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PubMed1985

Effects of chlordimeform on cardiovascular functional parameters: Part 1. Lethality and arrhythmogenicity in the geriatric rat.

Chlordimeform (CDM), a formamidine pesticide, had a profound effect on the cardiovascular function of geriatric rats. Two-year-old pentobarbital-anesthetized Sprague-Dawley rats (n = 8) received sequential intravenous CDM injections of 5, 10, 30, and 60 mg/kg. A control group of rats (n = 8) received multiple injections of normal saline vehicle over a similar time period, followed by a single CDM injection of 60 mg/kg. Heart rate (HR), arterial blood pressure (BP), and electrocardiogram (ECG) were monitored for all animals. CDM produced abrupt decreases in HR and BP at all doses. In addition, striking changes in ECG waveforms and intervals and various conduction-related arrhythmias were observed. These acute effects triggered a reflex-mediated overshoot in HR and BP above preinjection levels, followed by a delayed, persistent depression of these parameters. Three animals from the CDM-treated group died after injection of the 30-mg/kg dose, while 60 mg/kg was lethal in the remaining animals. In the majority of cases, death appeared to be due to cardiac arrest.

Aging↗
PubMed1986

Effects of chlordimeform on cardiovascular functional parameters: Part 2. Acute and delayed effects following intravenous administration in the postweanling rat.

The effects of intravenous (iv) administration of chlordimeform (CDM) were investigated in 22- to 30-d-old pentobarbital-anesthetized Sprague-Dawley rats. Animals (n = 25) were given sequential iv injections of 5, 10, 30, 60, and 120 mg CDM/kg, or normal saline vehicle followed by a single injection of 60 mg CDM/kg. Heart rate (HR), arterial blood pressure (BP), and electrocardiogram (ECG) were monitored for all animals, while body temperature was maintained at control levels (37 degrees C). CDM produced profound acute effects on all cardiovascular parameters monitored and persistent delayed effects on HR and BP. These effects were similar to but less severe than those observed in a previous study using geriatric animals. Younger animals also appeared to be more resistant to the lethal actions of CDM.

Amidines↗
PubMed1986

Effects of chlordimeform on cardiovascular functional parameters: Part 3. Comparison of different routes of administration in the postweanling rat.

The effects of intraperitoneal (ip) administration of chlordimeform (CDM) were investigated in 22- to 24-d-old pentobarbital-anesthetized Sprague-Dawley rats. Animals (n = 32) received a single ip injection of CDM at either 10, 30, or 60 mg/kg, or of normal saline vehicle. Heart rate (HR) and electrocardiogram (ECG) were monitored for all animals, while body temperature was maintained at control levels (37 degrees C). HR decreased 21-29% in the treated animals, and there were no differences observed across dose groups or over time. ECG effects were confined to rate-related changes only. The decrease in HR produced by CDM in these animals was comparable to the delayed HR effect seen in previous studies from this laboratory, despite major differences in dosing regimens and routes of administration.

Amidines↗
PubMed1989

Modulating effect of body temperature on the toxic response produced by the pesticide chlordimeform in rats.

Previous studies from this laboratory have demonstrated significant deficits in cardiovascular function in rats exposed to the pesticide chlordimeform (CDM) when body core temperature (TCO) was maintained at 37 degrees C. To investigate the role of TCO on CDM toxicity, similar experiments were conducted over a range of TCO values. Adult rats (n = 30) were anesthetized with sodium pentobarbital (35 mg/kg) and randomly assigned to one of six equal groups. Groups were paired and TCO was maintained in the rats in each of the respective group pairs at one of three levels (37, 35, or 33 degrees C). Rats in one group at each temperature level (groups T37, T35, and T33) were injected intraperitoneally with 60 mg/kg of CDM. Animals in the corresponding temperature-matched groups (groups C37, C35, and C33, respectively) received volume-matched injections of normal saline vehicle and served as time-paired controls. The electrocardiogram and heart rate (HR) were monitored throughout the experimental procedure. There was a significant decrease in HR in all CDM-treated groups when compared to the control group animals. The magnitude of the observed cardiac effect was attenuated in the T35 group when compared to that of the other treated groups. Similarly, lethality rates (number of deaths/total) for the T37, T35, and T33 groups were 2/5, 0/5, and 3/5, respectively; there were no deaths among the control-group animals. From these and previous data from this laboratory, we conclude there may be a beneficial effect of moderate hypothermia in rats exposed to toxic agents while more severe hypothermia appears to offer no advantage and may actually exacerbate the toxic effect.

Amidines↗
PubMed1991

The formamidine pesticides chlordimeform and amitraz decrease hepatic glutathione in mice through an interaction with alpha 2-adrenoceptors.

Recent studies have provided evidence that formamidine pesticides, such as chlordimeform (CDM; N'-4-chloro-o-tolyl-N,N-dimethylformamidine) or amitraz (AMZ; N'-2-4-(dimethylphenyl)-N-[((2,4-dimethylphenyl)imino)methyl]-N- methanimidamide) exert some of their toxic effects by an interaction with alpha 2-adrenoceptors. Since epinephrine and clonidine have been shown to decrease hepatic glutathione (GSH) by activating alpha 2-adrenoceptors, and alpha 2-antagonists partially antagonize GSH depletion and hepatotoxicity caused by bromobenzene and cocaine, we have investigated whether the formamidines would affect hepatic GSH levels in mice. Both CDM and AMZ decreased hepatic nonprotein sulfydryls (NPSH) to a maximum of about 40%, in a dose-dependent manner. The effect of AMZ was longer lasting than that of CDM. For both compounds, decrease of hepatic NPSH was antagonized by the alpha 2-antagonist yohimbine but not by the alpha 1-antagonist prazosin or the beta-antagonist propanolol. The alpha 2-agonist clonidine also caused a dose-dependent decrease of hepatic NPSH (to a maximum of 40%), which was prevented only by yohimbine. The effects of AMZ, CDM, and clonidine were not additive, suggesting that all compounds act on a common site and/or with a common mechanism. Adrenalectomy or destruction of peripheral sympathetic nerves with 6-hydroxydopamine did not alter the ability of CDM and AMZ to decrease hepatic NPSH. These results indicate that formamidine pesticides can affect the levels of hepatic GSH, possibly through a direct interaction with hepatic alpha 2-adrenoceptors.

Animals↗
PubMed1990

Formamidines as synergists of cypermethrin in susceptible and pyrethroid resistant house flies (Diptera: Muscidae).

Mechanisms of formamidine synergism of pyrethroid insecticides were investigated in the house fly, Musca domestica L. A bioassay method was developed to show formamidine synergism of cypermethrin in adult house flies. Flies were exposed to a residue of cypermethrin with and without formamidine for 30 min and then transferred to a clean container. Mortality was recorded 24 h later. Synergism of cypermethrin occurred in flies exposed simultaneously to cypermethrin plus formamidines and in flies exposed to cypermethrin either before or after exposure to a formamidine. Synergism ranged up to 11.8-fold and was greater in susceptible than in resistant house flies. A monomeric derivative of amitraz (BTS 27271) was the most active synergist, chlordimeform was intermediate, and amitraz was least active. Synergism of cypermethrin also occurred in flies injected with octopamine and then exposed to cypermethrin, suggesting that formamidines may be acting as octopamine agonists. Measurements of the effects of formamidines on uptake of cypermethrin showed that BTS 27271 increased uptake less than chlordimeform and that amitraz had almost no effect. Both target site and behavioral effects are discussed as possible mechanisms of formamidine synergism of cypermethrin and other pyrethroids.

Amidines↗
PubMed1986

Biological monitoring of agricultural workers exposed to pesticides: II. Monitoring of intact pesticides and their metabolites.

Analytical methods have been developed for the detection of a variety of compounds that are found intact or as metabolites in biological samples from workers exposed to pesticides. Such tests are used primarily in research settings to describe patterns of absorption, metabolism, and excretion, to derive exposure limits for occupational exposure, to evaluate the adequacy of these limits and of work practices in field settings, and to confirm the etiology of poisonings for medicolegal purposes. We review here methods used in studies of occupational pesticide exposure, with particular attention to validation in terms of dose-response relationships, to technical complexity and cost, to the requirements for analytical quality control, and to the utility of these methods for field research purposes. Biological monitoring for intact pesticides or metabolites in agricultural workers is limited to a few chemicals, notably, pentachlorophenol, methyl bromide, and chlordimeform. These programs and their use in regulation and enforcement are described.

Agricultural Workers' Diseases↗
PubMed1995

The effects of phenelzine and other monoamine oxidase inhibitor antidepressants on brain and liver I2 imidazoline-preferring receptors.

1. The binding of [3H]-idazoxan in the presence of 10(-6) M (-)-adrenaline was used to quantitate I2 imidazoline-preferring receptors in the rat brain and liver after chronic treatment with various irreversible and reversible monoamine oxidase (MAO) inhibitors. 2. Chronic treatment (7-14 days) with the irreversible MAO inhibitors, phenelzine (1-20 mg kg-1, i.p.), isocarboxazid (10 mg kg-1, i.p.), clorgyline (3 mg kg-1, i.p.) and tranylcypromine (10 mg kg-1, i.p.) markedly decreased (21-71%) the density of I2 imidazoline-preferring receptors in the rat brain and liver. In contrast, chronic treatment (7 days) with the reversible MAO-A inhibitors, moclobemide (1 and 10 mg kg-1, i.p.) or chlordimeform (10 mg kg-1, i.p.) or with the reversible MAO-B inhibitor Ro 16-6491 (1 and 10 mg kg-1, i.p.) did not alter the density of I2 imidazoline-preferring receptors in the rat brain and liver; except for the higher dose of Ro 16-6491 which only decreased the density of these putative receptors in the liver (38%). 3. In vitro, phenelzine, clorgyline, 3-phenylpropargylamine, tranylcypromine and chlordimeform displaced the binding of [3H]-idazoxan to brain and liver I2 imidazoline-preferring receptors from two distinct binding sites. Phenelzine, 3-phenylpropargylamine and tranylcypromine displayed moderate affinity (KiH = 0.3-6 microM) for brain and liver I2 imidazoline-preferring receptors; whereas chlordimeform displayed high affinity (KiH = 6 nM) for these receptors in the two tissues studied, Clorgyline displayed very high affinity for rat brain (KiH = 40 pM) but not for rat liver I2 imidazoline-preferring receptors (KiH = 169 nM). 4. Preincubation of cortical or liver membranes with phenelzine (10-4 M for 30 min) did not alter the total density of I2 imidazoline-preferring receptors, indicating that this irreversible MAO inhibitor does not irreversibly bind to I2 imidazoline-preferring receptors. In contrast, preincubation with 10-6 Mclorgyline reduced by 40% the Bmax of [3H]-idazoxan to brain and liver I2 imidazoline-preferring receptors.5. Chronic treatment (7 days) with the inducers of cytochrome P-450 enzymes phenobarbitone (40 or 80 mg kg-1, i.p.), 3-methylcholanthrene (20 mg kg-1, i.p.) or 2-methylimidazole (40 mg kg-1, i.p.) did not alter the binding parameters of [3H]-idazoxan to brain and liver 12 imidazoline-preferring receptors.The compound SKF 525A, a potent inhibitor of cytochrome P-450 enzymes which forms a tight but reversible complex with the haemoprotein, completely displaced with moderate affinity (KiH = 2-10 microM)the specific binding of [3H]-idazoxan to brain and liver 12 imidazoline-preferring receptors. Preincubation of total liver homogenates with 3 x 10-4 M phenelzine in the presence of 10-3 M NADH, a treatment that irreversibly inactivates the haeme group of cytochrome P-450, did not reduce the density of liver I2 imidazoline-preferring receptors. These results discounted a possible interaction of [3H]-idazoxan with the haeme group of cytochrome P-450 enzymes.6. Together the results indicate that the down-regulation of I2 imidazoline-preferring receptors is associated with an irreversible inactivation of MAO (at least in the brain) that is not related either to the affinity of the MAO inhibitors for I2 imidazoline-preferring receptors or to an irreversible binding to these putative receptors. These findings indicate a novel effect of irreversible MAO inhibitors in the brain and suggest a new target for these compounds that could be of relevance in the treatment of depression, a disease in which an increased density of brain I2 imidazoline-preferring receptors has been reported.

Adrenergic alpha-Antagonists↗
PubMed1991

Suppression of the luteinizing hormone surge by chlordimeform in ovariectomized, steroid-primed female rats.

The midcycle surge of luteinizing hormone (LH) from the pituitary provides the physiological trigger in the mammalian female for the process of ovulation. Accordingly, any agent that compromises the LH surge could function as a reproductive toxicant. Since ovariectomized (OVX) rats implanted with oestradiol capsules will exhibit daily afternoon surges, such animals can serve as a useful model for the investigation of toxicant-induced alterations in this functional hormonal event. The acaricide chlordimeform (CDF) has previously been found to decrease serum LH, probably by altering the hypothalamic noradrenergic transmitter control of LH secretion. Consequently, the present study focused on the effect of acute CDF administration on the appearance of the induced LH surge. Single intraperitoneal injections of CDF (0, 10, 25, 50 mg/kg) in OVX, oestradiol-implanted female Long-Evans rats approximately 5 hr prior to the expected surge caused a complete suppression at 25 and 50 mg/kg. Ten mg/kg had no effect on surge amplitude, but advanced the LH peak by 2 hr. The observed suppression did not persist beyond the day of CDF administration. Earlier dosing at 11 or 18 hr prior to the surge was without effect. Since CDF has been found to elevate serum corticosterone (CORT), 10 mg CORT/rat were given at different times prior to the surge. Twenty hr after administration only a partial lowering was seen; 5 hr exposure were ineffective. This indicates that an indirect adrenal effect was not the principal route, but may accompany an action of CDF on the hypothalamic mechanisms regulating the surge and becomes evident after more prolonged exposure.

Animals↗
PubMed1992

Calcium entry blockade as a mechanism for chlordimeform-induced inhibition of motor activity in the isolated guinea-pig ileum.

Central and peripheral alpha 2-adrenoceptors, including those of the gastrointestinal tract, have been indicated as a toxicity target of formamidine pesticides in mammals. In this study, the inhibitory effect of chlordimeform on twitch contractions from electrically-stimulated longitudinal muscle-myenteric plexus preparations (LMMPs) of the guinea-pig ileum was found to be resistant to the action of the alpha 2-adrenoceptor antagonist idazoxan. This drug was also ineffective on chlordimeform-induced inhibition of peristalsis recorded in whole ileal segments. As expected, idazoxan antagonized the inhibitory effect of the alpha 2-adrenoceptor agonist clonidine on twitch contractions and peristaltic activity. Chlordimeform reduced the amplitude of direct mechanical responses to a variety of spasmogens such as acetylcholine, histamine and substance P, suggesting a muscular site of action. Moreover, Ca(2+)-free, K(+)-depolarized LMMPs, chlordimeform inhibited submaximal contractions caused by addition of exogenous calcium, through an action apparently similar to that of the Ca2+ entry blocker nifedipine. Both chlordimeform- and nifedipine-induced inhibition of calcium contractions were reversed by the calcium channel activator BAY K 8644. This compound also partially prevented the inhibitory action of chlordimeform on peristaltic activity. On the whole, these results indicate that chlordimeform-induced depression of motor activity in the guinea-pig ileum is, at least in part, related to inhibition of transmembrane Ca2+ fluxes responsible for smooth muscle contraction.

Adrenergic alpha-Antagonists↗
PubMed1984

Caffeine and related methylxanthines: possible naturally occurring pesticides.

Natural and synthetic methylxanthines inhibit insect feeding and are pesticidal at concentrations known to occur in plants. These effects are due primarily to inhibition of phosphodiesterase activity and to an increase in intracellular cyclic adenosine monophosphate. At lower concentrations, methylxanthines are potent synergists of other pesticides known to activate adenylate cyclase in insects. These data suggest that methylxanthines may function as natural insecticides and that phosphodiesterase inhibitors, alone or in combination with other compounds, may be useful in insect control.

1-Methyl-3-isobutylxanthine↗
PubMed1992

Incidence of bladder cancer in a cohort of workers exposed to 4-chloro-o-toluidine while synthesising chlordimeform.

Between 1982 and 1990 seven cases of bladder cancer were detected in a group of 49 workers who were synthesising chlordimeform from 4-chloro-o-toluidine. Latency periods ranged from 15 to 23 years. The incidence of bladder tumours in this group was significantly higher than that of the cancer registers of the former GDR, Saarland, and Denmark by factors of 89.7, 53.8, and 35.0 respectively. This provides further evidence that monocyclic aromatic amines such as 4-chloro-o-toluidine may be carcinogenic in humans.

Adult↗
PubMed1976

Chemistry, biological activity, and uses of formamidine pesticides.

The formamidines, a relatively new group of acaricide-insecticides, are novel both in their range of biological activities and in their mode of action, which is presently unknown. This paper is a review of the historical development, properties, structures, uses, and chemistry of this group of pesticides, with particular emphasis on chlordimeform (Galecron or Fundal), N'-4-chloro-o-tolyl-N,N-dimethylformamidine, and amitraz, 1,3=di-(2,4-dimethylphenylimino)-2-methyl-2-azapropane. Their biological activity and uses are defined by their toxicity to spider mites, ticks, and certain insects, and they are particularly effective against juvenile and resistant forms of these organisms. A significant, but poorly understood feature of their field effectiveness is their breadth of toxic action which includes direct lethality, excitant-repellant behavioral effects, and chemosterilization. They are generally of low hazard for nontarget species with the significant exception of predaceous mites. Several aspects of the chemistry of these compounds are considered, including structure--activity relations, synthetic pathways, isomerism and configuration, and their chemical and environmental stability. A significant feature of the metabolism and toxicity of these agents is the possible activation of chlordimeform by N-demethylation in vivo. Strong evidence for this has been presented with the cattle tick, but recent results discussed here suggest that in other species, i.e., mice, German cockroaches or black cutworm eggs, N-demethylation is neither a strong activation nor a detoxication reaction.

Amidines↗
PubMed1976

Biochemical and physiological effects of chlordimeform.

Chlordimeform is a relatively new acaricide/insecticide, whose mode of action we have investigated. It appears to interfere with amine-mediated control of nervous and endocrine systems in a variety of ways. Specifically, chlordimeform causes a build-up of the amines 5-hydroxytryptamine and to a lesser extent norepinephrine in the rat brain in vivo, antagonizes the in vivo action of reserpine in the rat (reserpine depletes amine stores in the CNS), inhibits monoamine oxidase from rat liver in vitro, and causes hypotension in rabbits. In the American cockroach it directly stimulates the heart in situ, acts synergistically with tryptamine in vivo, inhibits amine-N-acetyltransferase from cockroach head in vitro, causes accumulation of indolamines in cockroaches in vivo, and blocks the stimulation of adenylate cyclase by octopamine in the cockroach CNS in situ. It also inhibits tryptamine metabolism in whole mites in vitro.

Amidines↗
PubMed2005

Octopamine and experience-dependent modulation of aggression in crickets.

Intraspecific aggression is influenced in numerous animal groups by the previous behavioral experiences of the competitors. The underlying mechanisms are, however, mostly obscure. We present evidence that a form of experience-dependent plasticity of aggression in crickets is mediated by octopamine, the invertebrate counterpart of noradrenaline. In a forced-fight paradigm, the experience of flying maximized the aggressiveness of crickets at their first encounter and accelerated the subsequent recovery of aggressiveness of the normally submissive losers, without enhancing general excitability as evaluated from the animals' startle responses to wind stimulation. This effect is transitory and concurrent with the activation of the octopaminergic system that accompanies flight. Hemocoel injections of the octopamine agonist chlordimeform (CDM) had similar effects on aggression but also enhanced startle responses. Serotonin depletion, achieved using alpha-methyl-tryptophan, enhanced startle responses without influencing aggression, indicating that the effect of CDM on aggression is not attributable to increased general excitation. Contrasting this, aggressiveness was depressed, and the effect of flying was essentially abolished, in crickets depleted of octopamine and dopamine using alpha-methyl-p-tyrosine (AMT). CDM restored aggressiveness in AMT-treated crickets, indicating that their depressed aggressiveness is attributable to octopamine depletion rather than to dopamine depletion or nonspecific defects. Finally, the flight effect was blocked in crickets treated with the octopamine receptor antagonist epinastine, or with the alpha-adrenoceptor and octopamine receptor antagonist phentolamine, but not with the beta-adrenoceptor antagonist propranolol. The idea that activity-specific induction of the octopaminergic system underlies other forms of experience-dependent plasticity of aggressive motivation in insects is discussed.

Adrenergic alpha-Antagonists↗
PubMed1977

The efficacy of chlordimeform for the control of the northern fowl mite, Ornithonyssus sylvarium (Canestrini and Fanzago) (Acarina, Dermanyssidae).

Chlordimeform applied as a 0.06% low pressure spray controlled the northern fowl mite (NFM) for at least 90 days. Tetrachlorvinphos applied as a 0.5% low pressure spray was equally effective. Chi square analysis of NFM population estimates indicated that NFM populations on the untreated control birds stayed essentially the same throughout the test, whereas, the NFM populations on both acaricide-treated groups were significantly lowered by the seventh day of the test (P less than .01). Chlordimeform seemed to work more slowly than tetrachlorvinphos in controlling NFM.

Amidines↗