Retronecine

155.196

155.19

2P5723M6II

Crystals from acetone

43.7

-0.56 @ 25 deg C /Estimated/

1.29±0.1 g/cm3(Predicted)

119-120 °C

80 °C @ Press: 0.01 Torr

In water, 8X10+5 mg/L @ 25 deg C /Estimated/

2-8°C

1.5X10-5 mm Hg @ 25 deg C /Estimated/

LD50 i.v. in mice: 634.0 ±26.0 mg/kg (Harris)

20D +4.95° (c = 0.58 in alc)

Henry's Law constant = 4.1X10-11 atm-cu m/mol @ 25 °C /Estimated/

pKa = 7.75 /Estimated/

Hydroxyl radical reaction rate constant = 1.2X10-10 cu cm/molec-sec /Estimated/

6.1(b)

1544

3

VH7175000

Stable at room temperature in closed containers; for long periods the substance is best stored under nitrogen at 15 deg C.

Readily hydrolysed with alkali, reacts with oxidizing agents (slowly with atmospheric oxygen) to form dihydropyrrolizine and other derivatives.

LD50 Mouse iv 634.0 + or - 26.0 mg/kg

MOST OF SENECIO SPECIES CONTAIN ALKALOIDS...KNOWN AS PYRROLIZIDINE ALKALOIDS...RETRORSINE /CONTAINS/ (RETRONECINE + ISATINECIC ACID). SENECIO JACOBAEA CONTAINS JACOBINE (RETRONECINE + JACOBINECIC ACID)... /SENECIO/

Lactating rats dosed with (3)H-retronecine excreted within 3 hr approx 0.08% of the applied radioactivity in the milk mainly as yet not identified water soluble retronecine-derived metabolites and approx 0.02% as unchanged pyrrolizidine alkaloids (pas). Highest tissue levels of pas and metabolites, 6 hr after admin were found in liver and lungs.

Steric hindrance around the ester groups was the major factor inhibiting hydrolysis of pyrrolizidine alkaloids. Enzymic hydrolysis of retronecine di-isovalerate occurred primarily at the allylic 9-ester group. The results supported the view that a factor contributing to the lower hepatotoxicity of semisynthetic retronecine diesters compared with some natural pyrrolizidine alkaloids, is their greater susceptibility to detoxication by hydrolysis.|Levels of pyrrolic metabolites were measured in the livers of rats given some pyrrolizidine alkaloids and semisynthetic derivatives. Structural and chemical features favoring the formation of such metabolites were defined. The most important of these were steric hindrance or chemical properties giving resistance to ester hydrolysis; lipophilic character, allowing access to hepatic microsomal enzymes; a conformation favoring microsomal oxidation of the pyrroline ring in preference to n-oxidation.|Levels of pyrrolic metabolites were measured in the livers of rats given some pyrrolizidine alkaloids and semisynthetic derivatives. ... Heliotridine-based alkaloids gave more pyrrole than similar retronecine esters, heliotridine ditiglate gave less pyrrole than retronecine ditiglate because the former was more open to hydrolytic attack.

Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/|Presentation depends on the active toxic agent. In most cases, vomiting, abdominal pain, and diarrhea occur within 60 to 90 minutes of significant ingestion. With some toxins, severe gastroenteritis may result in massive fluid and electrolyte loss. ... Maintain open airway and assist ventilation if necessary. Administer supplemental oxygen. Treat coma, seizures, arrhythmias, and hypotension if they occur. Replace fluid loss caused by gastroenteritis with intravenous crystalloid solutions. ... Administer activated charcoal if available ... Gastric emptying is not necessary if activated charcoal is given promptly. /Plants and Herbal Medicines: Group 1/

/HUMAN EXPOSURE STUDIES/ The two main sources of pyrrolizidine alkaloid poisoning reported in human beings are the consumption of cereal grain contaminated by weeds containing the alkaloids and the use of alkaloid-containing herbs for medicinal and dietary purposes. ...Three of the largest outbreaks of the disease have been reported from South Asia, two from the same site in central India and one from North-West Afghanistan. The first Indian outbreak... occurred in a group of 5 tribal villages in central India in 1972-73. ...Out of a total population of 2,060 in these villages, 71 households with 366 members were investigated. Among these, 39 cases had developed and 19 had died before commencement of the investigations. The incidence rate was 1.1% and the case fatality rate was 50%. All cases occurred among 20 households. In many households, several members were affected. In one household, 4 out of 5 cases died. ...The etiological factor of this outbreak was not established, though dietary contamination with pyrrolizidine alkaloids was considered. A second outbreak occurred at the same site in 1975... . A total population of 486 was affected, 67 cases were reported, of whom 28 (46%) had died. There was a strong family history... . In a later survey, 108 patients were studied and the mortality rate was estimated to be 63%. This time the etiological factor was identified as the plant Crotalaria nana Burm, which had been growing in the fields of millet (Panicum miliare), their staple food crop. The seeds of this plant became mixed with the cereal grain during harvesting. The toxic seeds contained pyrrolizidine alkaloids that were identified as a macrocyclic ester closely similar to monocrotaline. The total alkaloid content was estimated to be 5.3 g/kg of seed, expressed as monocrotaline. The levels of contamination of the millet with seeds were reported to be 0-3.4 g/kg in the unaffected and 0-19 g/kg in the affected households... . /Pyrrolizidine alkaloids/|/HUMAN EXPOSURE STUDIES/ The largest outbreak reported to date occurred in the Gulran district of Herat Province in northwest Afghanistan, close to the border of the USSR. ...The outbreak, was estimated to have affected a population of approximately 35,000 in 98 villages. Examination of 7,200 inhabitants of the affected villages showed evidence of disease in 22.6%, which was more serious in 15%. Thus, it was estimated that approximately 8,000 subjects suffered from the disease including 5,000 who were seriously affected. All age groups were affected, but 46% of subjects were below 14 years of age. However, no sign of disease was found in children below 2 years of age. A detailed report concerning the pathological material obtained from 14 liver biopsies and 8 autopsies was made... /although/ the time interval between the onset of symptoms and the biopsy/autopsy was not indicated. Pathological findings were characteristic, ranging from acute disease with characteristic veno-occlusion to non-portal cirrhosis, which was observed in 5 of the above 22 cases. The outbreak was ascribed to massive contamination of wheat, the staple food crop, following 2 years of drought, with the seeds of Heliotropium popovii H. Riedl subsp. gillianum H. Riedl, which had been growing profusely among the wheat crop. The seeds contained pyrrolizidine alkaloids at concentrations reported by 2 laboratories to be 7.2 and 13.2-14.9 g/kg, identified mainly as the N-oxide of heliotrine (74%)..., and one or two other compounds similar in character to lasiocarpine. Samples of wheat from several villages contained an average of 40 seeds/kg, i.e., 0.03% by weight. It was estimated that an adult consumed at least 700 g flour/day, containing approximately 2 mg alkaloid (based on a mean of the seed analyses). /Pyrrolizidine alkaloids/

heliotridine

... /Senecio/ isatideus is a high-yielding source suitable for preparative purposes.|The most common base portion of pyrrolizidine alkaloids.

A PROCEDURE WAS DEVELOPED FOR THE ANALYSIS OF PYRROLIZIDINE ALKALOIDS IN MILK. RETRONECINE WAS DETERMINED BY ELECTRON CAPTURE GAS CHROMATOGRAPHY. SENSITIVITY OF THE METHOD WAS EST TO BE 0.1 PPM.|THE ANALYSIS OF PLANT MATERIAL FOR PYRROLIZIDINE ALKALOIDS IS BASED ON A GENERAL PROCEDURE FOR EXTRACTION OF THE TERTIARY BASE ALKALOIDS BEFORE AND AFTER REDUCTION OF THE ALKALOID N-OXIDES WHICH ARE ALSO USUALLY PRESENT. THE DIFFERENCE IN THE TWO RESULTS IS AN APPROXIMATE MEASURE OF THE N-OXIDE CONTENT OF THE PLANT MATERIAL. THE LEVELS OF BOTH TERTIARY BASE AND N-OXIDE FORMS OF THE ALKALOID ARE RELEVANT TO AN EVALUATION OF THE TOXICITY OF THE PLANT MATERIAL. THE INDIVIDUAL BASES ARE SEPARATED AND ESTIMATED BY PARTITION CHROMATOGRAPHY OR THIN-LAYER, PAPER OR GAS CHROMATOGRAPHY. /PYRROLIZIDINE ALKALOIDS/|PYRROLIZIDINE ALKALOIDS, UNSATURATED AT THE 1,2 POSITION, WERE DETECTED FOLLOWING TLC DIRECT OXIDATION TO PYRROLES BY USING O-CHLORANIL, FOLLOWED BY SPRAYING WITH EHRLICH'S REAGENT. N-OXIDES WERE DETECTED BY SPRAYING WITH AC20 FOLLOWED BY EHRLICH'S REAGENT. /PYRROLIZIDINE ALKALOIDS/|Underivatized pyrrolizidine alkaloids ... from natural sources (plants and insects) have been analysed by capillary gas chromatography-mass spectrometry. Thin-layer chromatography (TLC) and nuclear magnetic resonance (NMR) spectroscopy have also been used to detect pyrrolizidine alkaloids in plant extracts. /Pyrrolizidine Alkaloids/

Pyrrolizidine alkaloids may be estimated in animal tissues and fluids by removing protein, chromatographing on Florisil and estimating colorimetrically with methyl orange. /Pyrrolizidine Alkaloids/