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PubMed1978

The ganglionic blocking properties of the cholinesterase reactivator, HS-6.

Following intravenous administration of the cholinesterase reactivator HS-6 (30 mg/kg), blood pressure fell (up to 50 mmHg) and maximal blood levels of HS-6 reached 242 microgram/ml. HS-6 attenuated the pressor response resulting from carotid occlusion and the depressor effect of vagal stimulation. Doses of HS-6 below those used to protect against soman in different animal species (10--30 mumol/kg) progressively blocked the ganglion-stimulating effects of nicotine and dimethylphenylpiperazinium but not the pressor effect following adrenaline, a pattern similar to that produced by hexamethonium but only 1/84 as potent. HS-6, like hexamethonium and mecamylamine, progressively blocked the contraction of the nictitating membrane of the cat resulting from preganglionic stimulation. The results indicate that HS-6 possesses ganglion-blocking properties at doses likely to be used in the protection against soman poisoning. The ganglion-blocking properties of the drug may be a factor in the beneficial effects of HS-6.

Animals↗
PubMed1979

Drug uptake into everted intestinal sacs. I. Enhancement by hypertonicity.

The transfer of the cationic drugs, pralidoxime (PAM) and tetraethylammonium, and anionic ampicillin from the mucosal-to-serosal sides of everted rat jejunal sacs is enhanced by mucosal hypertonicity. PAM uptake, which is proportional to initial mucosal concentrations up to 2.3 mM, is enhanced by mucosal hypertonicity due to addition of sodium, potassium, lithium and choline chloride, sodium sulfate, and the nonionic solutes, urea, sucrose, and mannitol. Bicarbonate, Tris, or phosphate buffer and the presence of magnesium and calcium do not affect this hypertonicity-induced acceleration of PAM passage. Serosal osmolality has no effect on transfer and mucosal hypertonicity is equally effective in the presence and absence of a transmural osmotic gradient. This observation and minimal changes in the concentration of inulin placed in the sacs suggest that fluid shifts and solvent drag are not responsible for the enhanced mucosal-to-serosal transfer of PAM from hypertonic buffer. Mucosal hypertonicity at 450 mosmol/kg causes reversible enhancement of PAM transfer, whereas the effect of 600 mosmol/kg cannot be reversed by replacing the tissue in isotonic buffer. The effect of osmotic manipulation on PAM transfer across the intestine thus differs from its effect on the passage of other ionized species and drugs across other epithelia.

Ampicillin↗
PubMed1979

Drug uptake into everted intestinal sacs. II. Inhibition of secretion by hypertonicity.

Mucosal hypertonicity, metabolic inhibitors, or absence of glucose and oxygen enhance mucosal-to-serosal influx of the cationic drug, pralidoxime (PAM), into sacs of everted rat jejunum in vitro. Conversely, efflux of PAM, which is twice the influx rate, is inhibited by mucosal hypertonicity or cyanide and iodoacetate. When sacs containing PAM, 0.87 mM, and glucose, 10 mM, were placed in identical drug- and sugar-containing mediums, the inside (serosal) concentration of PAM fell by over half in 120 min, whereas that of glucose more than doubled. Mucosal hypertonicity depressed PAM efflux and glucose influx regardless of serosal osmolarity. Although azide and mucosal hypertonicity each depressed glucose uptake and oxygen consumption while accelerating net PAM influx, azide more effectively depressed glucose and oxygen uptake, whereas hypertonicity caused greater acceleration of PAM uptake. Hypertonicity did not affect PAM binding to intestinal tissue. Varying mucosal pH did not change PAM or glucose uptake. Thus, mucosal hypertonicity apparently enhances net mucosal-to-serosal transfer of PAM by blocking its active secretion from serosa to mucosa.

Animals↗
PubMed1989

Effects of soman and its antidotes on tracheal mucociliary transport of ferrets.

The purpose of this study was to examine the role of acetylcholinesterase on mucociliary transport by use of a potent anticholinesterase agent, soman, and potential antagonists, atropine (muscarinic antagonist) and pralidoxime (acetylcholinesterase reactivator). Initial measurements of mucociliary transport rate were obtained in anesthetized ferrets at 30-min intervals for 5.5 h. These rates remained constant at a mean of 18.2 +/- 1.0 (SE) mm/min. We studied the effects of intravenously administered soman (1-8 micrograms/kg) and observed a dose-related change in the rate of mucociliary transport [-1.1 +/- 2.7 (SE) mm/min after 1 microgram/kg, 9.8 +/- 2.9 mm/min after 5 micrograms/kg, and 14.4 +/- 4.3 mm/min after 8 micrograms/kg of soman]. Pretreatment with atropine completely prevented the response to soman, whereas pretreatment with pralidoxime did not significantly alter the response. We postulate that soman's effect on mucociliary transport relates directly to its cholinergic activity. Failure of pralidoxime to inhibit the effects of soman may relate to pralidoxime's inability to reactivate acetylcholinesterase successfully.

Animals↗
PubMedDate not supplied

Therapeutic dosing of pralidoxime chloride.

Pralidoxime chloride is a useful agent in the treatment of organophosphate poisoning. Poisindex, a widely used poisoning treatment resource, recommends dosing pralidoxime chloride as an intermittent iv infusion every 8-12 hours, whereas other authors have used continuous iv infusion with good results. Available animal data suggest that a serum concentration of 4 micrograms/ml may be a minimal level to protect against the toxic effects of organophosphates. Pharmacokinetic simulations, based on parameters obtained from healthy nonpoisoned subjects, show that pralidoxime levels fall rapidly to less than 4 micrograms/ml within 1.5-2 hours after a 1-g iv bolus. Continuous iv infusion (0.5 g/h) maintains pralidoxime levels greater than 4 micrograms/ml throughout the length of infusion. We conclude that continuous iv infusion of pralidoxime chloride may be the preferred method of administration in patients with acute organophosphate poisoning. Clinical trials will be necessary to document the effectiveness of this regimen.

Animals↗
PubMed2005

The comparison of the efficacy of scoring systems in organophosphate poisoning.

The purpose of this study was to evaluate the impact of the Glasgow Coma Scale (GCS), Acute Physiology and Chronic Health Evaluation (APACHE) II and Simplified Acute Physiology Score (SAPS) II scoring systems for organophosphate poisoning (OPP) in an intensive care unit (ICU). The following data were collected on all consecutive patients who were admitted to the ICU between June 1999 and December 2004. Demographic data, GCS, APACHE II and SAPS II scoring systems were recorded. Predicted mortality was calculated using original regression formulas. Standardized mortality ratio (SMR) was computed with 95% confidence intervals (CI). The sensitivity and specificity for each scoring system were evaluated by calculating the Area Under the Receiver Operating Characteristic Curves. The actual mortality in OPP was 21.9%. Predicted mortality by all systems was not significantly different from actual mortality [SMR and 95% CI for GCS: 1.00 (0.65 1.35), APACHE II: 0.87 (0.54-1.03), SAPS II: 1.40 (0.98-1.82)]. The area under the ROC curve for APACHE II is largest, but there is no statistically significant difference when compared with SAPS II and GCS (GCS 0.900 +/- 0.059, APACHE II 0.929 +/- 0.045 and SAPS II 0.891 +/- 0.057). In our ICU group of patients, in predicting the mortality rates in OPP, the three scoring systems, which are GCS, APACHE II and SAPS II, had similar impacts; however, GCS system has superiority over the other systems in being easy to perform, and not requiring complex physiologic parameters and laboratory methods.

APACHE↗
PubMed2000

Aldicarb poisoning.

Aldicarb (2-methyl-2(methylthio) propanal o-[(methylamino)-carbonyl] oxime) is a pesticide manufactured since 1965. This carbamate ester is sold under the tradename, Temik, and is used as insecticide and nematicide. The Environmental Protection Agency has classified aldicarb in the highest toxicity category and has defined a strict control for its delivery and use. In Brazil and the Caribbean island, aldicarb is illegally used as a household rodenticide with a widespread risk of poisoning. Our study presents the first review of aldicarb poisoning circumstances associated with clinical and analytical findings. Moreover, the oxime treatment is discussed. Eighteen patients with cholinergic symptoms admitted to the Emergency Unit and two deceased with a history of aldicarb poisoning were included in the study. As agricultural workers, only two of them could legally use Temik. Seventy percent of the patients was managed by the Emergency Mobil Unit. Serum cholinesterase activity was always lower than 30% of the normal range and aldicarb was identified by UV spectra and retention time after liquid chromatography separation. The most common muscarinic effect was diarrhea, the main nicotinic sign fasciculation and almost half of the poisoned patients had central nervous system (CNS) depression (Glasgow Coma Score lower than 8). Four patients had serious conduction abnormalities and two of them died. These results suggest that aldicarb intoxication is always severe. Oxime treatment did not produce side effects and should be recommended whenever the pesticide involved is unknown. Effective measures should be implemented to stamp out the illicit use of aldicarb.

Adolescent↗
PubMed2001

Repeated measurements of aldicarb in blood and urine in a case of nonfatal poisoning.

A nonfatal case of poisoning involving aldicarb, an extremely toxic carbamate pesticide, is presented. A 39-year-old female ingested an unknown amount of aldicarb, together with alprazolam and sertraline. On admission to ICU (T0), she displayed marked cholinergic symptoms and a deep coma. The patient was given pralidoxime and atropine. Her condition gradually improved on days 2 and 3 and she was discharged at T0+80 h. Aldicarb was assayed by high-performance liquid chromatography on 21 blood and 8 urine samples successively taken during hospitalization. At the same time, serum pseudocholinesterase activity was followed on 21 successive samples. Blood aldicarb level was 3.11 microg/mL at T0 and peaked at T0+3.5 h (3.22 microg/mL), then followed a two-slope decay with a terminal half-life of ca. 20 h. Aldicarb was detected in all urine samples (peak level: 6.95 microg/mL at T0+31.5 h) and was still present at the time of discharge. Serum pseudo-cholinesterase activity remained low (< or = 10% of normal) until the 30th hour then rapidly increased and returned to normal after the 60th hour. The patient's clinical picture closely followed blood aldicarb levels and serum pseudo-cholinesterase activities. To our knowledge, this is the first report of an aldicarb poisoning documented by repeated measurements of the drug in the intoxicated person.

Adult↗
PubMed2004

The effect of plasmapheresis on plasma cholinesterase levels in a patient with organophosphate poisoning.

OBJECTIVE: To describe the role of plasmapheresis in management of organophosphate poisonings. DESIGN: Case report. SETTING: A medical intensive care unit of a medical faculty. PATIENT: A patient with organophosphate poisoning whose cholinesterase levels continuously decline and then increase up to a normal level after plasmapheresis is performed for his sepsis. INTERVENTIONS: Plasmapheresis with fresh frozen plasma. MEASUREMENTS AND MAIN RESULTS: Baseline plasma cholinesterase (ChE) level was 4001 IU/L (normal values: 4000-10000 IU/L). Aspiration pneumonia was developed on day 3, and sepsis occurred on day 5. During this period, ChE levels gradually decreased. On day 5, plasmapheresis was performed for sepsis. Interestingly, plasma ChE levels increased from 2101 IU/L to 6144 IU/L after plasmapheresis. Atropine and pralidoxime were stopped, and a high level of ChE continued during hospitalization. The patient was successfully weaned from mechanical ventilation 3 days after plasmapheresis. CONCLUSION: Plasma exchange therapy may be considered for patients with organophosphate poisoning unresponsive to atropine and pralidoxime.

Antidotes↗
PubMed2004

Benefits of magnesium sulfate in the management of acute human poisoning by organophosphorus insecticides.

Organophosphorus chemicals (OPs) are the pesticides most often involved in serious human poisoning. Treatment of intoxication with OPs conventionally involves atropine for reduction of muscarinic signs and oximes that increase the rate of hydrolysis of the phosphorylated enzyme acetylcholinesterase (AChE). Although atropine and oximes (pralidoxime or obidoxime) are traditionally used in the management of such poisoning, their efficacy remains a major issue of debate; thus, the goal of this prospective clinical trial was to elaborate the value of magnesium sulfate (MgSO4) in the management and outcome of OP insecticide poisoning. This unicenter, randomized, single-blind trial study was conducted on patients who were acutely poisoned with OPs and admitted to the Poisoning Center of Loghman-Hakim Hospital in Tehran, Iran. In a systematic sampling, every fourth eligible patient was chosen to undergo MgSO4 treatment. Magnesium sulfate was administered at dose of 4 g/day i.v. continued for only the first 24 hours after admission. The mean daily oxime requirement and the mean daily atropine requirement were not statistically significant between two treated groups. The mortality rate and hospitalization days of patients who received MgSO4 treatment were significantly lower than those who had not received MgSO4 (P < 0.01). It is concluded that administration of MgSO4, in a dose of 4 g/day concurrent to conventional therapy, in OP acute human poisoning is beneficial by reducing the hospitalization days and rate of mortality.

Adolescent↗
PubMed1984

Chemical reactivations of inactivated acetylcholinesterase after 2-PAM therapy in fenitrothion-poisoned rat and rabbit.

We investigated the reactivation of inactivated acetylcholinesterase (AChE) after 2-PAM therapy in acute fenitrothion poisonings of two species of rat and rabbit. By single treatment with 2-PAM carried out immediately after fenitrothion administration, the significant reactivations of inactivated AChE in red blood cell (RBC) and brain as well as inactivated cholinesterase (ChE) in plasma were observed at 2 h after administration of 20 mg/kg fenitrothion in rat, while these reactivations became less in rats severely poisoned with 500 mg/kg fenitrothion. Although these significant reactivations disappeared 6 h after the single treatment with 2-PAM, the repeated treatments with 2-PAM induced the prolongation of the reactivations of inactivated AChEs and ChE. These results suggest that 2-PAM would be more effective to light poisoning with fenitrothion, and that the repetition of 2-PAM treatment would be very important to obtain the sufficient antidotal actions. In rabbits as well as rats, the considerable reactivations of inactivated AChEs in RBC and brain and inactivated ChE in plasma were observed by the single treatment with 2-PAM in fenitrothion poisoning. These reactivations in brain AChE indicate that 2-PAM can penetrate the blood brain barrier of both rat and rabbit, despite its quaternary character.

Acetylcholinesterase↗
PubMed1985

Effects of oximes, diacetylmonoxime, pyridine-2-aldoxime, and pyridine-2-aldoxime methochloride, on the electrical and mechanical activities of guinea pig cardiac ventricular muscles.

Effects of 3 oximes, diacetylmonoxime (DAM), pyridine-2-aldoxime (PAM) and pyridine-2-aldoxime methochloride (2-PAM), on the normal electrical and mechanical activities and on the slow response action potentials were examined in the guinea pig ventricular muscles. DAM and long-term exposure to high concentrations of PAM produced decreases in contractile force, action potential duration and slow response action potentials, whereas 2-PAM and low concentrations of PAM tended to increase these parameters. Thus, these 3 oximes did not act uniformly on cardiac muscle. It was speculated that DAM and high concentrations of PAM may act as slow channel inhibitors, whereas 2-PAM and low concentrations of PAM may act as slow channel activators.

Action Potentials↗