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S Caroldi

Publications and source records attributed to S Caroldi.

At least 19 recordsLinked to original sources
PubMed1995

Comparative effects of two dithiocarbamates disulfiram and thiram, on adrenal catecholamine content and on plasma dopamine-beta-hydroxylase activity.

Both disulfiram (tetraethylthiuram disulfide), an alcohol aversive drug, and thiram (tetramethyl-thiuram disulfide), a widely used pesticide, significantly increased the dopamine pool in the adrenal glands of dosed rats. The dopamine increase was detectable within 4 h of oral dosing with 100 mg/kg of either dithiocarbamate and peaked 24 h later at 10 times control values. In control rats the dopamine turnover was 0.51 h-1 as calculated by the assumed first order decline of dopamine after a single injection of alpha-methyl-p-tyrosine (alpha-MT, 400 mg/kg i.p.) resulting in a dopamine-beta-hydroxylase (DBH) activity of 0.73 nmol/h per pair of adrenals. In the adrenals of rats pretreated with thiram and then injected with alpha-MT, the adrenal dopamine content did not significantly decline, indicating that thiram reduced the conversion of dopamine to noradrenaline, eventually leading to the observed dopamine increase. Plasma DBH activity was significantly reduced 4 h and 24 h after dosing with thiram, but was unchanged after treatment with disulfiram. The determination of plasma DBH activity could be a marker to monitor the effect of thiram on catecholamine metabolism in occupationally exposed workers but not that of disulfiram in abstinent alcoholics.

Administration, Oral↗
PubMed1995

In vitro effect of dithiocarbamate pesticides and of CaNa2EDTA on human serum dopamine-beta-hydroxylase.

Serum dopamine-beta-hydroxylase (DBH) inhibition has been reported in lead workers treated with CaNa2EDTA and in alcoholic patients repeatedly treated with the alcohol aversive drug Disulfiram. The mechanism of inhibition involves Cu++ chelation at the active site of DBH. The effect of CaNa2EDTA and Disulfiram on serum DBH has been compared to the effect of dithiocarbamate pesticides in vitro for the possible use of serum DBH determination for the biological monitoring of workers exposed to these pesticides. Most dithiocarbamates inhibit human serum DBH at micromolar concentrations (range of I50, 0.027-1.6 mumol/L). The inhibitory potency increased from methyl- and dimethyl dithiocarbamates to diethyl dithiocarbamates up to the most potent ethylene bisdithiocarbamates. The I50 of CaNa2EDTA was 3.8 mumol/L, higher than those of dithiocarbamates. Copper addition to the test system reactivated at stoichiometric concentrations dithiocarbamate-inhibited DBH indicating that both base line values and percent of inhibition can be calculated in a single blood sample. Results suggest that serum DBH determination could be useful in case of acute poisoning involving high doses of dithiocarbamate pesticides.

Alcohol Deterrents↗
PubMed1994

In vivo inhibition of serum dopamine-beta-hydroxylase by CaNa2 EDTA injection.

1. In humans CaNa2EDTA increases urinary excretion of lead as well as that of essential metals such as zinc, ferrum and manganese but not that of copper. 2. We studied the effect of CaNa2EDTA injection on serum dopamine-beta-hydroxylase, a copper-dependent enzyme, in three male lead welders hospitalized for suspected lead poisoning. 3. Injection of CaNa2EDTA (1000 mg i.v.) resulted in rapid reduction of serum dopamine-beta-hydroxylase activity which returned to normal level within 24 hours. 4. Copper sulphate (8 microns) but not ethylmaleimide (10 mM) restored in vitro serum dopamine-beta-hydroxylase activity to pre-dosing values which indicates that CaNa2EDTA inhibits dopamine-beta-hydroxylase by removing copper from the enzyme. 5. An inverse dose effect relationship between injected CaNa2EDTA and residual serum dopamine-beta-hydroxylase activity was observed. 6. In spite of the reported lack of changes in copper serum concentration, CaNa2EDTA significantly affects the activity of a copper-dependent enzyme in the serum. 7. As CaNa2EDTA is currently the drug of choice for the treatment of asymptomatic lead poisoning in children, the effect of CaNa2EDTA on copper-enzymes requires further investigation.

Adult↗
PubMed1992

Blood concentration of carbon disulphide in "normal" subjects and in alcoholic subjects treated with disulfiram.

Assay of free and acid labile carbon disulphide (free and total CS2 respectively) in human blood was performed by gas chromatography/spectrometry. The method used a large dynamic head space volume and a "cryogenic trap". Blood CS2 concentration was measured in 42 subjects not occupationally exposed to CS2 (group A) and in 11 alcoholic subjects (group B) treated with disulfiram. Free CS2 concentration showed a mean value of 261 ng/l in the 42 subjects in group A and 9482 ng/l in eight subjects of group B. Total CS2 concentration was 897 ng/l and 40,084 ng/l in groups A and B respectively. Differences between the groups were highly significant for concentrations of both free and total CS2. Total CS2 concentration was about four times as high as free CS2 concentration in both groups. A significant correlation was found between free and total CS2 concentration both in group A and in group B. In the alcoholic subjects (group B), blood concentrations of both free and total CS2 were related to time of sampling after treatment with disulfiram.

Alcoholism↗
PubMed1991

Interaction of methamidophos with hen and human acetylcholinesterase and neuropathy target esterase.

Methamidophos causes acute cholinergic toxicity in several species, including man, and organophosphate-induced delayed polyneuropathy which has been reported in man but not in the hen. Acetylcholinesterase (AChE) and neuropathy target esterase (NTE) are thought to be the molecular targets of acute and delayed toxicity, respectively. The rate constants of inhibition (ka) and reactivation (k + 3) of human and hen brain AChE and NTE by methamidophos resolved optical isomers are here reported. NTE inhibition was progressive and irreversible. Human and hen NTE ka (M-1.m-1) for D-(+) methamidophos was 88 and 59, respectively, and for L-(-) methamidophos 3.2 and 3.0, respectively. AChE spontaneously reactivates after inhibition. D-(+) methamidophos 10(-3).ka (M-1.m-1) for human and hen AChE was 0.24 and 0.13; 10(3).k+3 (m-1) was 0.83 and 0.69, respectively. L-(-) Methamidophos 10(-3).ka (M-1.m-1) for human and hen AChE was 5.7 and 2.8, whereas 10(3).k+3 (m-1) was 6.50 and 1.52, respectively. L-(-)-Inhibited AChE reactivated to about 60% for human and 30% for hen enzymes, respectively. D-(+)-Inhibited AChE reactivated to about 10-20% for both species. Maximal reactivation occurred within 4-6 h when a plateau was reached. The larger and faster reactivation of human AChE inhibited in vitro by L-(-) methamidophos suggests that a corresponding effect might be possible in vivo and therefore explain, in part, the relatively higher susceptibility of man to delayed polyneuropathy induced by racemic methamidophos which occurs, however, with doses always causing severe cholinergic toxicity.

Acetylcholinesterase↗
PubMed1991

Chlorpyrifos-induced delayed polyneuropathy.

Chlorpyrifos [0,0-diethyl 0-(3,5,6-trichloro-pyridyl) phosphorothioate] caused delayed polyneuropathy in man. Contrary to previous studies, we report here that it also causes delayed polyneuropathy in the hen, the animal model for this toxicity. The minimal neuropathic dose was 60-90 mg/kg p.o., corresponding to 4-6 times the estimated LD50. Consequently, pralidoxime (2-PAM) in conjunction with atropine was necessary to reverse acetylcholinesterase (AChE) inhibition and cholinergic toxicity in hens given high enough doses of chlorpyrifos to cause neuropathy. Chlorpyrifos was slowly absorbed after single oral doses and the threshold of inhibition (greater than 70%) of neuropathy target esterase (NTE), the putative target for delayed neuropathy, was reached within 5-6 days. High AChE inhibition (greater than 90%), however, was measured within hours after dosing because of the higher potency of chlorpyrifos to inhibit this enzyme. In vitro studies showed that chlorpyrifos-oxon, the active metabolite of chlorpyrifos, was 10-20 times more active against AChE than against NTE, confirming the clinical observation. No differences were seen between human and hen enzymes in this respect. Hen and human brain homogenates contain A-esterases which hydrolysed chlorpyrifos to about the same extent in both species. In conclusion, chlorpyrifos causes delayed polyneuropathy in the hen, as was reported in man. The reasons for previous negative data in the hen are probably due to the relatively lower doses which were used. Judging from in vitro studies with hen and human enzymes, there are no differences in the two species as far as their relative sensitivity to delayed polyneuropathy. It is likely that delayed polyneuropathy would develop in both species only after severe cholinergic toxicity requiring aggressive antidotal treatment.

Animals↗
PubMed1991

Promotion of organophosphate-induced delayed polyneuropathy by phenylmethanesulfonyl fluoride.

Certain sulfonates, like phenylmethanesulfonyl fluoride (PMSF), carbamates, and phosphinates, when given prior to neuropathic doses of organophosphates such as diisopropyl phosphorofluoridate (DFP), protect hens from organophosphate-induced delayed polyneuropathy (OPIDP). Protection was related to inhibition of the putative target of OPIDP, which is called Neuropathy Target Esterase (NTE). NTE inhibition above 70-80% in the nervous system of hens followed by a molecular rearrangement called aging initiates OPIDP. PMSF and other protective chemicals inhibit NTE but OPIDP does not develop because aging cannot occur. DFP (1 mg/kg sc) inhibited NTE above 70-80% in peripheral nerve and caused OPIDP in hens. Lower doses (0.3 and 0.5 mg/kg sc) caused about 40-60% NTE inhibition and no or marginal OPIDP. Chlorpyrifos (90 mg/kg po) also caused OPIDP. When repeated (30 mg/kg sc daily for 9 days) or single (5-120 mg/kg sc) doses of PMSF were given after either DFP or chlorpyrifos, OPIDP developed in birds treated with nonneuropathic doses of DFP and was more severe in birds treated with chlorpyrifos or higher doses of DFP. PMSF increased NTE inhibition to greater than 90%. Promotion of OPIDP with a single dose of PMSF (120 mg/kg sc) was obtained in birds up to 11 days after a marginally neuropathic dose of DFP (0.5 mg/kg sc). Promotion was also obtained with phenyl N-methyl N-benzyl carbamate (40 mg/kg iv) but not with non-NTE inhibitors in vivo such as paraoxon or benzenesulfonyl fluoride when given at maximum tolerated doses. These results indicate that protection from OPIDP is only one effect of PMSF because promotion of OPIDP is also observed depending upon the sequence of dosing. Either effect is always related to the doses of PMSF, which inhibit NTE.

Animals↗
PubMed1989

Biochemical approach to occupational neurotoxicology.

Dose-effect and dose-response relationships in occupational neurotoxicology are rarely studied by means of biochemical methods. Some biochemical markers are however available to extrapolate from animal to man and to use in monitoring human exposures. They might be framed in three categories exploring: the delivery of chemicals to the site of action, the modifications of the molecular target induced by chemicals, the biochemical consequences of these modifications. Estimation of absorbed doses in man is possible for virtually every neurotoxic chemical by means of analytical chemistry of body fluids. Protein adducts, as measured in cellular and other blood components, might assess more closely the delivery in vivo, to the site of action. In this way also in vivo comparisons across species will be more precise. Examples include haemoglobin adducts, plasma pseudocholinesterase inhibition etc. In addition measurements of blood enzymes involved in the detoxification (e.g. A-esterases and organophosphorus esters) might contribute to assess metabolic capabilities. Once the molecular target of neurotoxicity is known, extrapolations across species are easy to make. Biochemical markers reflecting in vivo the effect at the site of action are available in very few cases, when the same target is accessible in body fluids. In such circumstances the biochemical marker represents an integrated dose/effect index. Examples include Red Blood Cell Acetylcholinesterase and Lymphocyte Neuropathy Target Esterase for acute and delayed neurotoxicity of organophosphorus esters. The understanding of the pathogenesis of a neurotoxic effect might lead to markers reflecting biochemical consequences of the interaction of the chemical with the target. The specificity of the test will dissect the chain of pathogenetic events from secondary consequences.(ABSTRACT TRUNCATED AT 250 WORDS)

Humans↗
PubMed1988

Blood copper in organophosphate-induced delayed polyneuropathy.

Some organophosphorous esters cause a polyneuropathy which becomes clinically evident 2 weeks after a single dose. The pathogenesis involves modifications of a target protein, neuropathy target esterase, in the axons and a selective inhibition of retrograde axonal transport. It was suggested that copper metabolism might also be involved because of increased levels of plasma copper and ceruloplasmin in animals developing this polyneuropathy. Our results do not confirm this observation; treatment of hens with highly neuropathic single doses of two organophosphates (dihexyl-2,2-dichlorovinyl phosphate and mono-o-cresyl diphenyl phosphate) does not affect total and plasma free copper when measured several times during the development of polyneuropathy. We concluded that copper homeostasis is not affected and that copper changes are unlikely to be involved in the pathogenesis of this polyneuropathy.

Animals↗
PubMed1987

Central-peripheral delayed neuropathy caused by diisopropyl phosphorofluoridate (DFP): segregation of peripheral nerve and spinal cord effects using biochemical, clinical, and morphological criteria.

Systemic injection of diisopropyl phosphorofluoridate (DFP; 1 mg/kg, sc) causes delayed neuropathy in hens. This effect is associated with a high level of organophosphorylation of neuropathy target esterase (NTE) followed by an intramolecular rearrangement called "aging." Phenylmethanesulfonyl fluoride (PMSF) also attacks the active center of NTE but "aging" cannot occur. This compound does not cause neuropathy and protects against a subsequent challenge systemic dose of DFP. Intraarterial injection of DFP (0.185 mg/kg) into only one leg of hens caused a high NTE inhibition (greater than 80%) in the sciatic nerve of the injected leg, but not in other parts of the nervous system (37% average). A unilateral neuropathy with typical histopathological lesions developed in the injected leg. PMSF (0.55 mg/kg) injected into each sciatic artery caused 47% inhibition of sciatic nerve NTE but only 17-22% inhibition of NTE elsewhere; it did not produce clinical or histopathological lesions. When these hens were challenged with DFP (1 mg/kg, sc), high inhibition of residual-free NTE (greater than 85%) occurred throughout the nervous system and clinical signs of a syndrome different from the classical delayed neuropathy developed: this spinal cord type of ataxia was associated with histopathological lesions in the spinal cord but not in peripheral nerve. PMSF (1 mg/kg) injected into only one sciatic artery caused selective protective inhibition of sciatic nerve NTE of that leg. After systemic challenge by DFP, clinical effects expressed were a combination of spinal cord ataxia plus unilateral peripheral neuropathy. The challenge dose of DFP (1 mg/kg, sc) was insufficient to produce clear histopathological lesions in unprotected peripheral nerves although spinal lesions were found in these hens. Thus clinical evaluation of the peripheral nervous system by means of walking tests and a simple test of "leg retraction" reflexes was more sensitive and specific in diagnosis of peripheral neuropathy than was the histopathology.

Animals↗
PubMed1987

The potentiation of the non-behavioural effects of amphetamine by carbon disulphide.

In agreement with the inhibition of dopamine-beta-hydroxylase by exposure to CS2, the extension of exposure time from 4 to 16 h increased dopamine concentrations in the hypothalmus and adrenals, and decreased noradrenaline concentration in the hypothalmus. The extension of exposure time also increased the toxicity of amphetamine. In conscious animals the stereotypic activity produced by 6.0 mg/kg and even that of 3.0 mg/kg amphetamine sulphate was suppressed by severe hyperthermia resulting in exhaustion, prostration and eventually death. A 16 h exposure to CS2 did not increase the lethal or hyperthermic effects of amphetamine in rats anaesthetized with 60 mg/kg sodium pentobarbitone. In fact the CS2 exposed rats became more hypothermic than non-exposed rats.

Adrenal Glands↗
PubMed1985

Carbon disulphide exposure affects the response of rat adrenal medulla to hypothermia and hypoglycaemia.

The effects of hypothermia and hypoglycaemia on adrenal catecholamines and dopamine-beta-hydroxylase were compared in control and carbon disulphide (CS2) exposed rats 24 h after the last of ten daily 4 h inhalation exposures to CS2, 2 mg 1(-1) air. Animals were either kept in a cold room (0 degrees C) for 210 min with or without immobilization or were injected with insulin 100 u kg-1. Before these treatments CS2 exposed rats had more dopamine and less adrenaline in their adrenals than controls, and CS2 exposure also elevated the adrenal synthesis of catecholamines. Cold with immobilization or insulin treatment depressed the adrenal adrenaline content and increased the plasma concentrations of noradrenaline and adrenaline. There were no consistent differences between control and CS2 exposed rats. The adrenal dopamine content increased during cold exposure with immobilization or after insulin treatment both in CS2 exposed and control rats. The increase was smaller in CS2 exposed rats but the final dopamine values were nearly identical in the two groups. Exposure to cold (without immobilization) increased the adrenal dopamine content and the rate of catecholamine synthesis in control, but not in CS2 exposed rats. The increase in controls was less than the difference between the pre-cold exposure values of control and CS2 exposed rats. It is concluded that the elevation of adrenal dopamine content and catecholamine synthesis in CS2 exposed rats satisfy part of the demand placed on the adrenal medulla by hypothermia and hypoglycaemia. Consequently the changes induced by the latter treatments were smaller in CS2 exposed than in non-exposed rats. Moreover, when CS2 exposed rats were subjected to cold stress without immobilization their catecholamine synthesis was higher than the level measured in control rats after cold exposure.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1984

Intra-arterial injection of diisopropylfluorophosphate or phenylmethanesulphonyl fluoride produces unilateral neuropathy or protection, respectively, in hens.

Hens injected in one sciatic artery with diisopropylfluorophosphate (DFP) (0.184 mg/kg) developed monolateral ataxia on the injected side 10-12 days later. The inhibition of neuropathy target esterase (NTE) was 85% in the sciatic nerve of the injected leg and less than 60% in the contralateral sciatic nerve, in spinal cord and in brain. Other hens injected in the wing vein with the same dose of DFP showed low inhibition of NTE in the nervous system and did not develop delayed neuropathy. Hens injected in one sciatic artery with phenylmethanesulphonyl fluoride (PMSF) (1 mg/kg) and 24 hr later with high subcutaneous dose of DFP (1.1 mg/kg) developed monolateral ataxia 10-12 days later on the side not injected with PMSF. The level of NTE inhibition after PMSF was greater than 40% in the sciatic nerve on the injected side compared with less than 20% in other parts of the nervous system. The same dose of PMSF injected in the wing vein produced low NTE inhibition in the nervous system and failed to protect the animals from the same high systemic dose of DFP. We conclude that both toxic and protective effects of NTE inhibitors for delayed neuropathy are better related to the level of NTE inhibition in the peripheral nerve on the site of injection than to NTE inhibition in other parts of the nervous system. Furthermore we suggest that NTE inhibition should also be measured in the peripheral nerve in the standard toxicity testing for organophosphate-induced delayed neurotoxicity.

Animals↗
PubMed1984

Stimulation of dopamine-beta-hydroxylase in rat adrenals by repeated exposures to carbon disulphide.

The conversion of dopamine to noradrenaline, measured shortly after exposure to carbon disulphide, is reduced in the adrenals of rats. However, alongside this effect, carbon disulphide produces a gradual increase in the adrenal content of dopamine-beta-hydroxylase indicated by the increase of in vitro estimated enzyme activity and by the increased in vivo conversion of dopamine to noradrenaline observed 24 hr after the ninth exposure. Thus, after repeated exposures, the reduced rate of noradrenaline synthesis detectable immediately after the exposure alternates with the increased rate of synthesis.

Adrenal Glands↗
PubMed1984

In vivo inhibition of dopamine-beta-hydroxylase in rat adrenals during exposure to carbon disulphide.

Male rats were exposed for a maximum of 4 h to carbon disulphide at atmospheric levels of 1.0-4.0 mg/l and the turnover rates of adrenal dopamine was determined by injecting alpha-methyl-p-tyrosine and measuring the rate at which dopamine disappears. Although the level of exposure was significantly higher than the 30.0 micrograms/l permissible limit, or the average occupational exposure, similar or even higher peak exposure values were reported from the viscose rayon industry. After inhibition of tyrosine hydroxylase by alpha-methyl-p-tyrosine, adrenal dopamine contents declined at a slower rate in rats exposed to carbon disulphide than in controls. The reduced rate of dopamine metabolism during exposure to carbon disulphide indicates inhibition of dopamine-beta-hydroxylase in vivo. The size of this effect, which could be detected as soon as 30 min after starting the exposure to carbon disulphide, was dose dependent. The rate of dopamine turnover was still reduced 2 h after the end of a single exposure. However at that time, because of the larger dopamine pool present in the adrenals, the amount of dopamine converted per unit of time was again at pre-exposure levels.

Adrenal Glands↗
PubMed1981

Enzyme studies with human and hen autopsy tissue suggest omethoate does not cause delayed neuropathy in man.

Levels of acetylcholinesterase and neurotoxic esterase were measured in brain autopsy material. In tissue from a fatal human poisoning and from hens given 4-8 x unprotected LD50 AChE was highly inhibited and neurotoxic esterase uninhibited. The findings correlate with the inhibitory power of omethoate against these enzymes in vitro. It is concluded that omethoate has negligible potential to cause delayed neuropathy and a published report of human neuropathy due to omethoate is criticised.

Acetylcholinesterase↗
PubMed1981

Delayed neurotoxicity caused by a single massive dose of dichlorvos to adult hens.

A moderate neuropathic response was obtained in hens 2 weeks after being given a single massive s.c. dose of dichlorvos (100 mg/kg of active ingredient in a commercial 50% formulation). 1 day after dosing inhibition of neurotoxic esterase in peripheral nerve was 79-90%, in spinal cord 70-81% and in brain 89-92%. It is unlikely that repeated exposure of man to dichlorvos could cause neuropathy except at doses causing severe cholinergic effects at every exposure.

Animals↗