterinary Record 42: 669–670,

1973.

Noxious Weeds of Victoria. Inkata Press, Melbourne, Australia.

  • 71. Panter E. and Keeler F.; Piperidine alkaloids of poison hemlock (Conium maculatum). In: Cheeke, P.R., Editor; Toxicants of Plant OriginAlkaloids vol. 1; CRC Press, Boca Raton, USA, pp. 109–132, 1989.

  • 72. Bowman W. C. and Sanghvi, I. S. Pharmacological actions of hemlock (Conium maculatum) alkaloids. J. Pharm. Pharmacol. 15: 1-25, 1963.

  • 73. Shepard, T. H.; Catalog of Teratogenic Agents, 9th ed.; The Johns Hopkins University Press: Baltimore, MD, p 593, 1998.

  • 74. del Castillo J. and Katz B.; J. Physiol. (Lond.), 128: 157-181, 1955.

  • 75. Schweitzer A. and Wright S.; J. Physiol. Lond., 94: 136-147, 1938.