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Marcello Lotti

Publications and source records attributed to Marcello Lotti.

9 recordsLinked to original sources
PubMed2006

Do carbamates cause polyneuropathy?

Carbamates are reversible inhibitors of acetylcholinesterase, and some also inhibit neuropathy target esterase (NTE), the target in organophosphate-induced delayed polyneuropathy. However, based on mechanistic considerations, these carbamates were thought to be unable to initiate polyneuropathy. Consequently, clinical reports of polyneuropathy associated with carbamate exposures have been disregarded. We discuss three cases of polyneuropathy that occurred after severe poisoning by methylcarbamates. In addition, high repeated doses of phenyl N-methyl N-benzylcarbamate caused nearly 100% NTE inhibition and polyneuropathy in the hen model. These data suggest the need to reconsider the long-standing tenet that carbamates cannot cause polyneuropathy. Alternatively, a preexisting subclinical neuropathy in these individuals may have been amplified by carbamates, as observed in animal models. We suggest that individuals with underlying neuropathy (e.g., diabetics) who are poisoned by carbamates should be followed closely. In addition, procedures for the current risk assessment of carbamate pesticides may need to be reconsidered.

Adult↗
PubMed2005

Peripheral nerve esterases and the promotion of organophosphate-induced neuropathy in hens.

Several esterase inhibitors, not capable of causing peripheral neuropathy by themselves, exacerbate organophosphate-induced delayed polyneuropathy (OPIDP) and other axonopathies. This effect was called promotion of axonopathies and it was found not to be associated with inhibition of neuropathy target esterase (NTE), the molecular target of OPIDP. The search for an esterase as the target of promotion has started long ago, when an eterogeneous group of esterases-hydrolysing phenyl valerate (PV) was identified in hen's sciatic nerve by means of selective inhibitors. Correlation studies in vivo indicated that the target of promotion may have been among the proteins present in the soluble fraction. When this soluble PV-esterase activity was separated on a Sephacryl-S-300 column, correlation was found between promotion and its inhibition in vivo. The electrophoretic analysis of this fraction indicated the presence of several proteins. Subsequent ion-exchange chromatography identified a protein of about 80 kDa molecular weight that was associated with PV-esterase activity. The inhibition of this activity did also correlate with promotion. The sequence of this protein identified it as ovotransferrin, but commercial preparations of ovotransferrin were found to lack PV-esterase activity. Binding experiments on this purified PV-activity and on commercial ovotransferrin using radiolabelled promoters were inconclusive. Titration of this PV-activity showed that about 20-30% of it is resistant to high concentrations of several inhibitors, suggesting heterogeneity of the fraction. In fact, bi-dimensional electrophoresis indicated the presence of several proteins. Finally, in vivo correlation experiments with p-toluensulfonyl fluoride showed that whereas this chemical does not promote OPIDP induced by dibutyl dichlorovinyl phosphate, it does inhibit about 80% of this PV-activity. In conclusion, available data indicate that the target of promotion is unlikely to be ovotransferrin. However, all promoters identified so far are esterase inhibitors suggesting that the target of promotion might be, indeed, a protein with esteratic activity.

Animals↗
PubMed2005

Organophosphate-induced delayed polyneuropathy.

Organophosphate-induced delayed polyneuropathy (OPIDP) is a rare toxicity resulting from exposure to certain organophosphorus (OP) esters. It is characterised by distal degeneration of some axons of both the peripheral and central nervous systems occurring 1-4 weeks after single or short-term exposures. Cramping muscle pain in the lower limbs, distal numbness and paraesthesiae occur, followed by progressive weakness, depression of deep tendon reflexes in the lower limbs and, in severe cases, in the upper limbs. Signs include high-stepping gait associated with bilateral foot drop and, in severe cases, quadriplegia with foot and wrist drop as well as pyramidal signs. In time, there might be significant recovery of the peripheral nerve function but, depending on the degree of pyramidal involvement, spastic ataxia may be a permanent outcome of severe OPIDP. Human and experimental data indicate that recovery is usually complete in the young. At onset, the electrophysiological changes include reduced amplitude of the compound muscle potential, increased distal latencies and normal or slightly reduced nerve conduction velocities. The progression of the disease, usually over a few days, may lead to non-excitability of the nerve with electromyographical signs of denervation. Nerve biopsies have been performed in a few cases and showed axonal degeneration with secondary demyelination. Neuropathy target esterase (NTE) is thought to be the target of OPIDP initiation. The ratio of inhibitory powers for acetylcholinesterase and NTE represents the crucial guideline for the aetiological attribution of OP-induced peripheral neuropathy. In fact, pre-marketing toxicity testing in animals selects OP insecticides with cholinergic toxicity potential much higher than that to result in OPIDP. Therefore, OPIDP may develop only after very large exposures to insecticides, causing severe cholinergic toxicity. However, this was not the case with certain triaryl phosphates that were not used as insecticides but as hydraulic fluids, lubricants and plasticisers and do not result in cholinergic toxicity. Several thousand cases of OPIDP as a result of exposure to tri-ortho-cresyl phosphate have been reported, whereas the number of cases of OPIDP as a result of OP insecticide poisoning is much lower. In this article, we mainly discuss OP pesticide poisoning, particularly when caused by chlorpyrifos, dichlorvos, isofenphos, methamidophos, mipafox, trichlorfon, trichlornat, phosphamidon/mevinphos and by certain carbamates. We also discuss case reports where neuropathies were not convincingly attributed to fenthion, malathion, omethoate/dimethoate, parathion and merphos. Finally, several observational studies on long-term, low-level exposures to OPs that sometimes reported mild, inconsistent and unexplained changes of unclear significance in peripheral nerves are briefly discussed.

Animals↗
PubMed2003

Pharmacokinetics and blood levels of polychlorinated biphenyls.

Despite the enormous number of reports on polychlorinated biphenyl (PCB) toxicology, both the causal interpretation of epidemiological studies and the risk assessment of human exposures have been hampered by the lack of information on the pharmacokinetics of various PCB isomers and congeners. Thus, the assessment of exposure by means of measuring either total PCBs or individual congeners in the blood has so far been unsatisfactory. For example, the concentration and the pattern of congeners in the blood did not correlate with that at site(s) of action. In fact, the same levels of blood PCBs correlated with either toxic effects or no effects (both in clinical and epidemiological studies). In addition, when toxicity caused by PCBs was observed, the severity of the signs did not correlate with blood levels. Reasons for such a qualified failure are manifold and include different ways of reporting blood measurements, the different toxicological characteristics of each PCB, and different timing of sampling the blood, etc. Therefore, only limited conclusions can be drawn concerning what blood PCB measurements mean.

Environmental Exposure↗
PubMed2002

Promotion of organophosphate induced delayed polyneuropathy by certain esterase inhibitors.

Organophosphate induced delayed polyneuropathy (OPIDP) is an axonopathy caused by single doses of some organophosphates (OPs). Other OPs, sulphonyl halides, carbamates, thiocarbamates and phosphinates do not cause axonopathy but elicit or intensify the clinical expression of OPIDP when given after a neuropathic OP (promotion of OPIDP). One enzymatic activity (M200) was identified by means of selective inhibitors in hen peripheral nerve crude homogenates. Promotion of OPIDP initiated with several OPs was found to correlate with inhibition of M200 when various promoters were given to hens. Most M200 is in the soluble fraction of peripheral nerves and was separated from other esterases by means of molecular exclusion chromatography. In a second series of experiments, inhibition of this fraction also correlated with promotion when induced by the same chemicals. Further ion exchange chromatography identified a protein (60 kDa MW): the inhibition of its enzymatic activity correlated with promotion in another series of in vivo experiments. Biochemical and structural analyses of this protein are underway. Several experiments indirectly suggest that promotion may be related to mechanisms of repair and/or compensation of peripheral nerves. These include the observation that promotion results in clinical expression of biochemical lesions that otherwise would be well compensated, that promotion is not specific because axonopathies of other etiology are also exaggerated, and that promoters are effective when given several days before the neuropathic insult. Moreover, developing animals are more resistant to promotion.

Animals↗
PubMed2002

The relationship between isofenphos cholinergic toxicity and the development of polyneuropathy in hens and humans.

Species differences have been observed between hen and human clinical manifestations of isofenphos toxicities. Hens treated with the insecticide isofenphos (90 mg/kg p.o.) developed severe cholinergic toxicity followed by mild organophosphate-induced delayed polyneuropathy (OPIDP). However, a patient developed severe OPIDP, which was preceded by very mild cholinergic signs, after an attempted suicide with a commercial formulation containing isofenphos and phoxim, an insecticide not causing OPIDP (estimated doses were 500 and 125 mg/kg, respectively). To explain this difference the following hypotheses were tested: (1) phoxim is a promoter of isofenphos-induced OPIDP; (2) whereas neuropathy target esterase (NTE) is thought to be the target of OPIDP, activation of isofenphos by liver microsomes causes the formation of more potent NTE inhibitor(s) in humans than in hens; (3) in contrast to hen NTE, the sensitivity of the human enzyme to such inhibitor(s) is higher than that of acetylcholinesterase (AChE), the target of cholinergic toxicity. Results showed that phoxim (22.5 mg/kg p.o.) was not a promoter of OPIDP in hens and that the ratio AChE inhibition:NTE inhibition by microsome-activated isofenphos was similar for both hen and human enzymes. The schedule of antidotal treatment in hens is the likely explanation for the observed difference from the patient. Peak AChE inhibition was maintained in hen brain up to 6 days after a single dose of isofenphos, suggesting prolonged pharmacokinetics. However, the AChE reactivator pyridine-2-aldoxime (2-PAM) was given to hens before isofenphos and then every 8 h, whereas continuous 2-PAM infusion was provided to the patient. When 2-PAM was given to hens every hour after isofenphos (90 mg/kg p.o.), the birds remained asymptomatic. Since other organophosphates may have a prolonged pharmacokinetics, testing procedures for the potential of these insecticides to cause OPIDP may underestimate the risk for humans.

Animals↗
PubMed2002

Age-related sensitivity of the nervous system to neurotoxic insults.

Complex genomic activity and environmental factors regulate neuronal plasticity, which operates during pre- and postnatal development, can be reactivated after injury, and is impaired during aging. In these contexts, the effects of chemicals are often unpredictable because the developing and aging nervous system may or may not be equally susceptible as that of the adult. Thus, the developing central nervous system may be more susceptible to the acute toxicity of certain organophosphorus esters, whereas the developing peripheral nervous system is resistant to organophosphate-induced delayed polyneuropathy. Reasons for age-related susceptibility are manifold, including both differences in toxicokinetics and toxicodynamics and in intrinsic susceptibility of the nervous system, which is related to given physiological conditions. Therefore, the identification of genetic and environmental factors regulating neuronal plasticity becomes critical to the understanding of age-related sensitivity to chemicals. The example of age-related sensitivity to organophosphate-induced delayed polyneuropathy is illustrated together with that of the promotion of axonopathies by certain esterase inhibitors, which also seem modulated according to age. The identification of the molecular targets of both organophosphate neuropathy and promotion of neuropathy might allow the understanding of processes involved in the expression of peripheral neurotoxicities according to age.

Age Factors↗
PubMed2002

Low-level exposures to organophosphorus esters and peripheral nerve function.

This review evaluates the epidemiological and clinical evidence linking low-level and prolonged exposures to organophosphorus esters, used as insecticides or nerve agents, to peripheral nerve dysfunction. The clinical effects of large doses of these chemicals-including the cholinergic syndrome, the intermediate syndrome, and the delayed polyneuropathy-are all well established and are summarized. Based on these clinical observations and experimental studies, dose-effect relationships indicate that peripheral neuropathy always develops after cholinergic toxicity. However, several studies have suggested that this relationship may be different after low-level prolonged exposures, as, for instance, those experienced by Gulf War veterans and British sheep farmers, thereby leading to the development of peripheral neuropathy without preceding cholinergic toxicity. A critical assessment of these studies, involving subjects with either current or past exposures, indicates that changes in peripheral nerve function were mild, inconsistent, and unexplained and that most studies lack exposure data. Suggestions made about individual hypersusceptibility to delayed polyneuropathy lack support. It is concluded that there is no evidence of peripheral nerve dysfunction caused by low-level prolonged exposures to organophosphate insecticides or nerve agents.

Animals↗