Kinetics and thresholds of several indices of lindane-induced toxicity

The effects of lindane, administered either IP (4, 6 or 8 mg/kg in dimethylsulfoxide, 0.5 ml/kg) or PO (30, 40 or 50 mg/kg in oil, 1 ml/kg), were compared in male rats. Effects appeared later and lasted longer after PO administration. After either route, convulsant effects occurred first and were over before hypothermic effects were maximal. Also, hypothermia subsided before hypophagia ended. After IP administration, hypothermia had the lowest threshold and convulsions the next lowest; reduced food intake was produced only by the highest dose, which also produced 43% deaths. By contrast, after PO administration, all doses reduced food intake and produced hypothermia, but deaths did not occur after even the highest dose. The different time courses and thresholds for the different indices of toxicity suggest that different target sites or mechanisms may be involved. Thus, effects on the gut, in addition to effects on the brain, may account for the longer duration and greater sensitivity of reduced food intake, compared to lethal and hypothermic effects, after PO administration of lindane. After administration of lindane IP, peripheral vasodilation (as demonstrated by an increase in tail temperature) preceded colonic hypothermia. This could be explained if lindane inappropriately activated heat-loss mechanisms.     

Central nervous system toxicity and early peripheral neuropathy following dermal exposure to methyl bromide

CASE REPORT: We describe a case of early peripheral neuropathy and central nervous system toxicity as a result of acute predominantly dermal exposure to methyl bromide. A 32-year-old male was admitted after an accidental predominantly dermal exposure to methyl bromide while fumigating soil for pest control. The patient suffered dermal burns and vesicles on the upper and lower limbs. One week following exposure, he developed progressive weakness of the lower limbs, ataxia, paresthesiae of both legs and the left arm, hyperactive tendon reflexes in the lower limbs, and left Babinski sign. Nerve conduction velocity testing was compatible with axonal neuropathy. The patient recovered gradually from his burns. Three months postexposure he showed no signs of central nervous system toxicity, but the peripheral neuropathy was still present. DISCUSSION: Neurological effects primarily referable to the central nervous system following severe inhalation of methyl bromide have frequently been reported. The patient described in this study developed an unusual early peripheral neuropathy following dermal exposure. Peripheral neuropathy can be an outcome of methyl bromide intoxication, but is usually a late sequela of acute central nervous system toxicity or an aftereffect of repetitively inhaled chronic exposure. In this case, exposure to methyl bromide through abraded skin caused early peripheral neuropathy and central nervous system toxicity.     

Increased aggression and toxicity in grouped male mice treated with tranquilizing benzodiazepines

N-demethyldiazepam, diazepam and oxazepam incorporated in the diet were fed to albino Swiss male and female mice (10–50 mg per day per kg of body weight) for 6 months. Increased mortality was observed in grouped male mice but not in female or isolated male mice. Multiple skin lesions and necroses found in grouped male mice were probably due to increased aggression.     

Comparison of typical and atypical benzodiazepines on the central and peripheral benzodiazepine receptors

The affinities of typical and atypical benzodiazepines (BZs) for 3H-flunitrazepam (FLU) and 3H-Ro 5-4864, "peripheral" BZ, binding sites in the central nervous system (CNS) were compared. Each dissociation constant (Kd) value of the 3H-FLU binding sites in the cerebellum, cortex, hippocampus and spinal cord showed the similar results, although the binding maximum (Bmax) for the cortex and cerebellum yielded the largest value and the smallest Bmax appeared in the spinal cord. In contrast, Bmax for 3H-Ro 5-4864 binding sites were about three-fold higher in the spinal cord than in the cerebellum. Among the drugs tested, brotizolam demonstrated the highest affinity for 3H-FLU binding sites in the four regions. Typical and atypical BZs did not normally show different affinities for the two BZ receptor subtypes, except for CL 218,872 and Ro 5-4864. A series of compounds including Ro 5-4864, PK 11195, diazepam and brotizolam had high affinity for the 3H-Ro 5-4864 binding sites in the cerebellum and spinal cord. Other BZs did not show affinity for "peripheral" BZ binding sites in the CNS. In conclusion, brotizolam (or atypical BZ) had the binding affinity to both "central" and "peripheral" BZ receptors, like diazepam (a typical BZ).     

Effects of peripheral benzodiazepines upon the O2 consumption of neuroblastoma cells

The effects of peripheral benzodiazepines on the respiration of a neuronal cell, the mouse C 1300 neuroblastoma, were analyzed. The presence of 'peripheral receptors' to the [3H]PK 11195 ligand was checked in these cells. A dose-dependent decrease of the O2 consumption in the presence of Ro 5-4864 and PK 11195 was observed at concentrations consistent with a receptor-mediated action. Diazepam, clonazepam and Ro 15-1788 were inactive. Previous studies have localized the peripheral benzodiazepine receptors on the mitochondrial outer membrane. We report here an effect of the peripheral ligand on mitochondrial metabolism.     

"Conflict" situation based on intracranial self-stimulation behavior and the effect of benzodiazepines

Based on lateral hypothalamic self-stimulation behavior of the rat in a Skinner box, a "conflict" situation was established by combining foot shock punishment with brain stimulation. Diazepam (10-20 mg/kg, PO) caused a marked increase in the lever pressing response in the punished period without affecting the unpunished response. Bromazepam (10--20 mg/kg PO) also caused an increase in the lever pressing response in the punished period and a decrease of the punished response. These results indicate that a "conflict" situation based on self-stimulation behavior is useful for the evaluation of antianxiety action.     

Cardiovascular toxicity and distribution kinetics of intravenous chloroquine.

Chloroquine diphosphate (3 mg base kg-1) was given by constant rate intravenous injection over 10 min to 12 healthy adult male volunteers. Plasma concentrations of chloroquine and the principal metabolite desethylchloroquine, electrocardiograph intervals, and arterial blood pressure were measured at frequent intervals to determine the relationship between cardiovascular effects and plasma concentrations. Peak plasma concentrations ranged between 784 and 6649 (mean 2913) ng ml-1. The decline in plasma concentrations was multiexponential with an initial rapid distribution phase; mean (+/- s.d.) first order rate constant 0.65 +/- 0.14 min-1, and an estimated apparent volume of the central compartment of 0.18 +/- 0.15 l kg-1. There was no serious toxicity, but subjective side effects were reported in all patients and there was a significant fall in systolic blood pressure (110 +/- 9.5 to 101 +/- 12.5 mm Hg; P = 0.03) and rise in heart rate which paralleled the change in plasma chloroquine concentrations. Coincident with changes in blood pressure, there was a significant prolongation of the electrocardiograph QRS interval; 81 +/- 15 to 92 +/- 13 ms (P less than 0.01) but no change in the QTc interval. These findings suggest that the cardiovascular toxicity of parenteral chloroquine is related to transiently high plasma concentrations occurring early in the distribution phase. This results from incomplete distribution from a central compartment that is approximately one thousand times smaller than the eventual total apparent volume of distribution at steady state. Rate of administration is therefore a major determinant of toxicity.     

Regulation of "peripheral-type" binding sites for benzodiazepines in the pineal gland

The density of "peripheral-type" binding sites for benzodiazepines (PBS) in the rat pineal gland was reduced by approximately 50% three weeks after superior cervical ganglionectomy or exposure to constant light; the apparent affinity of [3H]Ro 5-4864 (the prototype ligand for these sites) remained unchanged. In contrast, neither the density of PBS nor the apparent affinity of [3H]Ro 5-4864 for these sites was altered in cerebral cortex by these procedures. The demonstration that PBS density is under neural control in the pineal gland suggests that these sites may have a physiologic role. The high density of PBS in pineal (approximately 24 pmol/mg protein) suggests that this tissue may be a useful model to study both the physiologic and pharmacologic function of these sites.     

Central/peripheral nervous system and immune responses

Maintenance of health is dependent on numerous regulatory interactions between organ systems. This review discusses interorgan communication between the nervous, endocrine, and immune systems and environmental and genetic influences on this neuroendocrine immune circuitry. Stresses of multiple types, including psychological and exposure to chemicals and infectious agents, may combine to enhance neuroimmunotoxicology. Altered nervous system functions can alter immunity which could result in exacerbation of infections, cancers or other immune-associated problems. Inversely, aberrant immune system activities could lead to pathologies associated with altered nervous activities, such as Alzheimer's disease, chronic fatigue, or multiple sclerosis. The nervous, endocrine and immune circuitry is multi-directional, and a chemical, physical or emotional stress could upset the homeostasis.     

Involvement of the "peripheral" benzodiazepine receptor type (omega 3) in the tolerance to the electroencephalographic effects of benzodiazepines in rats: comparison of diazepam and clonazepam

Rapid tolerance to the sedative effect of large doses of diazepam (10 mg/kg IV), but not of large doses of clonazepam (2 mg/kg IV) occurs in rats after 5 days of treatment on a once-a-day regimen. Electroencephalographic (EEG) studies show that such behavioral tolerance is associated with a decreased induction of spindle bursts and with an increased induction of 20-30 Hz waves (beta-like activity). Administration of clonazepam plus the agonist of the "peripheral" benzodiazepine receptor type (omega 3) Ro 5-4864 (4 mg/kg IV) for 5 days induces signs of behavioral and EEG tolerance to sedative effects of the benzodiazepine agonist. In animals treated for 5 days with diazepam plus the omega 3 antagonist PK 11195 (5 mg/kg IV), no signs of EEG and behavioral tolerance are observed. These results suggest that omega 3 type activation influences the development of rapid tolerance to the sedative effect of diazepam in rats.     

Central and peripheral alpha-adrenergic effects of some imidazolidines.

The central hypotensive activity of clonidine and of 12 structurally related analogues was determined following intravenous administration to pentobarbital-anaesthetized, normotensive rats. This sympathoinhibitory action was characterized by means of a pC30, calculated from dose-response curves. The centrally mediated depressor activity (pC30) was correlated with the peripherally induced pressor activity of the compounds (pC100) reported on previously and which had been established after intravenous application to pithed rats. In these correlations, the quantitative ability of the substances to penetrate into the central nervous system had been taken into account. The octanol/buffer (pH = 7.4) partition coefficients were used as a measure of lipophilic behaviour. A positive correlation was found between the central hypotensive activity and the linear combination of peripheral alpha-sympathomimetic activity and lipophilicity.     

Central and peripheral components of morphine mydriasis in mice

Mice treated with morphine (intracerebroventricularly, retrobulbarly or intraperitoneally) demonstrated dose related bilateral mydriasis. Intracerebroventricular (ICV) injection was much more potent than either retrobulbar (RB) or intraperitoneal (IP) injections. Morphine applied topically onto one eye resulted in bilateral mydriasis which was more marked in the treated eye. The mydriatic effect was antagonized by naloxone administered either IP or ICV or given on one eye. Here again, ICV naloxone was most effective. Naloxone eye drops diminished the mydriasis produced by systemic morphine bilaterally but more in the treated eye. These results suggest that in mice the mydriasis produced by morphine is mainly of central origin, but a local ocular effect also occurs.     

Central and peripheral antialgesic action of aspirin-like drugs.

The peripheral and central effects of some non-steroid anti-inflammatory drugs, aspirin, indomethacin, paracetamol and phenacetin were studied by comparing their intraplantar and intracerebroventricular effects on hyperalgesia induced by carrageenin injected into the rat paw. Hyperalgesia was measured by a modification of the Randall-Selitto test. The agents tested had antialgesic effects when given by any route. Their intraventricular administration enhanced the antialgesic effect of anti-inflammatory drugs administered into the paw. Previous treatment of one paw with carrageenin reduced the oedema caused by a second injection of carrageenin in the contralateral paw. In contrast, it had no effect on the intensity of hyperalgesia but shortened the time necessary for it to reach a plateau. Administration of a prostaglandin antagonist (SC-19220) in the cerebral ventricles, in the rat paw or in both sites, significantly inhibited the hyperalgesia evoked by carrageenin. The maximal hyperalgesic effect of intraplantar injections of prostaglandin E2 could be further enhanced by its cerebroventricular administration. It was suggested that carrageenin hyperalgesia has a peripheral and a central component and that the cyclo-oxygenase inhibitors used may exert an antialgesic effect by preventing the hyperalgesia induced by a peripheral and/or central release of prostaglandins.