piperidines and Abnormalities--Drug-Induced

Piperidine alkaloids are acutely toxic to adult livestock species and produce musculoskeletal deformities in neonatal animals. These teratogenic effects include multiple congenital contracture (MCC) deformities and cleft palate in cattle, pigs, sheep, and goats. Poisonous plants containing teratogenic piperidine alkaloids include poison hemlock (Conium maculatum), lupine (Lupinus spp.), and tobacco (Nicotiana tabacum) [including wild tree tobacco (Nicotiana glauca)]. There is abundant epidemiological evidence in humans that link maternal tobacco use with a high incidence of oral clefting in newborns; this association may be partly attributable to the presence of piperidine alkaloids in tobacco products. In this review, we summarize the evidence for piperidine alkaloids that act as teratogens in livestock, piperidine alkaloid structure-activity relationships and their potential implications for human health.

Topics: Abnormalities, Drug-Induced; Alkaloids; Animals; Animals, Domestic; Health; Humans; Nicotiana; Piperidines; Structure-Activity Relationship; Teratogens

The recent expansion of electronic health and medical record systems may present an opportunity to generate robust post-approval safety data and obviate the limitations of prospective pregnancy exposure registries. We examined and compared, over the same time frame, the outcomes of triptan exposure in pregnancy using (1) a retrospective claims database and (2) a previously completed pregnancy registry.. Using the Marketscan database, the risk of major birth defects was ascertained in live-born infants whose birth mothers were exposed to sumatriptan, naratriptan, or sumatriptan/naproxen during pregnancy. The frequencies of outcomes observed were compared with the findings of the 16-year sumatriptan, naratripan, and sumatriptan/naproxen prospective pregnancy registry.. About 5120 pregnancies were identified in the retrospective claims cohort in contrast to 617 included in the prospective registry during the same time frame. The proportion of major birth defects among first-semester sumatriptan exposures was 4.0%, which is exactly the same as the proportion of major birth defects reported for first-semester sumatriptan exposures in the registry. There were very few non-livebirth outcomes in both the claims analyses and registry.. These results confirm broad agreement between the database analysis and the registry regarding the safety of triptans during pregnancy. Of note, the number of triptan-exposed pregnancies identified in this large US database was about 7-fold that included in the prospective registry over the same time frame. The findings of this study support an approach of using existing health care database (s) in the post-approval assessment of medication exposure in pregnancy.

Topics: Abnormalities, Drug-Induced; Administrative Claims, Healthcare; Adolescent; Adult; Databases, Factual; Drug Combinations; Electronic Health Records; Female; Humans; Infant, Newborn; Migraine Disorders; Naproxen; Piperidines; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prospective Studies; Registries; Retrospective Studies; Sumatriptan; Tryptamines; United States; Young Adult

The objective of this study was to investigate the human teratogenic potential of oral prenoxdiazine treatment during pregnancy. The analysis of cases with congenital abnormalities and their matched controls without congenital abnormalities was performed in the large population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996. Of the 22,843 pregnant women who had offspring with congenital abnormalities, 158 (0.7%) were treated with prenoxdiazine. Of the 38,151 pregnant women who had babies without any defects in the study period (control group), 226 (0.6%) were treated with prenoxdiazine (adjusted prevalence odds ratio, 1.0; 95% confidence interval, 0.8-1.3). The comparison of cases and their matched controls did not show a significantly higher rate of prenoxdiazine treatment during the second and third months of gestation in the total (adjusted prevalence odds ratio, 1.4; 95% confidence interval, 0.9-2.2) or in any group of congenital abnormalities. Treatment with prenoxdiazine during pregnancy did not have any teratogenic risk to the fetus. Thus, prenoxdiazine treatment in pregnant women with an unproductive cough may be beneficial.

Topics: Abnormalities, Drug-Induced; Administration, Oral; Adult; Bacterial Infections; Case-Control Studies; Female; Humans; Hungary; Piperidines; Pregnancy; Pregnancy Complications; Pregnancy Trimester, Second; Pregnancy Trimester, Third

The objective of this prospective multicenter study was to determine whether cisapride is associated with increased risk of malformations, spontaneous abortions, or decreased birthweight when used during pregnancy. Cases were paired for age, smoking, and alcohol consumption with controls exposed to nonteratogens, as well as with disease-paired controls. One hundred and twenty-nine pregnant women were exposed to cisapride during pregnancy, including 88 during the period of fetal organogenesis. There were no differences in maternal history, birthweight, gestational age at delivery, and rates of livebirths, spontaneous or therapeutic abortions, fetal distress, and major or minor malformations among groups. It is concluded that exposure to cisapride during pregnancy is not associated with a major increased risk of malformations or spontaneous abortions or with decreased birthweight.

Topics: Abnormalities, Drug-Induced; Abortion, Spontaneous; Adult; Birth Weight; Case-Control Studies; Cisapride; Cohort Studies; Female; Gastrointestinal Agents; Humans; Infant, Newborn; Piperidines; Pregnancy; Pregnancy Complications; Prospective Studies; Risk Factors

Coniine, an alkaloid from Conium maculatum (poison hemlock), is a known teratogen in many domestic species with maternal ingestion resulting in arthrogryposis of the offspring. We have previously shown that rats are not susceptible and rabbits only weakly susceptible to coniine-induced arthrogryposis. However, the chick embryo does provide a reproducible laboratory animal model of coniine-induced teratogenesis. The reason for this cross-species variation is unknown. The purpose of this study was to evaluate coniine binding to nicotinic receptors and to measure coniine metabolism in vitro between susceptible and non-susceptible species. Using the chick model, neither the peripheral nicotinic receptor antagonist d-tubocurarine chloride nor the central nicotinic receptor antagonist trimethaphan camsylate blocked the teratogenesis or lethality of 1.5% coniine (50 microliters/egg). Trimethaphan camsylate enhanced coniine-induced lethality in a dose-dependent manner. Neither nicotinic receptor blocker prevented nicotine sulfate-induced malformations but d-tubocurarine chloride did block lethality in a dose-dependent manner. Competition by coniine for [125I]-alpha-bungarotoxin to nicotinic receptors isolated from adult rat diaphragm and chick thigh muscle and competition by coniine for [3H]-cytisine to receptors from rat and chick brain were used to assess coniine binding to nicotinic receptors. The IC50 for coniine in rat diaphragm was 314 microM while that for chick leg muscle was 70 microM. For neuronal nicotinic receptors, the IC50s of coniine for maternal rat brain, fetal rat brain, and chick brain were 1100 microM, 820 microM, and 270 microM, respectively. There were no differences in coniine biotransformation in vitro by microsomes from rat or chick livers. Differences in apparent affinity of coniine for nicotinic receptors or differences in the quantity of the nicotinic receptor between the rat and chick may explain, in part, the differences in susceptibility of coniine-induced teratogenesis between these two species.

Topics: Abnormalities, Drug-Induced; Alkaloids; Analgesics; Animals; Biotransformation; Brain; Chick Embryo; Embryo, Nonmammalian; Male; Microsomes, Liver; Muscle, Skeletal; Nicotinic Antagonists; Piperidines; Rats; Rats, Sprague-Dawley; Survival Rate

The teratogenic potential of cis-1-[4-(p-menthane-8-yloxy)phenyl] [corrected] piperidine (YM9429) was evaluated using CD (SD) rats. YM9429 induced cleft palate and specific skeletal variations including accessory cervical and lumbar ribs or excessive formation of the 7th lumbar vertebra by oral treatment during the organogenetic periods. No visceral or external malformations were induced, and no embryo/fetal mortality or fetal growth retardation was observed. Maternal plasma biochemical examination revealed decreases of cholesterol and phospholipid levels during days 15-17 of pregnancy after the treatment. The results suggest that YM9429 is a potent and specific teratogen inducing cleft palate in CD rats, and the reduced maternal plasma levels of cholesterol and phospholipid during the period of palatine closure are related to the induction of cleft palate.

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Animals; Cholesterol; Cleft Palate; Female; Fetus; Lumbar Vertebrae; Phospholipids; Piperidines; Pregnancy; Rats; Rats, Sprague-Dawley; Ribs; Teratogens

Conium maculatum (poison hemlock, CM) is teratogenic in several domestic species, presumably due to its piperidine alkaloids, including coniine, which has been verified to be teratogenic in cattle. Coniine/CM teratogenicity culminates in production of arthrogryposis. The purpose of this study was to evaluate coniine-induced teratogenicity in two laboratory animal species, Sprague-Dawley rats and New Zealand white rabbits. Pregnant rats were given coniine (25 mg/kg body weight) by oral gavage at 8-hour intervals on gestation days 16-18. Pregnant rabbits were given coniine (40 mg/kg body weight) by oral gavage at 8-hour intervals on gestation days 20-24. Rats were killed on day 19 and rabbits on day 29. Fetuses were immediately removed, weighed, and examined for external abnormalities. Alternate fetuses were either stained for skeletal examinations with alizarin red-S or fixed in Bouin's solution for visceral examination. Symptoms of maternal intoxication due to coniine administration were observed in both the rat and the rabbit, and higher doses were uniformly lethal. Rabbits treated with coniine appeared to lose more weight and eat less than controls, but there was no statistically significant difference between groups. Fetal weights were significantly lower in coniine-exposed rat and rabbit fetuses indicating fetotoxicity. The only statistically significant treatment-related visceral or skeletal malformation was a reduction of cranial ossification of rabbit fetuses, probably related to maternal toxicity. Coniine-exposed rabbit litters tended to be affected by arthrogryposis (no bony deformities noted on skeletal exam) more than controls (2/6 vs. 0/9).

Topics: Abnormalities, Drug-Induced; Alkaloids; Animals; Arthrogryposis; Birth Weight; Feeding Behavior; Female; Fetal Death; Litter Size; Piperidines; Pregnancy; Rabbits; Rats; Rats, Sprague-Dawley; Teratogens

Fetal movement, observed by ultrasound imaging, was significantly reduced (P less than or equal to 0.001) in pregnant goats gavaged with Conium seed and Nicotiana glauca and temporarily reduced with fresh Conium plant. Conium seed and Nicotiana glauca induced cleft palate and multiple congenital contractures in 100% of the kids born to pregnant goats gavaged with these plants. Multiple congenital contractures included torticollis, scoliosis, lordosis, arthrogryposis, rib cage anomalies, over extension, and flexure and rigidity of the joints. However, in goats gavaged with fresh Conium plant, fetal movement was inhibited for only about 5 hours after each individual dosage and gradually returned to control levels 12 hours after dosing. Fetal malformations in this group were limited from modest to moderate contractures of the front limbs, which resolved by 8-10 weeks post partum. No cleft palates were induced. Fetal movement was not inhibited in goats fed Lupinus caudatus and no cleft palates or multiple congenital contractures were induced in their offspring. The duration of the reduction in fetal movement appears to be an important factor in the severity and permanence of the deformities, particularly with cleft palate, spinal column defects, and severe joint deviation and fixation.

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Administration, Oral; Alkaloids; Animals; Cleft Palate; Female; Fetal Movement; Goats; Maternal-Fetal Exchange; Piperidines; Pregnancy

Topics: Abnormalities, Drug-Induced; Animals; Antidepressive Agents; Body Weight; Dose-Response Relationship, Drug; Female; Litter Size; Paroxetine; Piperidines; Pregnancy; Pregnancy, Animal; Rabbits; Rats; Serotonin Antagonists

A congenital deformity condition called crooked calf disease, of widespread occurrence in western North America, is known to be induced by maternal ingestion during gestation of certain members of the Lupinus genus containing the quinolizidine alkaloid teratogen anagyrine. Because some piperidine alkaloids from other sources induce a similar condition, we have investigated the alkaloid composition and teratogenicity of Lupinus formosus, reported by others to be low in quinolizidines but rich in the type of piperidine alkaloids that we have speculated would be teratogenic. GC/MS analysis of L. formosus showed seven major and nine minor components in the total alkaloid fraction. All seven major and five of the nine minor components, representing all but 3% of the fraction, were identified by mass spectrometric fragmentation patterns and GC retention times. They included several potentially teratogenic piperidine alkaloids (including a very large amount of ammodendrine), as well as several nonteratogenic quinolizidine alkaloids plus a trace (at nonteratogenic levels) of the known quinolizidine teratogen anagyrine. The plant induced severe crooked calf disease with limb, spinal, and palate involvement in experimental calves. The deformities are believed to have been induced by ammodendrine.

Topics: Abnormalities, Drug-Induced; Alkaloids; Animals; Cattle; Female; Limb Deformities, Congenital; Maternal-Fetal Exchange; Piperidines; Plants, Toxic; Pregnancy; Pregnancy Outcome; Spine

Nicotiana glauca, wild tree tobacco, induces arthrogrypotic congenital defects in piglets similar to those induced by Nicotiana tabacum, common tobacco. The present work was conducted to isolate the principal alkaloid of N. glauca, anabasine, in large quantity and good purity and to test the teratogenicity of the compound in pigs. The isolated compound was established to be anabasine and to be of suitable purity by chemical characterization. It proved to be teratogenic. Typical arthrogrypotic defects were induced in 21 of 26 offspring (three of three litters) when dams ingested 2.6 mg of the compound per kg body weight twice daily during the 43rd-53rd days of gestation. Of three dams dosed with 1.66 g/kg/day of the dried plant material during the 43rd-53rd days, one delivered deformed offspring representing one-third of all offspring in that group. These arthrogrypotic defects induced by anabasine were indistinguishable clinically from defects induced by either N. glauca or N. tabacum. In addition, anabasine at a dose of 2.6 mg/kg twice daily or N. glauca plant material at 1.66 gm/kg daily induced cleft palate in over three-fourths of offspring (100% of litters) when dams ingested either during the 30th-37th days of gestation or during longer periods that included those days.

Topics: Abnormalities, Drug-Induced; Anabasine; Animals; Arthrogryposis; Chromatography, Gas; Female; Gestational Age; Magnetic Resonance Spectroscopy; Mass Spectrometry; Nicotiana; Piperidines; Plants, Toxic; Pregnancy; Swine

Collections of Nicotiana glauca containing from 0.45-1.14 mg anabasine per gram dry weight of plant induced moderate - severe toxic signs in pregnant ewes and teratogenic effects in their offspring when the ewes were given single daily doses of the plant that provided from 1.66 - 3.42 mg anabasine per kg body weight. Toxic signs included excess salivation, irregular gait, wobbling while walking or standing, recumbency and death. Teratogenic effects occurred in offspring from animals fed those doses the 30th - 60th day of gestation. Terata expression included limb defects such as a fixed excessive carpal flexure with or without lateral or medial rotation of fore or rear limbs, lordosis, irregular shaped head or cleft palate.

Topics: Abnormalities, Drug-Induced; Alkaloids; Anabasine; Animals; Cattle; Cattle Diseases; Female; Gas Chromatography-Mass Spectrometry; Limb Deformities, Congenital; Male; Nicotiana; Piperidines; Plant Poisoning; Plants, Toxic; Pregnancy; Sheep; Sheep Diseases; Swine; Swine Diseases

Cows, ewes, and mares varied considerably in susceptibility to toxicoses from the oral administration of the piperidine alkaloid, coniine. Cows were most susceptible and ewes least. Only calves had teratogenic effects from maternal administration of coniine during gestation; lambs and foals were apparently resistant. Results suggest that the marked differences between cattle and sheep are probably not due to variation in gut absorption or rumen metabolism.

Topics: Abnormalities, Drug-Induced; Administration, Oral; Alkaloids; Animals; Ataxia; Cattle; Cattle Diseases; Female; Horse Diseases; Horses; Piperidines; Plants, Toxic; Pregnancy; Sheep; Sheep Diseases

Administration of Nicotiana glauca to four cows from the 50th to the 75th days of gestation induced congenital deformities in their calves. All four calves had arthrogryposis of forelimbs and one also had spinal curvature and rib cage deformity. The plant material contained 0.113% of the piperidine alkaloid anabasine as authenticated by gas chromatography and by infrared spectroscopy. Because of the presence of anabasine at a high concentration and because of its structural relationship to known teratogens, anabasine may be responsible teratogen.

Topics: Abnormalities, Drug-Induced; Anabasine; Animal Feed; Animals; Arthrogryposis; Cattle; Cattle Diseases; Dose-Response Relationship, Drug; Female; Piperidines; Plants; Pregnancy; Ribs; Spine; Teratogens

The plant Conium maculatum produced congenital defects in calves born to cows gavaged the fresh green plant during days 50-75 of gestation. Both arthrogryposis and spinal curvature were produced and were similar to the defects produced by the piperidine alkaloid coniine. The arthrogrypotic manifestations of the condition markedly increased in severity as the animals aged. Animals gavaged dry plant had either normal or equivocally deformed offspring. A number of chain length and ring saturation analogs of coniine were not teratogenic. No congenital defects arose in offspring from maternal inhalation of either the teratogenic alkaloid coniine, or from the teratogenic green plant.

Topics: Abnormalities, Drug-Induced; Alkaloids; Animals; Arthrogryposis; Cattle; Cattle Diseases; Female; Piperidines; Plants, Toxic; Pregnancy; Structure-Activity Relationship

Topics: Abnormalities, Drug-Induced; Animals; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Drug Evaluation, Preclinical; Female; Fetus; Hypnotics and Sedatives; Imides; Injections, Intraperitoneal; Mice; Piperidines; Piperidones; Pregnancy; Rats; Teratogens; Thalidomide

Topics: Abnormalities, Drug-Induced; Alkaloids; Animals; Animals, Newborn; Cattle; Chromatography, Gas; Female; Mass Spectrometry; Piperidines; Plant Poisoning; Plants; Pregnancy; Sheep

Topics: Abnormalities, Drug-Induced; Alkaloids; Animals; Female; Furans; Glycosides; Piperidines; Plants, Medicinal; Plants, Toxic; Pregnancy; Pyridines; Rats; Spiro Compounds; Steroids; Vegetables; Veratrum

Topics: Abnormalities, Drug-Induced; Animals; Bone and Bones; Bone Diseases, Developmental; Female; Fetal Death; Fetal Diseases; Forelimb; Gestational Age; Haplorhini; Hindlimb; Injections, Intravenous; Macaca; Piperidines; Pregnancy; Pyrrolidinones; Rabbits; Rats; Species Specificity; Spine; Thalidomide; Time Factors; Wrist

Topics: Abnormalities, Drug-Induced; Animals; Cats; Cattle; Chromosome Aberrations; Chromosome Disorders; Disease Models, Animal; Dogs; Ehlers-Danlos Syndrome; Freemartinism; Genetic Diseases, Inborn; Genetic Linkage; Heart Defects, Congenital; Humans; Immunologic Deficiency Syndromes; Karyotyping; Leukocytes; Mercury Poisoning; Mink; Mosaicism; Nicotiana; Piperidines; Plant Extracts; Plant Poisoning; Plants, Medicinal; Plants, Toxic; Sheep; Swine; Veratrum

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Animals; Azepines; Chick Embryo; Hindlimb; Imidazoles; Neuromuscular Junction; Nicotine; Piperidines; Pyridines; Pyrimidines; Spine; Structure-Activity Relationship

Topics: Abnormalities, Drug-Induced; Animals; Antitussive Agents; Female; Fetus; Gestational Age; Piperidines; Pregnancy; Pregnancy, Animal; Rats

Topics: Abnormalities, Drug-Induced; Animals; Cyclohexanes; Female; Fetal Death; Fetus; Hypnotics and Sedatives; Organ Size; Piperidines; Pregnancy; Rabbits; Uterus

Topics: Abdominal Muscles; Abnormalities, Drug-Induced; Animals; Embryo, Mammalian; Female; Fetal Death; Hernia; Hypnotics and Sedatives; Limb Deformities, Congenital; Meningocele; Piperidines; Pregnancy; Rabbits; Tail; Thalidomide

Topics: Abnormalities, Drug-Induced; Anesthetics; Animals; Anura; Chick Embryo; Depression, Chemical; Embryo, Nonmammalian; Female; Lysergic Acid Diethylamide; Mescaline; Models, Biological; Phencyclidine; Piperidines; Pregnancy; Pregnancy, Animal; Psilocybin

Topics: Abnormalities, Drug-Induced; Animals; Female; Humans; Mice; Piperidines; Piperidones; Pregnancy; Pregnancy, Animal; Rabbits; Research; Thalidomide; Toxicology

Topics: Abnormalities, Drug-Induced; Animals; Female; Humans; Pharmacology; Piperidines; Pregnancy; Rabbits; Research; Thalidomide; Toxicology

Topics: Abnormalities, Drug-Induced; Anti-Allergic Agents; Caffeine; Fetal Death; Histamine H1 Antagonists; Mice; Piperidines; Pregnancy; Pregnancy, Animal; Research; Thalidomide; Theophylline; Toxicology